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1
Li, Zhen, Shu Feng, Vanessa Lopez, Gina Elhammady, Matthew L. Anderson, Elena M. Kaftanovskaya und Alexander I. Agoulnik. „Uterine Cysts in Female Mice Deficient for Caveolin-1 and Insulin-Like 3 Receptor RXFP2“. Endocrinology 152, Nr. 6 (05.04.2011): 2474–82. http://dx.doi.org/10.1210/en.2010-1015.
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Gene mutations of insulin-like 3 (INSL3) peptide or its G protein-coupled receptor RXFP2 (relaxin family peptide receptor 2) lead to cryptorchidism. The role of INSL3 in adult females is less known, although INSL3 expression has been described in female reproductive organs. Caveolin-1 (CAV1), the main component of caveoli cell membrane invaginations, has been shown to play an important role in epithelial organization and stromal-epithelial interactions. We created a null allele of Cav1 mice by deleting its second exon through embryonic stem cell targeting. Immunohistochemical analysis demonstrated that CAV1 expression was primarily localized to endothelial blood vessel cells and the myometrium uterus, whereas the strongest expression of Rxfp2 was detected in the endometrial epithelium. By 12 months of age approximately 18% of Cav1−/− females developed single or multiple dilated endometrial cysts lined by a flattened, simple low epithelium. A deficiency for Rxfp2 on Cav1-deficient background led to more than a 2-fold increase in the incidence of uterine cysts (54–58%). Appearance of cysts led to a severe disorganization of uterine morphology. We have found that the cysts had an increased expression of β-catenin and estrogen receptor β in endometrial stromal and epithelial cells and increased epithelial proliferation. An analysis of simple dilated cysts in human patients for CAV1 expression did not show appreciable differences with control regardless of menstrual phase, suggesting an involvement of additional factors in human disease. The results of this study suggest a novel synergistic role of INSL3/RXFP2 and CAV1 in structural maintenance of the uterus.
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Hayer, Arnold, Miriam Stoeber, Danilo Ritz, Sabrina Engel, Hemmo H. Meyer und Ari Helenius. „Caveolin-1 is ubiquitinated and targeted to intralumenal vesicles in endolysosomes for degradation“. Journal of Cell Biology 191, Nr. 3 (01.11.2010): 615–29. http://dx.doi.org/10.1083/jcb.201003086.
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Caveolae are long-lived plasma membrane microdomains composed of caveolins, cavins, and a cholesterol-rich membrane. Little is known about how caveolae disassemble and how their coat components are degraded. We studied the degradation of caveolin-1 (CAV1), a major caveolar protein, in CV1 cells. CAV1 was degraded very slowly, but turnover could be accelerated by compromising caveolae assembly. Now, CAV1 became detectable in late endosomes (LE) and lysosomes where it was degraded. Targeting to the degradative pathway required ubiquitination and the endosomal sorting complex required for transport (ESCRT) machinery for inclusion into intralumenal vesicles in endosomes. A dual-tag strategy allowed us to monitor exposure of CAV1 to the acidic lumen of individual, maturing LE in living cells. Importantly, we found that “caveosomes,” previously described by our group as independent organelles distinct from endosomes, actually correspond to late endosomal compartments modified by the accumulation of overexpressed CAV1 awaiting degradation. The findings led us to a revised model for endocytic trafficking of CAV1.
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Joshi, Bharat, Michele Bastiani, Scott S. Strugnell, Cecile Boscher, Robert G. Parton und Ivan R. Nabi. „Phosphocaveolin-1 is a mechanotransducer that induces caveola biogenesis via Egr1 transcriptional regulation“. Journal of Cell Biology 199, Nr. 3 (22.10.2012): 425–35. http://dx.doi.org/10.1083/jcb.201207089.
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Caveolin-1 (Cav1) is an essential component of caveolae whose Src kinase-dependent phosphorylation on tyrosine 14 (Y14) is associated with regulation of focal adhesion dynamics. However, the relationship between these disparate functions remains to be elucidated. Caveola biogenesis requires expression of both Cav1 and cavin-1, but Cav1Y14 phosphorylation is dispensable. In this paper, we show that Cav1 tyrosine phosphorylation induces caveola biogenesis via actin-dependent mechanotransduction and inactivation of the Egr1 (early growth response-1) transcription factor, relieving inhibition of endogenous Cav1 and cavin-1 genes. Cav1 phosphorylation reduces Egr1 binding to Cav1 and cavin-1 promoters and stimulates their activity. In MDA-231 breast carcinoma cells that express elevated levels of Cav1 and caveolae, Egr1 regulated Cav1, and cavin-1 promoter activity was dependent on actin, Cav1, Src, and Rho-associated kinase as well as downstream protein kinase C (PKC) signaling. pCav1 is therefore a mechanotransducer that acts via PKC to relieve Egr1 transcriptional inhibition of Cav1 and cavin-1, defining a novel feedback regulatory loop to regulate caveola biogenesis.
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Jung, WooRam, Emma Sierecki, Michele Bastiani, Ailis O’Carroll, Kirill Alexandrov, James Rae, Wayne Johnston et al. „Cell-free formation and interactome analysis of caveolae“. Journal of Cell Biology 217, Nr. 6 (01.05.2018): 2141–65. http://dx.doi.org/10.1083/jcb.201707004.
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Caveolae have been linked to the regulation of signaling pathways in eukaryotic cells through direct interactions with caveolins. Here, we describe a cell-free system based on Leishmania tarentolae (Lt) extracts for the biogenesis of caveolae and show its use for single-molecule interaction studies. Insertion of expressed caveolin-1 (CAV1) into Lt membranes was analogous to that of caveolin in native membranes. Electron tomography showed that caveolins generate domains of precise size and curvature. Cell-free caveolae were used in quantitative assays to test the interaction of membrane-inserted caveolin with signaling proteins and to determine the stoichiometry of interactions. Binding of membrane-inserted CAV1 to several proposed binding partners, including endothelial nitric-oxide synthase, was negligible, but a small number of proteins, including TRAF2, interacted with CAV1 in a phosphorylation-(CAV1Y14)–stimulated manner. In cells subjected to oxidative stress, phosphorylated CAV1 recruited TRAF2 to the early endosome forming a novel signaling platform. These findings lead to a novel model for cellular stress signaling by CAV1.
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Aravamudan, Bharathi, Sarah K. VanOosten, Lucas W. Meuchel, Pawan Vohra, Michael Thompson, Gary C. Sieck, Y. S. Prakash und Christina M. Pabelick. „Caveolin-1 knockout mice exhibit airway hyperreactivity“. American Journal of Physiology-Lung Cellular and Molecular Physiology 303, Nr. 8 (15.10.2012): L669—L681. http://dx.doi.org/10.1152/ajplung.00018.2012.
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Caveolae are flask-shaped plasma membrane invaginations expressing the scaffolding caveolin proteins. Although caveolins have been found in endothelium and epithelium (where they regulate nitric oxide synthase activity), their role in smooth muscle is still under investigation. We and others have previously shown that caveolae of human airway smooth muscle (ASM), which express caveolin-1, contain Ca2+ and force regulatory proteins and are involved in mediating the effects of inflammatory cytokines such as TNF-α on intracellular Ca2+ concentration responses to agonist. Accordingly, we tested the hypothesis that in vivo, absence of caveolin-1 leads to reduced airway hyperresponsiveness, using a knockout (KO) (Cav1 KO) mouse and an ovalbumin-sensitized/challenged (OVA) model of allergic airway hyperresponsiveness. Surprisingly, airway responsiveness to methacholine, tested by use of a FlexiVent system, was increased in Cav1 KO control (CTL) as well as KO OVA mice, which could not be explained by a blunted immune response to OVA. In ASM of wild-type (WT) OVA mice, expression of caveolin-1, the caveolar adapter proteins cavins 1–3, and caveolae-associated Ca2+ and force regulatory proteins such as Orai1 and RhoA were all increased, effects absent in Cav1 KO CTL and OVA mice. However, as with WT OVA, both CTL and OVA Cav1 KO airways showed signs of enhanced remodeling, with high expression of proliferation markers and increased collagen. Separately, epithelial cells from airways of all three groups displayed lower endothelial but higher inducible nitric oxide synthase and arginase expression. Arginase activity was also increased in these three groups, and the inhibitor nor-NOHA ( N-omega-nor-l-arginine) enhanced sensitivity of isolated tracheal rings to ACh, especially in Cav1 KO mice. On the basis of these data disproving our original hypothesis, we conclude that caveolin-1 has complex effects on ASM vs. epithelium, resulting in airway hyperreactivity in vivo mediated by altered airway remodeling and bronchodilation.
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Tagawa, Akiko, Anna Mezzacasa, Arnold Hayer, Andrea Longatti, Lucas Pelkmans und Ari Helenius. „Assembly and trafficking of caveolar domains in the cell“. Journal of Cell Biology 170, Nr. 5 (29.08.2005): 769–79. http://dx.doi.org/10.1083/jcb.200506103.
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Using total internal reflection fluorescence microscopy (TIR-FM), fluorescence recovery after photobleaching (FRAP), and other light microscopy techniques, we analyzed the dynamics, the activation, and the assembly of caveolae labeled with fluorescently tagged caveolin-1 (Cav1). We found that when activated by simian virus 40 (SV40), a nonenveloped DNA virus that uses caveolae for cell entry, the fraction of mobile caveolae was dramatically enhanced both in the plasma membrane (PM) and in the caveosome, an intracellular organelle that functions as an intermediate station in caveolar endocytosis. Activation also resulted in increased microtubule (MT)-dependent, long-range movement of caveolar vesicles. We generated heterokaryons that contained GFP- and RFP-tagged caveolae by fusing cells expressing Cav1-GFP and -RFP, respectively, and showed that even when activated, individual caveolar domains underwent little exchange of Cav1. Only when the cells were subjected to transient cholesterol depletion, did the caveolae domain exchange Cav1. Thus, in contrast to clathrin-, or other types of coated transport vesicles, caveolae constitute stable, cholesterol-dependent membrane domains that can serve as fixed containers through vesicle traffic. Finally, we identified the Golgi complex as the site where newly assembled caveolar domains appeared first.
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Gerstenberger, Wladimir, Michaela Wrage, Eeva Kettunen, Klaus Pantel, Sisko Anttila, Stefan Steurer und Harriet Wikman. „Stromal Caveolin-1 and Caveolin-2 Expression in Primary Tumors and Lymph Node Metastases“. Analytical Cellular Pathology 2018 (2018): 1–8. http://dx.doi.org/10.1155/2018/8651790.
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The expression of caveolin-1 (CAV1) in both tumor cell and cancer-associated fibroblasts (CAFs) has been found to correlate with tumor aggressiveness in different epithelial tumor entities, whereas less is known for caveolin-2 (CAV2). The aim of this study was to investigate the clinicopathological significance and prognostic value of stromal CAV1 and CAV2 expression in lung cancer. The expression of these two genes was investigated at protein level on a tissue microarray (TMA) consisting of 161 primary tumor samples. 50.7% of squamous cell lung cancer (SCC) tumors showed strong expression of CAV1 in the tumor-associated stromal cells, whereas only 15.1% of adenocarcinomas (AC) showed a strong CAV1 expression (p<0.01). A strong CAV2 stromal expression was found in 46.0% of the lung tumor specimens, with no significant difference between the subtypes. Neither CAV1 nor CAV2 stromal expression was associated with any other clinicopathological factor including survival. When the stromal expression in matched primary tumors and lymph node metastases was compared, both CAV1 and CAV2 expressions were frequently found lost in the corresponding stroma of the lymph node metastasis (40.6%, p=0.003 and 38.4%, p=0.001, resp.). Loss of stromal CAV2 in the lymph node metastases was also significantly associated with earlier death (p=0.011). In conclusion, in contrast to the expression patterns in the tumor tissue of lung cancer, stromal expression of CAV1 in primary tumors was not associated with clinical outcome whereas the stromal expression of especially CAV2 in the metastatic lymph nodes could be associated with lung cancer pathogenesis.
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Copeland, Courtney A., Bing Han, Ajit Tiwari, Eric D. Austin, James E. Loyd, James D. West und Anne K. Kenworthy. „A disease-associated frameshift mutation in caveolin-1 disrupts caveolae formation and function through introduction of a de novo ER retention signal“. Molecular Biology of the Cell 28, Nr. 22 (November 2017): 3095–111. http://dx.doi.org/10.1091/mbc.e17-06-0421.
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Caveolin-1 (CAV1) is an essential component of caveolae and is implicated in numerous physiological processes. Recent studies have identified heterozygous mutations in the CAV1 gene in patients with pulmonary arterial hypertension (PAH), but the mechanisms by which these mutations impact caveolae assembly and contribute to disease remain unclear. To address this question, we examined the consequences of a familial PAH-associated frameshift mutation in CAV1, P158PfsX22, on caveolae assembly and function. We show that C-terminus of the CAV1 P158 protein contains a functional ER-retention signal that inhibits ER exit and caveolae formation and accelerates CAV1 turnover in Cav1–/– MEFs. Moreover, when coexpressed with wild-type (WT) CAV1 in Cav1–/– MEFs, CAV1-P158 functions as a dominant negative by partially disrupting WT CAV1 trafficking. In patient skin fibroblasts, CAV1 and caveolar accessory protein levels are reduced, fewer caveolae are observed, and CAV1 complexes exhibit biochemical abnormalities. Patient fibroblasts also exhibit decreased resistance to a hypo-osmotic challenge, suggesting the function of caveolae as membrane reservoir is compromised. We conclude that the P158PfsX22 frameshift introduces a gain of function that gives rise to a dominant negative form of CAV1, defining a new mechanism by which disease-associated mutations in CAV1 impair caveolae assembly.
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Păunescu, Teodor G., Hua A. J. Lu, Leileata M. Russo, Núria M. Pastor-Soler, Mary McKee, Margaret M. McLaughlin, Bianca E. Bartlett, Sylvie Breton und Dennis Brown. „Vasopressin induces apical expression of caveolin in rat kidney collecting duct principal cells“. American Journal of Physiology-Renal Physiology 305, Nr. 12 (15.12.2013): F1783—F1795. http://dx.doi.org/10.1152/ajprenal.00622.2012.
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Caveolin (Cav)1 is expressed in the basolateral membrane domain of renal collecting duct (CD) principal cells (PCs), where it is associated with caveolae. To reveal any potential involvement of Cav1 in vasopressin signaling, we used specific monoclonal and polyclonal antibodies to examine its localization in CD PCs of Brattleboro (BB) rats treated with vasopressin (DDAVP). Compared with controls, immunofluorescence revealed a time-dependent increase in Cav1 expression in the apical membrane domain of PCs, where it overlapped with aquaporin-2 (AQP2). After 24 h of DDAVP treatment, Cav1 was visible as an increased number of small apical spots. The staining gradually became more extensive, and, after 2 wk of DDAVP, it occupied the majority of the apical membrane domain of many PCs. Cav1 also assumed an apical localization in PCs of DDAVP-treated Sprague-Dawley and Long-Evans rats. Similarly, Cav2 appeared at the apical pole of PCs after DDAVP treatment of BB, Sprague-Dawley, and Long-Evans rats. Immunogold electron microscopy confirmed bipolar Cav1 membrane expression in DDAVP-treated BB rats, whereas caveolae were only detected on the basolateral membrane. Immunoblot analysis of BB rat whole kidney homogenates revealed no significant increase in Cav1 levels in DDAVP-treated rats, suggesting that DDAVP induces Cav1 relocalization or modifies its targeting. We conclude that Cav1 and Cav2 trafficking and membrane localization are dramatically altered by the action of DDAVP. Importantly, the absence of apical caveolae indicates that while Cavs may have an as yet undetermined role in vasopressin-regulated signaling processes, this is probably unrelated to AQP2 internalization by caveolae.
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Zimnicka, Adriana M., Yawer S. Husain, Ayesha N. Shajahan, Maria Sverdlov, Oleg Chaga, Zhenlong Chen, Peter T. Toth et al. „Src-dependent phosphorylation of caveolin-1 Tyr-14 promotes swelling and release of caveolae“. Molecular Biology of the Cell 27, Nr. 13 (Juli 2016): 2090–106. http://dx.doi.org/10.1091/mbc.e15-11-0756.
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Caveolin 1 (Cav1) is a required structural component of caveolae, and its phosphorylation by Src is associated with an increase in caveolae-mediated endocytosis. Here we demonstrate, using quantitative live-cell 4D, TIRF, and FRET imaging, that endocytosis and trafficking of caveolae are associated with a Cav1 Tyr-14 phosphorylation-dependent conformational change, which spatially separates, or loosens, Cav1 molecules within the oligomeric caveolar coat. When tracked by TIRF and spinning-disk microscopy, cells expressing phosphomimicking Cav1 (Y14D) mutant formed vesicles that were greater in number and volume than with Y14F-Cav1-GFP. Furthermore, we observed in HEK cells cotransfected with wild-type, Y14D, or Y14F Cav1-CFP and -YFP constructs that FRET efficiency was greater with Y14F pairs than with Y14D, indicating that pY14-Cav1 regulates the spatial organization of Cav1 molecules within the oligomer. In addition, albumin-induced Src activation or direct activation of Src using a rapamycin-inducible Src construct (RapR-Src) led to an increase in monomeric Cav1 in Western blots, as well as a simultaneous increase in vesicle number and decrease in FRET intensity, indicative of a Src-mediated conformational change in CFP/YFP-tagged WT-Cav1 pairs. We conclude that phosphorylation of Cav1 leads to separation or “spreading” of neighboring negatively charged N-terminal phosphotyrosine residues, promoting swelling of caveolae, followed by their release from the plasma membrane.
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Khater, Ismail M., Fanrui Meng, Ivan Robert Nabi und Ghassan Hamarneh. „Identification of caveolin-1 domain signatures via machine learning and graphlet analysis of single-molecule super-resolution data“. Bioinformatics 35, Nr. 18 (13.02.2019): 3468–75. http://dx.doi.org/10.1093/bioinformatics/btz113.
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Abstract Motivation Network analysis and unsupervised machine learning processing of single-molecule localization microscopy of caveolin-1 (Cav1) antibody labeling of prostate cancer cells identified biosignatures and structures for caveolae and three distinct non-caveolar scaffolds (S1A, S1B and S2). To obtain further insight into low-level molecular interactions within these different structural domains, we now introduce graphlet decomposition over a range of proximity thresholds and show that frequency of different subgraph (k = 4 nodes) patterns for machine learning approaches (classification, identification, automatic labeling, etc.) effectively distinguishes caveolae and scaffold blobs. Results Caveolae formation requires both Cav1 and the adaptor protein CAVIN1 (also called PTRF). As a supervised learning approach, we applied a wide-field CAVIN1/PTRF mask to CAVIN1/PTRF-transfected PC3 prostate cancer cells and used the random forest classifier to classify blobs based on graphlet frequency distribution (GFD). GFD of CAVIN1/PTRF-positive (PTRF+) and -negative Cav1 clusters showed poor classification accuracy that was significantly improved by stratifying the PTRF+ clusters by either number of localizations or volume. Low classification accuracy (<50%) of large PTRF+ clusters and caveolae blobs identified by unsupervised learning suggests that their GFD is specific to caveolae. High classification accuracy for small PTRF+ clusters and caveolae blobs argues that CAVIN1/PTRF associates not only with caveolae but also non-caveolar scaffolds. At low proximity thresholds (50–100 nm), the caveolae groups showed reduced frequency of highly connected graphlets and increased frequency of completely disconnected graphlets. GFD analysis of single-molecule localization microscopy Cav1 clusters defines changes in structural organization in caveolae and scaffolds independent of association with CAVIN1/PTRF. Supplementary information Supplementary data are available at Bioinformatics online.
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Ariotti, Nicholas, Manuel A. Fernández-Rojo, Yong Zhou, Michelle M. Hill, Travis L. Rodkey, Kerry L. Inder, Lukas B. Tanner, Markus R. Wenk, John F. Hancock und Robert G. Parton. „Caveolae regulate the nanoscale organization of the plasma membrane to remotely control Ras signaling“. Journal of Cell Biology 204, Nr. 5 (24.02.2014): 777–92. http://dx.doi.org/10.1083/jcb.201307055.
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The molecular mechanisms whereby caveolae exert control over cellular signaling have to date remained elusive. We have therefore explored the role caveolae play in modulating Ras signaling. Lipidomic and gene array analyses revealed that caveolin-1 (CAV1) deficiency results in altered cellular lipid composition, and plasma membrane (PM) phosphatidylserine distribution. These changes correlated with increased K-Ras expression and extensive isoform-specific perturbation of Ras spatial organization: in CAV1-deficient cells K-RasG12V nanoclustering and MAPK activation were enhanced, whereas GTP-dependent lateral segregation of H-Ras was abolished resulting in compromised signal output from H-RasG12V nanoclusters. These changes in Ras nanoclustering were phenocopied by the down-regulation of Cavin1, another crucial caveolar structural component, and by acute loss of caveolae in response to increased osmotic pressure. Thus, we postulate that caveolae remotely regulate Ras nanoclustering and signal transduction by controlling PM organization. Similarly, caveolae transduce mechanical stress into PM lipid alterations that, in turn, modulate Ras PM organization.
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Rathor, Navneeta, Ran Zhuang, Jian-Ying Wang, James M. Donahue, Douglas J. Turner und Jaladanki N. Rao. „Src-mediated caveolin-1 phosphorylation regulates intestinal epithelial restitution by altering Ca2+ influx after wounding“. American Journal of Physiology-Gastrointestinal and Liver Physiology 306, Nr. 8 (15.04.2014): G650—G658. http://dx.doi.org/10.1152/ajpgi.00003.2014.
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Early mucosal restitution occurs as a consequence of intestinal epithelial cell (IEC) migration to reseal superficial wounds, but its exact mechanism remains largely unknown. Caveolin-1 (Cav1), a major component associated with caveolar lipid rafts in the plasma membrane, is implicated in many aspects of cellular functions. This study determined if c-Src kinase (Src)-induced Cav1 phosphorylation promotes intestinal epithelial restitution after wounding by activating Cav1-mediated Ca2+ signaling. Src directly interacted with Cav1, formed Cav1-Src complexes, and phosphorylated Cav1 in IECs. Inhibition of Src activity by its chemical inhibitor PP2 or suppression of the functional caveolin scaffolding domain by caveolin-scaffolding domain peptides prevented Cav1-Src interaction, reduced Cav1 phosphorylation, decreased Ca2+ influx, and inhibited cell migration after wounding. Disruption of caveolar lipid raft microdomains by methyl-β-cyclodextrin reduced Cav1-mediated Ca2+ influx and repressed epithelial restitution. Moreover, Src silencing prevented subcellular redistribution of phosphorylated Cav1 in migrating IECs. These results indicate that Src-induced Cav1 phosphorylation stimulates epithelial restitution by increasing Cav1-mediated Ca2+ signaling after wounding, thus contributing to the maintenance of gut mucosal integrity under various pathological conditions.
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Karhan, Asuman Nur, Jamila Zammouri, Martine Auclair, Emilie Capel, Feramuz Demir Apaydin, Fehmi Ates, Marie-Christine Verpont et al. „Biallelic CAV1 null variants induce congenital generalized lipodystrophy with achalasia“. European Journal of Endocrinology 185, Nr. 6 (01.12.2021): 841–54. http://dx.doi.org/10.1530/eje-21-0915.
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Objective CAV1 encodes caveolin-1, a major protein of plasma membrane microdomains called caveolae, involved in several signaling pathways. Caveolin-1 is also located at the adipocyte lipid droplet. Heterozygous pathogenic variants of CAV1 induce rare heterogeneous disorders including pulmonary arterial hypertension and neonatal progeroid syndrome. Only one patient was previously reported with a CAV1 homozygous pathogenic variant, associated with congenital generalized lipodystrophy (CGL3). We aimed to further delineate genetic transmission, clinical, metabolic, and cellular characteristics of CGL3. Design/Methods In a large consanguineous kindred referred for CGL, we performed next-generation sequencing, as well as clinical, imagery, and metabolic investigations. We studied skin fibroblasts from the index case and the previously reported patient with CGL3. Results Four patients, aged 8 months to 18 years, carried a new homozygous p.(His79Glnfs*3) CAV1 variant. They all displayed generalized lipodystrophy since infancy, insulin resistance, low HDL-cholesterol, and/or high triglycerides, but no pulmonary hypertension. Two patients also presented at the age of 15 and 18 years with dysphagia due to achalasia, and one patient had retinitis pigmentosa. Heterozygous parents and relatives (n = 9) were asymptomatic, without any metabolic abnormality. Patients’ fibroblasts showed a complete loss of caveolae and no protein expression of caveolin-1 and its caveolin-2 and cavin-1 partners. Patients’ fibroblasts also displayed insulin resistance, increased oxidative stress, and premature senescence. Conclusions The CAV1 null variant investigated herein leads to an autosomal recessive congenital lipodystrophy syndrome. Loss of caveolin-1 and/or caveolae induces specific manifestations including achalasia which requires specific management. Overlapping phenotypic traits between the different CAV1-related diseases require further studies.
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Zhang, Yanli, Xinyan Zhang, Wenru Kong und Shuqi Wang. „Reconstitution of Caveolin-1 into Artificial Lipid Membrane: Characterization by Transmission Electron Microscopy and Solid-State Nuclear Magnetic Resonance“. Molecules 26, Nr. 20 (14.10.2021): 6201. http://dx.doi.org/10.3390/molecules26206201.
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Caveolin-1 (CAV1), a membrane protein that is necessary for the formation and maintenance of caveolae, is a promising drug target for the therapy of various diseases, such as cancer, diabetes, and liver fibrosis. The biology and pathology of caveolae have been widely investigated; however, very little information about the structural features of full-length CAV1 is available, as well as its biophysical role in reshaping the cellular membrane. Here, we established a method, with high reliability and reproducibility, for the expression and purification of CAV1. Amyloid-like properties of CAV1 and its C-terminal peptide CAV1(168-178) suggest a structural basis for the short linear CAV1 assemblies that have been recently observed in caveolin polyhedral cages in Escherichia coli (E. coli). Reconstitution of CAV1 into artificial lipid membranes induces a caveolae-like membrane curvature. Structural characterization of CAV1 in the membrane by solid-state nuclear magnetic resonance (ssNMR) indicate that it is largely α-helical, with very little β-sheet content. Its scaffolding domain adopts a α-helical structure as identified by chemical shift analysis of threonine (Thr). Taken together, an in vitro model was developed for the CAV1 structural study, which will further provide meaningful evidences for the design and screening of bioactive compounds targeting CAV1.
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Manninen, Aki, Paul Verkade, Soazig Le Lay, Juha Torkko, Michael Kasper, Joachim Füllekrug und Kai Simons. „Caveolin-1 Is Not Essential for Biosynthetic Apical Membrane Transport“. Molecular and Cellular Biology 25, Nr. 22 (15.11.2005): 10087–96. http://dx.doi.org/10.1128/mcb.25.22.10087-10096.2005.
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ABSTRACT Caveolin-1 has been implicated in apical transport of glycosylphosphatidylinositol (GPI)-anchored proteins and influenza virus hemagglutinin (HA). Here we have studied the role of caveolin-1 in apical membrane transport by generating caveolin-1-deficient Madin-Darby canine kidney (MDCK) cells using retrovirus-mediated RNA interference. The caveolin-1 knockdown (cav1-KD) MDCK cells were devoid of caveolae. In addition, caveolin-2 was retained in the Golgi apparatus in cav1-KD MDCK cells. However, we found no significant alterations in the apical transport kinetics of GPI-anchored proteins or HA upon depletion of caveolin-1. Similar results were obtained using embryonic fibroblasts from caveolin-1-knockout mice. Thus, we conclude that caveolin-1 does not play a major role in lipid raft-mediated biosynthetic membrane trafficking.
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Cai, Ting, Haojie Wang, Yiliang Chen, Lijun Liu, William T. Gunning, Luis Eduardo M. Quintas und Zi-Jian Xie. „Regulation of caveolin-1 membrane trafficking by the Na/K-ATPase“. Journal of Cell Biology 182, Nr. 6 (15.09.2008): 1153–69. http://dx.doi.org/10.1083/jcb.200712022.
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Here, we show that the Na/K-ATPase interacts with caveolin-1 (Cav1) and regulates Cav1 trafficking. Graded knockdown of Na/K-ATPase decreases the plasma membrane pool of Cav1, which results in a significant reduction in the number of caveolae on the cell surface. These effects are independent of the pumping function of Na/K-ATPase, and instead depend on interaction between Na/K-ATPase and Cav1 mediated by an N-terminal caveolin-binding motif within the ATPase α1 subunit. Moreover, knockdown of the Na/K-ATPase increases basal levels of active Src and stimulates endocytosis of Cav1 from the plasma membrane. Microtubule-dependent long-range directional trafficking in Na/K-ATPase–depleted cells results in perinuclear accumulation of Cav1-positive vesicles. Finally, Na/K-ATPase knockdown has no effect on processing or exit of Cav1 from the Golgi. Thus, the Na/K-ATPase regulates Cav1 endocytic trafficking and stabilizes the Cav1 plasma membrane pool.
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Maniatis, Nikolaos A., Vasily Shinin, Dean E. Schraufnagel, Shigenori Okada, Stephen M. Vogel, Asrar B. Malik und Richard D. Minshall. „Increased pulmonary vascular resistance and defective pulmonary artery filling in caveolin-1−/− mice“. American Journal of Physiology-Lung Cellular and Molecular Physiology 294, Nr. 5 (Mai 2008): L865—L873. http://dx.doi.org/10.1152/ajplung.00079.2007.
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Caveolin-1, the structural and signaling protein of caveolae, is an important negative regulator of endothelial nitric oxide synthase (eNOS). We observed that mice lacking caveolin-1 ( Cav1−/−) had twofold increased plasma NO levels but developed pulmonary hypertension. We measured pulmonary vascular resistance (PVR) and assessed alterations in small pulmonary arteries to determine the basis of the hypertension. PVR was 46% greater in Cav1−/− mice than wild-type (WT), and increased PVR in Cav1−/− mice was attributed to precapillary sites. Treatment with NG-nitro-l-arginine methyl ester (l-NAME) to inhibit NOS activity raised PVR by 42% in WT but 82% in Cav1−/− mice, indicating greater NO-mediated pulmonary vasodilation in Cav1−/− mice compared with WT. Pulmonary vasculature of Cav1−/− mice was also less reactive to the vasoconstrictor thromboxane A2 mimetic (U-46619) compared with WT. We observed redistribution of type I collagen and expression of smooth muscle α-actin in lung parenchyma of Cav1−/− mice compared with WT suggestive of vascular remodeling. Fluorescent agarose casting also showed markedly decreased density of pulmonary arteries and artery filling defects in Cav1−/− mice. Scanning electron microscopy showed severely distorted and tortuous pulmonary precapillary vessels. Thus caveolin-1 null mice have elevated PVR that is attributed to remodeling of pulmonary precapillary vessels. The elevated basal plasma NO level in Cav1−/− mice compensates partly for the vascular structural abnormalities by promoting pulmonary vasodilation.
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Codrici, Elena, Lucian Albulescu, Ionela Daniela Popescu, Simona Mihai, Ana-Maria Enciu, Radu Albulescu, Cristiana Tanase und Mihail E. Hinescu. „Caveolin-1-Knockout Mouse as a Model of Inflammatory Diseases“. Journal of Immunology Research 2018 (29.08.2018): 1–10. http://dx.doi.org/10.1155/2018/2498576.
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Caveolin-1 (CAV1) is the scaffold protein of caveolae, which are minute invaginations of the cell membrane that are involved in endocytosis, cell signaling, and endothelial-mediated inflammation. CAV1 has also been reported to have a dual role as either a tumor suppressor or tumor promoter, depending on the type of cancer. Inflammation is an important player in tumor progression, but the role of caveolin-1 in generating an inflammatory milieu remains poorly characterized. We used a caveolin-1-knockout (CAV1−/−) mouse model to assess the inflammatory status via the quantification of the pro- and anti-inflammatory cytokine levels, as well as the ability of circulating lymphocytes to respond to nonspecific stimuli by producing cytokines. Here, we report that the CAV1−/−mice were characterized by a low-grade systemic proinflammatory status, with a moderate increase in the IL-6, TNF-α, and IL-12p70 levels. CAV1−/−circulating lymphocytes were more prone to cytokine production upon nonspecific stimulation than the wild-type lymphocytes. These results show that CAV1 involvement in cell homeostasis is more complex than previously revealed, as it plays a role in the inflammatory process. These findings indicate that the CAV1−/−mouse model could prove to be a useful tool for inflammation-related studies.
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El-Yazbi, Ahmed F., Woo Jung Cho, Richard Schulz und Edwin E. Daniel. „Caveolin-1 knockout alters β-adrenoceptors function in mouse small intestine“. American Journal of Physiology-Gastrointestinal and Liver Physiology 291, Nr. 6 (Dezember 2006): G1020—G1030. http://dx.doi.org/10.1152/ajpgi.00159.2006.
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β-Adrenoceptors are G protein-coupled receptors whose functions are closely associated with caveolae in the heart and cultured cell lines. In the gut, they are responsible, at least in part, for the mediation of the sympathetic stimulation that might lead to intestinal paralysis postoperatively. We examined the effect of caveolin-1 knockout on the β-adrenoceptor response in mouse small intestine. The relaxation response to (−)-isoprenaline in carbachol-contracted small intestinal tissue segments was reduced in caveolin-1 knockout mice (cav1−/−) compared with their genetic controls (cav1+/+). Immunohistochemical staining showed that β-adrenoceptor expression was similar in both strains in gut smooth muscle. Selective β-adrenoceptor blockers shifted the concentration response curve (CRC) of (−)-isoprenaline to the right in cav1+/+ intestine, but not in cav1−/−, with greatest shift in case of the β3-blocker, SR59230A. The CRC of the selective β3-agonist BRL 37344 was also shifted to the right in cav1−/− compared with cav1+/+. The cAMP-dependent protein kinase (PKA) inhibitor H-89 shifted the CRC of (−)-isoprenaline to the right in cav1+/+ but not in cav1−/−. H-89 reduced the relaxation due to forskolin and dibutyryl cAMP in cav1+/+ but not in cav1−/−, suggesting a reduction in PKA activity in cav1−/−. In cav1+/+, PKA was colocalized with caveolin-1 in the cell membrane, but PKA immunoreactivity persisted in cav1−/−. Examination of PKA expression in the lipid raft-rich membrane fraction of the jejunum revealed reduced PKA expression in cav1−/− compared with cav1+/+. The results of the present study show that the function of β-adrenoceptors is reduced in cav1−/− small intestine likely owing to reduced PKA activity.
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Sotodosos-Alonso, Laura, María García-García, Enrique Calvo, Aleksandra Norczyk-Simón, Jesús Vázquez, Asier Echarri und Miguel A. Del Pozo. „Cell tension controlling pathways and nutrient availability regulate plasma membrane ATP synthase trafficking“. IBJ Plus 1, s5 (03.06.2022): 45. http://dx.doi.org/10.24217/2531-0151.22v1s5.00045.
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Introduction: The interplay between mechanical stress and cell metabolism is an emerging topic. However, the mechanotransduction pathways coordinating cell metabolism to the tensional status of the cell are poorly understood. Here, we provide several evidences suggesting that caveolae – mechanosensitive plasma membrane invaginations-, nutrient availability and cell tension controlling conditions are important for the biology of mitochondrial ATP synthase. Material and Methods: For achieving the caveolar interactome, plasma membrane biotinylation and co-localization experiments, we have used human retinal pigment epithelial-1 (RPE-1) cells, murine vascular aortic smooth muscle (MOVAS) cells and mouse embryonic fibroblasts (MEF). We used proximity-dependent biotin identification (BioID) and mass spectrometry to obtain the different interactomes of caveolar components. For plasma membrane (PM) localization of the ATP synthase we used PM biotinylation under different metabolic and mechanical conditions (nutrient starving, cell confluence). To study co-localization, we performed Proximity Ligation Assays (PLAs) in combination with mitochondrial and caveolar markers. Results: First, we have identified the interactome of all core caveolar components. Among the interactors, we identified subunits α and β of the mitochondrial ATP synthase, which interact with most of the caveolar components. Apart from its main localization at the inner mitochondrial membrane, the ATP synthase has also been detected in the PM, facing the extracellular space; this pool is known as ecto-ATP synthase. We show that the interaction with Caveolin-1 (Cav1), one of the main components of caveolae, occurs outside caveolae and mitochondria. In addition, the presence of ecto- ATP synthase at the PM is dependent on Cav1. Furthermore, conditions regulating cell tension, and metabolic challenges that promote autophagy, impinge on ecto-ATP synthase trafficking Conclusions: This study has characterized the interactome of caveolar components and has focused on the subunits α and β of the ATP synthase, which are also present at the PM. These subunits interact with Cav-1, but this interaction seems to occur in intracellular trafficking vesicles. Moreover, this process could be altered by mechanical cues and nutrient deprivation. Thus, our study suggests that trafficking routes regulating PM residents, and regulated by several caveolar components, are linked to nutrient starvation and mitochondrial biology.
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Tang, Wenqing, Xuemei Feng, Si Zhang, Zhenggang Ren, Yinkun Liu, Biwei Yang, Bei lv, Yu Cai, Jinglin Xia und Ningling Ge. „Caveolin-1 Confers Resistance of Hepatoma Cells to Anoikis by Activating IGF-1 Pathway“. Cellular Physiology and Biochemistry 36, Nr. 3 (2015): 1223–36. http://dx.doi.org/10.1159/000430292.
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Background/Aims: Anoikis resistance is a prerequisite for hepatocellular carcinoma (HCC) metastasis. The role of Caveolin-1 (CAV1) in anoikis resistance of HCC remains unclear. Methods: The oncogenic effect of CAV1 on anchor-independent growth and anoikis resistance was investigated by overexpression and knockdown of CAV1 in hepatoma cells. IGF-1 pathway and its downstream signals were detected by immunoblot analysis. Caveolae invagination and IGF-1R internalization was studied by electron microscopy and 125I-IGF1 internalization assay, respectively. The role of IGF-1R and tyrosine-14 residue (Y-14) of CAV1 was explored by deletion experiment and mutation experiment, respectively. The correlation of CAV1 and IGF-1R was further examined by immunochemical analysis in 120 HCC specimens. Results: CAV1 could promote anchor-independent growth and anoikis resistance in hepatoma cells. CAV1-overexpression increased the expression of IGF-1R and subsequently activated PI3K/Akt and RAF/MEK/ERK pathway, while CAV1 knockdown showed the opposite effect. The mechanism study revealed that CAV1 facilitated caveolae invagination and 125I-IGF1 internalization. IGF-1R deletion or Y-14 mutation reversed CAV1 mediated anchor-independent growth and anoikis resistance. In addition, CAV1 expression was positively related to IGF-1R expression in human HCC tissues. Conclusion: CAV1 confers resistance of hepatoma cells to anoikis by activating IGF-1 pathway, providing a potential therapeutic target for HCC metastasis.
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Brännmark, Cecilia, Emma I. Kay, Unn Örtegren Kugelberg, Belén Chanclón, Man Mohan Shrestha, Ingrid Wernstedt Asterholm, Peter Strålfors und Charlotta S. Olofsson. „Adiponectin is secreted via caveolin 1-dependent mechanisms in white adipocytes“. Journal of Endocrinology 247, Nr. 1 (Oktober 2020): 25–38. http://dx.doi.org/10.1530/joe-20-0078.
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Here we have investigated the role of the protein caveolin 1 (Cav1) and caveolae in the secretion of the white adipocyte hormone adiponectin. Using mouse primary subcutaneous adipocytes genetically depleted of Cav1, we show that the adiponectin secretion, stimulated either adrenergically or by insulin, is abrogated while basal (unstimulated) release of adiponectin is elevated. Adiponectin secretion is similarly affected in wildtype mouse and human adipocytes where the caveolae structure was chemically disrupted. The altered ex vivo secretion in adipocytes isolated from Cav1 null mice is accompanied by lowered serum levels of the high-molecular weight (HMW) form of adiponectin, whereas the total concentration of adiponectin is unaltered. Interestingly, levels of HMW adiponectin are maintained in adipose tissue from Cav1-depleted mice, signifying that a secretory defect is present. The gene expression of key regulatory proteins known to be involved in cAMP/adrenergically triggered adiponectin exocytosis (the beta-3-adrenergic receptor and exchange protein directly activated by cAMP) remains intact in Cav1 null adipocytes. Microscopy and fractionation studies indicate that adiponectin vesicles do not co-localise with Cav1 but that some vesicles are associated with a specific fraction of caveolae. Our studies propose that Cav1 has an important role in secretion of HMW adiponectin, even though adiponectin-containing vesicles are not obviously associated with this protein. We suggest that Cav1, and/or the caveolae domain, is essential for the organisation of signalling pathways involved in the regulation of HMW adiponectin exocytosis, a function that is disrupted in Cav1/caveolae-depleted adipocytes.
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Christensen, Amy, und Paul Micevych. „CAV1 siRNA Reduces Membrane Estrogen Receptor-α Levels and Attenuates Sexual Receptivity“. Endocrinology 153, Nr. 8 (05.06.2012): 3872–77. http://dx.doi.org/10.1210/en.2012-1312.
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Although classic estrogen receptors (ER) have been proposed to mediate estradiol signaling, it has been relatively recently that mechanisms of trafficking these receptors have been elucidated. ERα is palmitoylated and associates with caveolin proteins to be targeted to the cell membrane. Caveolins are scaffold proteins that not only traffic ERα to the membrane but also are involved in establishing metabotropic glutamate receptor interactions that are necessary for activating G protein signaling. To demonstrate the role of caveolin proteins in regulating an estradiol-dependent behavior, sexual receptivity, we used small interfering RNA to knock down caveolin-1 (CAV1) expression in the arcuate nucleus of the hypothalamus. In CAV1 knockdown rats, membrane, but not intracellular levels of ERα, were significantly reduced. As expected, estrogenic stimulation of the arcuate nucleus of the hypothalamus to medial preoptic nucleus projection was abrogated in CAV1 knockdown rats, indicating that the membrane-initiated activation of this circuit was compromised. Moreover, estradiol-induced lordosis behavior that is dependent on activation of μ-opioid receptors in the medial preoptic nucleus was also significantly reduced. Thus, CAV1-mediated ERα trafficking to the cell membrane is required for estradiol activation of circuits underlying female sexual receptivity.
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Gangadharan, Vimal, Anja Nohe, Jeffrey Caplan, Kirk Czymmek und Randall L. Duncan. „Caveolin-1 regulates P2X7 receptor signaling in osteoblasts“. American Journal of Physiology-Cell Physiology 308, Nr. 1 (01.01.2015): C41—C50. http://dx.doi.org/10.1152/ajpcell.00037.2014.
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The synthesis of new bone in response to a novel applied mechanical load requires a complex series of cellular signaling events in osteoblasts and osteocytes. The activation of the purinergic receptor P2X7R is central to this mechanotransduction signaling cascade. Recently, P2X7R have been found to be associated with caveolae, a subset of lipid microdomains found in several cell types. Deletion of caveolin-1 (CAV1), the primary protein constituent of caveolae in osteoblasts, results in increased bone mass, leading us to hypothesize that the P2X7R is scaffolded to caveolae in osteoblasts. Thus, upon activation of the P2X7R, we postulate that caveolae are endocytosed, thereby modulating the downstream signal. Sucrose gradient fractionation of MC3T3-E1 preosteoblasts showed that CAV1 was translocated to the denser cytosolic fractions upon stimulation with ATP. Both ATP and the more specific P2X7R agonist 2′(3′)- O-(4-benzoylbenzoyl)ATP (BzATP) induced endocytosis of CAV1, which was inhibited when MC3T3-E1 cells were pretreated with the specific P2X7R antagonist A-839977. The P2X7R cofractionated with CAV1, but, using superresolution structured illumination microscopy, we found only a subpopulation of P2X7R in these lipid microdomains on the membrane of MC3T3-E1 cells. Suppression of CAV1 enhanced the intracellular Ca2+ response to BzATP, suggesting that caveolae regulate P2X7R signaling. This proposed mechanism is supported by increased mineralization in CAV1 knockdown MC3T3-E1 cells treated with BzATP. These data suggest that caveolae regulate P2X7R signaling upon activation by undergoing endocytosis and potentially carrying with it other signaling proteins, hence controlling the spatiotemporal signaling of P2X7R in osteoblasts.
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Le Saux, O., K. Teeters, S. Miyasato, J. Choi, G. Nakamatsu, J. A. Richardson, B. Starcher, E. C. Davis, E. K. Tam und C. Jourdan-Le Saux. „The role of caveolin-1 in pulmonary matrix remodeling and mechanical properties“. American Journal of Physiology-Lung Cellular and Molecular Physiology 295, Nr. 6 (Dezember 2008): L1007—L1017. http://dx.doi.org/10.1152/ajplung.90207.2008.
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Caveolin-1 (cav1) is a 22-kDa membrane protein essential to the formation of small invaginations in the plasma membrane, called caveolae. The cav1 gene is expressed primarily in adherent cells such as endothelial and smooth muscle cells and fibroblasts. Caveolae contain a variety of signaling receptors, and cav1 notably downregulates transforming growth factor (TGF)-β signal transduction. In pulmonary pathologies such as interstitial fibrosis or emphysema, altered mechanical properties of the lungs are often associated with abnormal ECM deposition. In this study, we examined the physiological functions and the deposition of ECM in cav1−/− mice at various ages (1–12 mo). Cav1−/− mice lack caveolae and by 3 mo of age have significant reduced lung compliance and increased elastance and airway resistance. Pulmonary extravasation of fluid, as part of the cav1−/− mouse phenotype, probably contributed to the alteration of compliance, which was compounded by a progressive increase in deposition of collagen fibrils in airways and parenchyma. We also found that the increased elastance was caused by abundant elastic fiber deposition primarily around airways in cav1−/− mice at least 3 mo old. These observed changes in the ECM composition probably also contribute to the increased airway resistance. The higher deposition of collagen and elastic fibers was associated with increased tropoelastin and col1α2 and col3α1 gene expression in lung tissues, which correlated tightly with increased TGF-β/Smad signal transduction. Our study illustrates that perturbation of cav1 function may contribute to several pulmonary pathologies as the result of the important role played by cav1, as part of the TGF-β signaling pathway, in the regulation of the pulmonary ECM.
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Haddad, Dania, Ashraf Al Madhoun, Rasheeba Nizam und Fahd Al-Mulla. „Role of Caveolin-1 in Diabetes and Its Complications“. Oxidative Medicine and Cellular Longevity 2020 (28.01.2020): 1–20. http://dx.doi.org/10.1155/2020/9761539.
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It is estimated that in 2017 there were 451 million people with diabetes worldwide. These figures are expected to increase to 693 million by 2045; thus, innovative preventative programs and treatments are a necessity to fight this escalating pandemic disorder. Caveolin-1 (CAV1), an integral membrane protein, is the principal component of caveolae in membranes and is involved in multiple cellular functions such as endocytosis, cholesterol homeostasis, signal transduction, and mechanoprotection. Previous studies demonstrated that CAV1 is critical for insulin receptor-mediated signaling, insulin secretion, and potentially the development of insulin resistance. Here, we summarize the recent progress on the role of CAV1 in diabetes and diabetic complications.
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Czikora, Istvan, Attila Feher, Rudolf Lucas, David J. R. Fulton und Zsolt Bagi. „Caveolin-1 prevents sustained angiotensin II-induced resistance artery constriction and obesity-induced high blood pressure“. American Journal of Physiology-Heart and Circulatory Physiology 308, Nr. 5 (01.03.2015): H376—H385. http://dx.doi.org/10.1152/ajpheart.00649.2014.
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The type 1 angiotensin II (ANG II) receptor (AT1R) undergoes internalization following stimulation by ANG II. Internalization reduces cell surface AT1Rs, and it is required for AT1R resensitization. In this process AT1R may interact with caveolin-1 (Cav1), the main scaffolding protein of caveolae. We hypothesized that the interaction between Cav1 and AT1R delays AT1R resensitization and thereby prevents sustained ANG II-induced resistance artery (RA) constriction under normal conditions and in experimental obesity. In rat and mouse skeletal muscle RA (diameter: ∼90–120 μm) ANG II-induced constrictions were reduced upon repeated (30-min apart) administrations. Upon disruption of caveolae with methyl-β-cyclodextrin or in RA of Cav1 knockout mice, repeated ANG II applications resulted in essentially maintained constrictions. In vascular smooth muscle cells, AT1R interacted with Cav1, and the degree of cell surface interactions was reduced by long-term (15-min), but not short-term (2-min), exposure to ANG II. When Cav1 was silenced, the amount of membrane-associated AT1R was significantly reduced by a short-term ANG II exposure. Moreover, Cav1 knockout mice fed a high-fat diet exhibited augmented and sustained RA constriction to ANG II and had elevated systemic blood pressure, when compared with normal or high-fat fed wild-type mice. Thus, Cav1, through a direct interaction, delays internalization and subsequent resensitization of AT1R. We suggest that this mechanism prevents sustained ANG II-induced RA constriction and elevated systemic blood pressure in diet-induced obesity.
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Vogel, Elizabeth R., Logan J. Manlove, Ine Kuipers, Michael A. Thompson, Yun-Hua Fang, Michelle R. Freeman, Rodney D. Britt et al. „Caveolin-1 scaffolding domain peptide prevents hyperoxia-induced airway remodeling in a neonatal mouse model“. American Journal of Physiology-Lung Cellular and Molecular Physiology 317, Nr. 1 (01.07.2019): L99—L108. http://dx.doi.org/10.1152/ajplung.00111.2018.
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Reactive airway diseases are significant sources of pulmonary morbidity in neonatal and pediatric patients. Supplemental oxygen exposure in premature infants contributes to airway diseases such as asthma and promotes development of airway remodeling, characterized by increased airway smooth muscle (ASM) mass and extracellular matrix (ECM) deposition. Decreased plasma membrane caveolin-1 (CAV1) expression has been implicated in airway disease and may contribute to airway remodeling and hyperreactivity. Here, we investigated the impact of clinically relevant moderate hyperoxia (50% O2) on airway remodeling and caveolar protein expression in a neonatal mouse model. Within 12 h of birth, litters of B6129SF2J mice were randomized to room air (RA) or 50% hyperoxia exposure for 7 days with or without caveolin-1 scaffolding domain peptide (CSD; caveolin-1 mimic; 10 µl, 0.25 mM daily via intraperitoneal injection) followed by 14 days of recovery in normoxia. Moderate hyperoxia significantly increased airway reactivity and decreased pulmonary compliance at 3 wk. Histologic assessment demonstrated airway wall thickening and increased ASM mass following hyperoxia. RNA from isolated ASM demonstrated significant decreases in CAV1 and cavin-1 in hyperoxia-exposed animals while cavin-3 was increased. Supplementation with intraperitoneal CSD mitigated both the physiologic and histologic changes observed with hyperoxia. Overall, these data show that moderate hyperoxia is detrimental to developing airway and may predispose to airway reactivity and remodeling. Loss of CAV1 is one mechanism through which hyperoxia produces these deleterious effects. Supplementation of CAV1 using CSD or similar analogs may represent a new therapeutic avenue for blunting hyperoxia-induced pulmonary damage in neonates.
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Wang, Kuo-Yang, Mey-Fann Lee, Hung-Chin Ho, Kae-Woei Liang, Chia-Chi Liu, Wan-Jane Tsai und Wei-Wen Lin. „Serum Caveolin-1 as a Novel Biomarker in Idiopathic Pulmonary Artery Hypertension“. BioMed Research International 2015 (2015): 1–7. http://dx.doi.org/10.1155/2015/173970.
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Pulmonary arterial hypertension (PAH) is a rare disease but with significant morbidity and high mortality. There is no specific way to diagnose PAH. Thus, an easy used with good sensitivity and specificity biomarker of PAH is highly desirable to aid in the screening, diagnosis, and follow-up. Caveolin-1 (Cav1) is the structural protein of caveolae and is highly expressed in type I pneumocytes. Lungs tissues from idiopathic PAH (IPAH) patients showed decreased expression of Cav1 in vascular endothelial cells. Therefore, we developed a direct sandwich immunoassay for the determination of Cav1 in IAPH patient’s serum. The result disclosed serum Cav1 level was significantly lower in IPAH than control groups. Using serum Cav1, 17.17 pg/mL as a cutoff value, the sensitivity was 0.59 and the specificity was 1.0. There were two major findings in our results. First, serum Cav1 might be a novel biomarker in the diagnosis of IPAH with fare sensitivity and good specificity. Second, Cav1 might be used to make differential diagnosis between COPD-PH and IPAH group.
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Sprenger, Richard R., Ruud D. Fontijn, Jan van Marle, Hans Pannekoek und Anton J. G. Horrevoets. „Spatial segregation of transport and signalling functions between human endothelial caveolae and lipid raft proteomes“. Biochemical Journal 400, Nr. 3 (28.11.2006): 401–10. http://dx.doi.org/10.1042/bj20060355.
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Lipid rafts and caveolae are biochemically similar, specialized domains of the PM (plasma membrane) that cluster specific proteins. However, they are morphologically distinct, implying different, possibly complementary functions. Two-dimensional gel electrophoresis preceding identification of proteins by MS was used to compare the relative abundance of proteins in DRMs (detergent-resistant membranes) isolated from HUVEC (human umbilical-vein endothelial cells), and caveolae immunopurified from DRM fractions. Various signalling and transport proteins were identified and additional cell-surface biotinylation revealed the majority to be exposed, demonstrating their presence at the PM. In resting endothelial cells, the scaffold of immunoisolated caveolae consists of only few resident proteins, related to structure [CAV1 (caveolin-1), vimentin] and transport (V-ATPase), as well as the GPI (glycosylphosphatidylinositol)-linked, surface-exposed protein CD59. Further quantitative characterization by immunoblotting and confocal microscopy of well-known [eNOS (endothelial nitric oxide synthase) and CAV1], less known [SNAP-23 (23 kDa synaptosome-associated protein) and BASP1 (brain acid soluble protein 1)] and novel [C8ORF2 (chromosome 8 open reading frame 2)] proteins showed different subcellular distributions with none of these proteins being exclusive to either caveolae or DRM. However, the DRM-associated fraction of the novel protein C8ORF2 (∼5% of total protein) associated with immunoseparated caveolae, in contrast with the raft protein SNAP-23. The segregation of caveolae from lipid rafts was visually confirmed in proliferating cells, where CAV1 was spatially separated from eNOS, SNAP-23 and BASP1. These results provide direct evidence for the previously suggested segregation of transport and signalling functions between specialized domains of the endothelial plasma membrane.
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Son, Young Hoon, Seok-Jin Lee, Ki-Baek Lee, Jin-Haeng Lee, Eui Man Jeong, Sun Gun Chung, Sang-Chul Park und In-Gyu Kim. „Dexamethasone downregulates caveolin-1 causing muscle atrophy via inhibited insulin signaling“. Journal of Endocrinology 225, Nr. 1 (16.02.2015): 27–37. http://dx.doi.org/10.1530/joe-14-0490.
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Glucocorticoids play a major role in the development of muscle atrophy in various medical conditions, such as cancer, burn injury, and sepsis, by inhibiting insulin signaling. In this study, we report a new pathway in which glucocorticoids reduce the levels of upstream insulin signaling components by downregulating the transcription of the gene encoding caveolin-1 (CAV1), a scaffolding protein present in the caveolar membrane. Treatment with the glucocorticoid dexamethasone (DEX) decreased CAV1 protein and Cav1 mRNA expression, with a concomitant reduction in insulin receptor alpha (IRα) and IR substrate 1 (IRS1) levels in C2C12 myotubes. On the basis of the results of promoter analysis using deletion mutants and site-directed mutagenesis a negative glucocorticoid-response element in the regulatory region of the Cav1 gene was identified, confirming that Cav1 is a glucocorticoid-target gene. Cav1 knockdown using siRNA decreased the protein levels of IRα and IRS1, and overexpression of Cav1 prevented the DEX-induced decrease in IRα and IRS1 proteins, demonstrating a causal role of Cav1 in the inhibition of insulin signaling. Moreover, injection of adenovirus expressing Cav1 into the gastrocnemius muscle of mice prevented DEX-induced atrophy. These results indicate that CAV1 is a critical regulator of muscle homeostasis, linking glucocorticoid signaling to the insulin signaling pathway, thereby providing a novel target for the prevention of glucocorticoid-induced muscle atrophy.
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Park, Heonyong, Young-Mi Go, Ritesh Darji, Jong-Whan Choi, Michael P. Lisanti, Matthew C. Maland und Hanjoong Jo. „Caveolin-1 regulates shear stress-dependent activation of extracellular signal-regulated kinase“. American Journal of Physiology-Heart and Circulatory Physiology 278, Nr. 4 (01.04.2000): H1285—H1293. http://dx.doi.org/10.1152/ajpheart.2000.278.4.h1285.
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Fluid shear stress activates a member of the mitogen-activated protein (MAP) kinase family, extracellular signal-regulated kinase (ERK), by mechanisms dependent on cholesterol in the plasma membrane in bovine aortic endothelial cells (BAEC). Caveolae are microdomains of the plasma membrane that are enriched with cholesterol, caveolin, and signaling molecules. We hypothesized that caveolin-1 regulates shear activation of ERK. Because caveolin-1 is not exposed to the outside, cells were minimally permeabilized by Triton X-100 (0.01%) to deliver a neutralizing, polyclonal caveolin-1 antibody (pCav-1) inside the cells. pCav-1 then bound to caveolin-1 and inhibited shear activation of ERK but not c-Jun NH2-terminal kinase. Epitope mapping studies showed that pCav-1 binds to caveolin-1 at two regions (residues 1–21 and 61–101). When the recombinant proteins containing the epitopes fused to glutathione- S-transferase (GST-Cav1–21 or GST-Cav61–101) were preincubated with pCav-1, only GST-Cav61–101 reversed the inhibitory effect of the antibody on shear activation of ERK. Other antibodies, including m2234, which binds to caveolin-1 residues 1–21, had no effect on shear activation of ERK. Caveolin-1 residues 61–101 contain the scaffolding and oligomerization domains, suggesting that binding of pCav-1 to these regions likely disrupts the clustering of caveolin-1 or its interaction with signaling molecules involved in the shear-sensitive ERK pathway. We suggest that caveolae-like domains play a critical role in the mechanosensing and/or mechanosignal transduction of the ERK pathway.
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Dalton, Cody M., Camille Schlegel und Catherine J. Hunter. „Caveolin-1: A Review of Intracellular Functions, Tissue-Specific Roles, and Epithelial Tight Junction Regulation“. Biology 12, Nr. 11 (05.11.2023): 1402. http://dx.doi.org/10.3390/biology12111402.
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Caveolin-1 (Cav1) is a vital protein for many cellular processes and is involved in both the positive and negative regulation of these processes. Cav1 exists in multiple cellular compartments depending on its role. Of particular interest is its contribution to the formation of plasma membrane invaginations called caveolae and its involvement in cytoskeletal interactions, endocytosis, and cholesterol trafficking. Cav1 participates in stem cell differentiation as well as proliferation and cell death pathways, which is implicated in tumor growth and metastasis. Additionally, Cav1 has tissue-specific functions that are adapted to the requirements of the cells within those tissues. Its role has been described in adipose, lung, pancreatic, and vascular tissue and in epithelial barrier maintenance. In both the intestinal and the blood brain barriers, Cav1 has significant interactions with junctional complexes that manage barrier integrity. Tight junctions have a close relationship with Cav1 and this relationship affects both their level of expression and their location within the cell. The ubiquitous nature of Cav1 both within the cell and within specific tissues is what makes the protein important for ongoing research as it can assist in further understanding pathophysiologic processes and can potentially be a target for therapies.
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Lobos-González, Lorena, Lorena Oróstica, Natalia Díaz-Valdivia, Victoria Rojas-Celis, America Campos, Eduardo Duran-Jara, Nicole Farfán, Lisette Leyton und Andrew F. G. Quest. „Prostaglandin E2 Exposure Disrupts E-Cadherin/Caveolin-1-Mediated Tumor Suppression to Favor Caveolin-1-Enhanced Migration, Invasion, and Metastasis in Melanoma Models“. International Journal of Molecular Sciences 24, Nr. 23 (29.11.2023): 16947. http://dx.doi.org/10.3390/ijms242316947.
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Caveolin-1 (CAV1) is a membrane-bound protein that suppresses tumor development yet also promotes metastasis. E-cadherin is important in CAV1-dependent tumor suppression and prevents CAV1-enhanced lung metastasis. Here, we used murine B16F10 and human A375 melanoma cells with low levels of endogenous CAV1 and E-cadherin to unravel how co-expression of E-cadherin modulates CAV1 function in vitro and in vivo in WT C57BL/6 or Rag−/− immunodeficient mice and how a pro-inflammatory environment generated by treating cells with prostaglandin E2 (PGE2) alters CAV1 function in the presence of E-cadherin. CAV1 expression augmented migration, invasion, and metastasis of melanoma cells, and these effects were abolished via transient co-expression of E-cadherin. Importantly, exposure of cells to PGE2 reverted the effects of E-cadherin expression and increased CAV1 phosphorylation on tyrosine-14 and metastasis. Moreover, PGE2 administration blocked the ability of the CAV1/E-cadherin complex to prevent tumor formation. Therefore, our results support the notion that PGE2 can override the tumor suppressor potential of the E-cadherin/CAV1 complex and that CAV1 released from the complex is phosphorylated on tyrosine-14 and promotes migration/invasion/metastasis. These observations provide direct evidence showing how a pro-inflammatory environment caused here via PGE2 administration can convert a potent tumor suppressor complex into a promoter of malignant cell behavior.
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Chaturvedi, Nagendra K., Adam K. Ahrens, Ashima Shukla, Christine E. Gilling, Amit K. Mittal, Philip Bierman, Dennis D. Weisenburger, Runqing Lu und Shantaram S. Joshi. „Stromal Tumor Microenvironment in CLL: Regulation of Leukemic Progression“. Blood 120, Nr. 21 (16.11.2012): 1781. http://dx.doi.org/10.1182/blood.v120.21.1781.1781.
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Abstract Abstract 1781 Chronic Lymphocytic Leukemia (CLL), the most prevalent adult B-cell malignancy in western countries, is a highly heterogeneous with a very variable clinical outcome. Emerging evidence indicates that the stromal tumor microenvironment (STME) play important roles in the pathogenesis of CLL. However, the precise mechanism and molecules of STME involved in this process remain unknown. In an attempt to explore the role of STME in this process, we examined the expression levels of stromal associated genes using gene expression profiling (GEP) of CLL cells from 53 patients’ lymph node (LN) (n=15), bone marrow (BM) (n =18), and peripheral blood (PB) (n=20). Using significant analyses of microarray (SAM), gene set enrichment analyses (GSEA), and ingenuity pathway analyses (IPA), among the major pathways associated with the differentially expressed genes, a cytoskeleton genes associated with stromal signatures are the focus of this report. Of these molecules, a significant number of molecules including: LUM, MMP9, MYLK, ITGA9, CAV1, CAV2, FBN1, PARVA, CALD1, ITGB5 and EHD2 were overexpressed and ITGB2, DLC1 and ITGA6 are under expressed in LN-CLL compared to BM-CLL and PB-CLL indicating a role of LN-mediated TME in CLL cell survival/progression. Among these genes, expression of myosin light chain kinase (MYLK), caveolin 1 (CAV1) and caveolin 2 (CAV2) correlated with clinical outcome (see adjacent Figure) as determined by time to treatment. We recently reported the role of a CAV1 in LN microenvironment-induced immune tolerance in CLL and possibility of their involvement in CLL cytoskeleton (Gilling et al, 2012). In the present study we report aberrant expression of other cytoskeleton genes such as MYLK and CAV2 are involved in the regulation of CLL cell survival in the stromal microenvironment affecting other members of the cytoskeletal signature via actin cytoskeleton signaling, integrin signaling and Pak signaling. In addition, MYLK and CAV2 are also involved in regulation of CLL proliferation. Together our studies show that members of the stromal signature particularly in the CLL cells from lymph nodes regulate the CLL cell survival and proliferation and thus leukemic progression. Figure: Association of MYLK expression with time to first treatment Figure:. Association of MYLK expression with time to first treatment Disclosures: No relevant conflicts of interest to declare.
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Ivanciu, Lacramioara, Cristina Lupu und Florea Lupu. „Caveolin-1 Deficiency in Mice Leads to Increased Protection Against Endotoxemia.“ Blood 108, Nr. 11 (16.11.2006): 1814. http://dx.doi.org/10.1182/blood.v108.11.1814.1814.
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Abstract Caveolin-1 (CAV1) is a scaffolding protein that is essential for the formation of caveolae membrane domains, functions as a master-regulator of signaling molecules in caveolae, and has major role in the regulation of endothelial nitric oxide synthase (eNOS). Although it is thought that caveolins play some immunomodulatory roles, the actual function of CAV1 with respect to innate immunity in response to bacterial challenge is not clear. The aim of our study was to examine the in vivo role of CAV1 in a mouse model of endotoxemia. CAV1 knock out (ko) and wild-type (WT) mice were intravenously injected with LD80 of E. coli lipopolysaccharide (LPS, 1 mg/kg). Assessment of mortality during 7 days showed that the survival rate of CAV1 ko mice was significantly higher than WT mice (46% vs. 19%). Another group of mice similarly injected with LPS were sacrificed after 2, 8 and 24 hrs, at which times we analyzed multiple parameters of the inflammatory, NO production and coagulation responses in plasma and tissues. Non-challenged CAV1 ko mice have slightly increased numbers of leukocytes comparing to WT mice. After LPS challenge, the amount of circulating leukocytes decreased at 2 hrs in both genotypes, but were significantly lower in CAV1 ko vs. WT mice and correspondingly increased into the tissues (e.g. lung). Interestingly, non-challenged CAV1 ko mice displayed slightly but significantly higher number of neutrophils in the lung than WT mice. After LPS challenge, neutrophils migration increased dramatically at 2 and 24 hrs in WT, but not in CAV1 ko mice. This was paralleled by an increase in myeloperoxidase (a neutrophil product) in WT vs. CAV1 ko mice at 2 hrs and 24 hrs post-challenge. The levels of several cytokines (GM-CSF, IL-1b, IL-5, IL-6, IL-12) were significantly lower in LPS-treated CAV1 ko versus the corresponding WT mice. Only TNF-alpha peaked in CAV1 ko vs. WT mice at 2 hrs post challenge, then decreased at 24 hrs. Several chemokines (KC, IP-10, MCP1, MIG, MIP1a) were transiently upregulated at 2 hrs and diminished at 24 hrs during endotoxemia, but no significant difference between groups was observed. NO generation in response to LPS was evaluated by measuring nitrite/nitrate production in plasma and tissues. While CAV1 ko mice generated higher NO levels during the early stages of sepsis, likely due to increased eNOS function, WT mice displayed 4-fold increase in nitrite/nitrate at 24 hrs, due to a significant upregulation of inducible NOS (iNOS) in tissue leukocytes, as visualized by immunocytochemistry. We observed a temporal correlation between WT mice morbidity and NO generation during the late stages of endotoxemia. Consistent with their increased survival, CAV1 ko mice had lower nitrite/nitrate levels. Non-challenged CAV1 ko mice already have increased tissue factor activity in the lung comparing to WT mice, which further increased at 8 hrs post LPS injection. The resulting procoagulant state was also reflected by elevated levels of thrombin-antithrombin complexes, decreased fibrinogen in plasma, increased fibrin deposition in the lung, increased D-dimmer (peak at 24 hrs after LPS administration) and soluble thrombomodulin plasma levels, as compared with the WT animals. In conclusion, our data reveal that CAV1 ko mice have a more procoagulant but less inflammatory phenotype, which may confer them better survival during endotoxemic challenge. The mechanisms underlying the increased procoagulant and anti-inflammatory functions in CAV1-deficient mice remain to be determined.
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Zhang, Chengbiao, Xiaotong Su, Lars Bellner und Dao-Hong Lin. „Caveolin-1 regulates corneal wound healing by modulating Kir4.1 activity“. American Journal of Physiology-Cell Physiology 310, Nr. 11 (01.06.2016): C993—C1000. http://dx.doi.org/10.1152/ajpcell.00023.2016.
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The expression of caveolin-1 (Cav1) in corneal epithelium is associated with regeneration potency. We used Cav1−/− mice to study the role of Cav1 in modulating corneal wound healing. Western blot and whole cell patch clamp were employed to study the effect of Cav1 deletion on Kir4.1 current density in corneas. We found that Ba2+-sensitive K+ currents in primary cultured murine corneal epithelial cells (pMCE) from Cav1−/− were dramatically reduced (602 pA) compared with those from wild type (WT; 1,300 pA). As a consequence, membrane potential was elevated in pMCE from Cav1−/− compared with that from WT (−43 ± 7.5 vs. −58 ± 4.0 mV, respectively). Western blot showed that either inhibition of Cav1 expression or Ba2+ incubation stimulated phosphorylation of the EGFR. The transwell migration assay showed that Cav1 genetic inactivation accelerated cell migration. The regrowth efficiency of human corneal epithelial cells (HCE) transfected with siRNA-Cav1 or negative control was evaluated by scrape injury assay. With the presence of mitomycin C (10 μg/ml) to avoid the influence of cell proliferation, Cav1 inhibition with siRNA significantly increased migration compared with control siRNA in HCE. This promoting effect by siRNA-Cav1 could not be further enhanced by cotransfection with siRNA-Kcnj10. By using corneal debridement, we found that wound healing was significantly accelerated in Cav1−/− compared with WT mice (70 ± 10 vs. 36 ± 3%, P < 0.01). Our findings imply that the mechanism by which Cav-1 knockout promotes corneal regrowth is, at least partially, due to the inhibition of Kir4.1 which stimulates EGFR signaling.
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El-Yazbi, Ahmed F., Woo Jung Cho, Geoffrey Boddy, Richard Schulz und Edwin E. Daniel. „Impact of caveolin-1 knockout on NANC relaxation in circular muscles of the mouse small intestine compared with longitudinal muscles“. American Journal of Physiology-Gastrointestinal and Liver Physiology 290, Nr. 2 (Februar 2006): G394—G403. http://dx.doi.org/10.1152/ajpgi.00321.2005.
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Recently, we showed that caveolin-1 (cav1) knockout mice (Cav1−/− mice) have impaired nitric oxide (NO) function in the longitudinal muscle (LM) layer of the small intestine. The defect was a reduced responsiveness of the muscles to NO compensated by an increase in the function of apamin-sensitive, nonadrenergic, noncholinergic (NANC) mediators. In the present study, we examined similarly the effects of cav1 knockout on the relaxation in circular muscle (CM) of the mouse small intestine. CM of Cav1−/− mice also showed defective NO function, but less than in LM, as well as more activation of apamin-sensitive NANC mediators. CM of Cav1−/− mice, like LM, lacked cav1 but retained small amounts of cav3 and caveolae in the outer CM layer. In addition, we also examined the effects of a soluble guanylate cyclase inhibitor, 1 H-[1,2,4]oxadiazolo-[4,3-α]quinazolin-1-one (ODQ), on electric field stimulation (EFS)-mediated relaxation in both LM and CM. ODQ had an effect similar to the block of NO synthesis. Moreover, we compared the actions of two NO donors in the LM and CM of control and Cav1−/− mice. Similar to LM, CM of Cav1−/− mice showed a reduced responsiveness to the NO donors sodium nitroprusside and S-nitroso- N-acetyl penicillamine. However, both ODQ and apamin blocked the inhibitory effects of the NO donors in LM, whereas apamin had no effect in CM. In conclusion, cav1 knockout affects NO function in both LM and CM, but its effects in CM differ significantly.
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Feldman, Rebecca, Zoran Gatalica, Sandeep K. Reddy, Michael Castro und Jasgit C. Sachdev. „Caveolin-1: Oncogenic role in breast cancer? Clues from molecular profiling.“ Journal of Clinical Oncology 33, Nr. 28_suppl (01.10.2015): 134. http://dx.doi.org/10.1200/jco.2015.33.28_suppl.134.
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134 Background: Caveolin-1 (CAV1) is the structural component of caveolae, compartments within the plasma membrane that sequester signaling molecules, thus facilitating molecular “hot spots”. The role of CAV1 in breast cancer is an active area of investigation. We sought to understand the clinical and pathological characteristics of CAV1 positive tumors (CAV 1+) through a retrospective analysis of molecularly-profiled breast cancer patients. Methods: 2,728 breast cancer patients molecularly profiled with a commercial assay (Caris Life Sciences) were evaluated retrospectively for expression of various biomarkers by immunohistochemistry (IHC) and in situ hybridization. JMP statistical analysis tool was used to ascertain distributional differences. Results: Using a threshold of 2+ and 30%, 121/2728 (4%) of patients exhibited CAV1 over-expression by IHC. To observe clinicopathologic differences in the CAV1 + and CAV1- tumors, distribution by age, metastatic disease, and triple negative histology (TNBC) were analyzed. Average age for both groups was 55. 39% vs. 54% were metastatic and 74% vs. 26% were TNBC (p = 0.0001) among CAV1+ and CAV1- groups, respectively. To evaluate the potential oncogenic associations of CAV1, we evaluated the relationship between CAV1+ and various oncogenic pathways. Positive EGFR protein expression and presence of EGFR gene amplification, as well as cKIT over-expression associated with CAV1+ (all p-values < 0.001), whereas HER2 expression and amplification were associated with CAV1- (p = 0.001 for both). In addition, higher Ki67, p53 and TOP2A expression by IHC were observed in CAV1+ patients compared to the CAV1- subgroup (90% vs. 66%, 50% vs. 36%, 84% vs. 65% ; all p-values < 0.0001). Biomarker expression differences that did not meet statistical significance: ERCC1, MGMT, PDGFRA, RRM1, SPARC, TS and TOPO1. Conclusions: The majority of CAV1+ breast cancers are comprised of triple negative, higher proliferative tumors, with aberrant p53 expression as well as expression of other growth factor signaling proteins. This data supports the potential role of CAV1 in fostering molecular hubs for signaling and CAV-1 being a potential target for future therapeutic investigation in TNBC.
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Campos, America, Renato Burgos-Ravanal, María González, Ricardo Huilcaman, Lorena Lobos González und Andrew Quest. „Cell Intrinsic and Extrinsic Mechanisms of Caveolin-1-Enhanced Metastasis“. Biomolecules 9, Nr. 8 (29.07.2019): 314. http://dx.doi.org/10.3390/biom9080314.
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Caveolin-1 (CAV1) is a scaffolding protein with a controversial role in cancer. This review will initially discuss earlier studies focused on the role as a tumor suppressor before elaborating subsequently on those relating to function of the protein as a promoter of metastasis. Different mechanisms are summarized illustrating how CAV1 promotes such traits upon expression in cancer cells (intrinsic mechanisms). More recently, it has become apparent that CAV1 is also a secreted protein that can be included into exosomes where it plays a significant role in determining cargo composition. Thus, we will also discuss how CAV1 containing exosomes from metastatic cells promote malignant traits in more benign recipient cells (extrinsic mechanisms). This ability appears, at least in part, attributable to the transfer of specific cargos present due to CAV1 rather than the transfer of CAV1 itself. The evolution of how our perception of CAV1 function has changed since its discovery is summarized graphically in a time line figure.
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Jozic, Ivan, Jérémy Chéret, Beatriz Abdo Abujamra, Mariya Miteva, Jennifer Gherardini und Ralf Paus. „A Cell Membrane-Level Approach to Cicatricial Alopecia Management: Is Caveolin-1 a Viable Therapeutic Target in Frontal Fibrosing Alopecia?“ Biomedicines 9, Nr. 5 (19.05.2021): 572. http://dx.doi.org/10.3390/biomedicines9050572.
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Irreversible destruction of the hair follicle (HF) in primary cicatricial alopecia and its most common variant, frontal fibrosing alopecia (FFA), results from apoptosis and pathological epithelial-mesenchymal transition (EMT) of epithelial HF stem cells (eHFSCs), in conjunction with the collapse of bulge immune privilege (IP) and interferon-gamma-mediated chronic inflammation. The scaffolding protein caveolin-1 (Cav1) is a key component of specialized cell membrane microdomains (caveolae) that regulates multiple signaling events, and even though Cav1 is most prominently expressed in the bulge area of human scalp HFs, it has not been investigated in any cicatricial alopecia context. Interestingly, in mice, Cav1 is involved in the regulation of (1) key HF IP guardians (TGF-β and α-MSH signaling), (2) IP collapse inducers/markers (IFNγ, substance P and MICA), and (3) EMT. Therefore, we hypothesize that Cav1 may be an unrecognized, important player in the pathobiology of cicatricial alopecias, and particularly, in FFA, which is currently considered as the most common type of primary lymphocytic scarring alopecia in the world. We envision that localized therapeutic inhibition of Cav1 in management of FFA (by cholesterol depleting agents, i.e., cyclodextrins/statins), could inhibit and potentially reverse bulge IP collapse and pathological EMT. Moreover, manipulation of HF Cav1 expression/localization would not only be relevant for management of cicatricial alopecia, but FFA could also serve as a model disease for elucidating the role of Cav1 in other stem cell- and/or IP collapse-related pathologies.
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Avchalumov, Yosef, Alison D. Kreisler, Wulfran Trenet, Mahasweta Nayak, Brian P. Head, Juan C. Piña-Crespo und Chitra D. Mandyam. „Caveolin-1 Expression in the Dorsal Striatum Drives Methamphetamine Addiction-Like Behavior“. International Journal of Molecular Sciences 22, Nr. 15 (30.07.2021): 8219. http://dx.doi.org/10.3390/ijms22158219.
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Dopamine D1 receptor (D1R) function is regulated by membrane/lipid raft-resident protein caveolin-1 (Cav1). We examined whether altered expression of Cav1 in the dorsal striatum would affect self-administration of methamphetamine, an indirect agonist at the D1Rs. A lentiviral construct expressing Cav1 (LV-Cav1) or containing a short hairpin RNA against Cav1 (LV-shCav1) was used to overexpress or knock down Cav1 expression respectively, in the dorsal striatum. Under a fixed-ratio schedule, LV-Cav1 enhanced and LV-shCav1 reduced responding for methamphetamine in an extended access paradigm compared to LV-GFP controls. LV-Cav1 and LV-shCav1 also produced an upward and downward shift in a dose–response paradigm, generating a drug vulnerable/resistant phenotype. LV-Cav1 and LV-shCav1 did not alter responding for sucrose. Under a progressive-ratio schedule, LV-shCav1 generally reduced positive-reinforcing effects of methamphetamine and sucrose as seen by reduced breakpoints. Western blotting confirmed enhanced Cav1 expression in LV-Cav1 rats and reduced Cav1 expression in LV-shCav1 rats. Electrophysiological findings in LV-GFP rats demonstrated an absence of high-frequency stimulation (HFS)-induced long-term potentiation (LTP) in the dorsal striatum after extended access methamphetamine self-administration, indicating methamphetamine-induced occlusion of plasticity. LV-Cav1 prevented methamphetamine-induced plasticity via increasing phosphorylation of calcium calmodulin kinase II, suggesting a mechanism for addiction vulnerability. LV-shCav1 produced a marked deficit in the ability of HFS to produce LTP and, therefore, extended access methamphetamine was unable to alter striatal plasticity, indicating a mechanism for resistance to addiction-like behavior. Our results demonstrate that Cav1 expression and knockdown driven striatal plasticity assist with modulating addiction to drug and nondrug rewards, and inspire new strategies to reduce psychostimulant addiction.
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Styers, Melanie L., Amber K. O'Connor, Robert Grabski, Estelle Cormet-Boyaka und Elizabeth Sztul. „Depletion of β-COP reveals a role for COP-I in compartmentalization of secretory compartments and in biosynthetic transport of caveolin-1“. American Journal of Physiology-Cell Physiology 294, Nr. 6 (Juni 2008): C1485—C1498. http://dx.doi.org/10.1152/ajpcell.00010.2008.
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We have utilized small interfering RNA (siRNA)-mediated depletion of the β-COP subunit of COP-I to explore COP-I function in organellar compartmentalization and protein traffic. Reduction in β-COP levels causes the colocalization of markers for the endoplasmic reticulum (ER)-Golgi intermediate compartment (ERGIC), Golgi, trans-Golgi network (TGN), and recycling endosomes in large, globular compartments. The lack of spatial differentiation of these compartments is not due to a general collapse of all cellular organelles since markers for the early endosomes and lysosomes do not redistribute to the common structures. Anterograde trafficking of the transmembrane cargo vesicular stomatitis virus membrane glycoprotein and of a subset of soluble cargoes is arrested within the common globular compartments. Similarly, recycling traffic of transferrin through the common compartment is perturbed. Furthermore, the trafficking of caveolin-1 (Cav1), a structural protein of caveolae, is arrested within the globular structures. Importantly, Cav1 coprecipitates with the γ-subunit of COP-I, suggesting that Cav1 is a COP-I cargo. Our findings suggest that COP-I is required for the compartmentalization of the ERGIC, Golgi, TGN, and recycling endosomes and that COP-I plays a novel role in the biosynthetic transport of Cav1.
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Curry-Koski, Tala, Brikena Gusek, Ross M. Potter, T. Bucky Jones, Raechel Dickman, Nathan Johnson, John N. Stallone, Roshanak Rahimian, Johana Vallejo-Elias und Mitra Esfandiarei. „Genetic Manipulation of Caveolin-1 in a Transgenic Mouse Model of Aortic Root Aneurysm: Sex-Dependent Effects on Endothelial and Smooth Muscle Function“. International Journal of Molecular Sciences 25, Nr. 23 (26.11.2024): 12702. http://dx.doi.org/10.3390/ijms252312702.
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Marfan syndrome (MFS) is a systemic connective tissue disorder stemming from mutations in the gene encoding Fibrillin-1 (Fbn1), a key extracellular matrix glycoprotein. This condition manifests with various clinical features, the most critical of which is the formation of aortic root aneurysms. Reduced nitric oxide (NO) production due to diminished endothelial nitric oxide synthase (eNOS) activity has been linked to MFS aortic aneurysm pathology. Caveolin-1 (Cav1), a structural protein of plasma membrane caveolae, is known to inhibit eNOS activity, suggesting its involvement in MFS aneurysm progression by modulating NO levels. In this study, we examined the role of Cav1 in aortic smooth muscle and endothelial function, aortic wall elasticity, and wall strength in male and female MFS mice (FBN1+/Cys1041Gly) by generating developing Cav1-deficient MFS mice (MFS/Cav1KO). Our findings reveal that Cav1 ablation leads to a pronounced reduction in aortic smooth muscle contraction in response to phenylephrine, attributable to an increase in NO production in the aortic wall. Furthermore, we observed enhanced aortic relaxation responses to acetylcholine in MFS/Cav1KO mice, further underscoring Cav1’s inhibitory impact on NO synthesis within the aorta. Notably, van Gieson staining and chamber myography analyses showed improved elastin fiber structure and wall strength in male MFS/Cav1KO mice, whereas these effects were absent in female counterparts. Cav1’s regulatory influence on aortic root aneurysm development in MFS through NO-mediated modulation of smooth muscle and endothelial function, with notable sex-dependent variations.
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Pulgarín-Alfaro, Marta, Mauro Catalá, Inmaculada Navarro-Lérida, Nadia Mercader, Ignacio Flores und Carlos Garrido. „Role of caveolin-1 in heart extracellular matrix deposition and remodelling upon myocardial infarction“. IBJ Plus 1, s5 (03.06.2022): 38. http://dx.doi.org/10.24217/2531-0151.22v1s5.00038.
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Introdution: Changes in tissue stiffness or forces transmitted across tissues drive cell functions and behaviour. Cardiovascular system is inherently mechanical, and how its cells and tissues interplay with mechanical forces are an important aspect of its physiology. For example, upon heart damage, the non-injured myocardium is subjected to mechanical overload to preserve heart functionality. Caveolin-1 (Cav1) is an essential constituent of caveolae, flask- shaped invaginated nanodomains of the plasma membrane that act as mechanosensing and mechanoadapting structures through tension-driven flattening and disassembly and membrane trafficking. Cav1 phospho-Tyr14 is an important regulatory node that regulates caveolae internalization and specific downstream functions, but its relevance to cardiac remodelling and function has not been explored. In this study, we have assessed the role of Cav1 on mechanical adaptation to myocardial infarction, specifically on scar establishment and remodelling. Matherial and methods: To study the role of Cav1 on cardiac regeneration potential and extracellular matrix (ECM) remodelling ability upon myocardial infarction (MI), mice that express a non-phosphorylatable form of Cav1 on Tyr14 (Cav1Y14F/Y14F) were used. As a model of MI, postnatal day 1 mice were subjected to heart cryoinjury. Mice were anesthetized by hypothermia, lateral thoracotomy was performed to expose the heart and a metal probe cooled in liquid nitrogen was applied to the left ventricle. The deposition of fibrotic tissue at 7 days postinjury was assessed by H&E and Picrosirius Red histological stainings. Proteomics analysis of cryoinjured hearts was performed. Cardiac lesions were further characterized by immunofluorescence for several markers (CD68, αSMA, Cav1, pHis3, etc.). Results: We previously found that Cav1 is a pivotal regulator of physical ECM remodelling, determining cell migration and tissue fibrosis, and also that specific non-collagen ECM components, are sorted into exosomes through a Cav1- dependent mechanisms. Proteomics analysis of infarcted hearts suggest that Cav1 mutant mice present an altered deposition of ECM proteins, which might impair the recovery of cardiac function. In agreement with this, aberrant histopathological features were observed in scars formed in mutant hearts. Increased macrophage density was observed in Cav1Y14F/Y14F mice, but no significant differences on cell proliferation were found. Conclusions: Here, we provide several evidences suggesting that Cav1 is a key player on mechanoadaptation and machanoresponse in challenged hearts and that Cav1 phospho-Tyr14 is involved in ECM deposition and remodelling and immune infiltration in cryoinjured hearts.
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Geletu, Mulu, Zaid Taha, Rozanne Arulanandam, Reva Mohan, Hikmat H. Assi, Maria G. Castro, Ivan Robert Nabi, Patrick T. Gunning und Leda Raptis. „Effect of caveolin-1 on Stat3-ptyr705 levels in breast and lung carcinoma cells“. Biochemistry and Cell Biology 97, Nr. 5 (Oktober 2019): 638–46. http://dx.doi.org/10.1139/bcb-2018-0367.
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We recently demonstrated that Cav1 (caveolin-1) is a negative regulator of Stat3 (signal transducer and activator of transcription-3) activity in mouse fibroblasts and human lung carcinoma SHP77 cells. We now examined whether the cellular context may affect their levels as well as the relationship between them, by assessing Cav1 and Stat3-ptyr705 amounts in different cell lines. In MDA-MB-231, A549, and HaCat cells, Cav1 levels were high and Stat3-ptyr705 levels were low, consistent with the notion of a negative effect of endogenous Cav1 on Stat3-ptyr705 levels in these lines. In addition, manipulation of Cav1 levels revealed a negative effect in MCF7 and mouse fibroblast cells, while Cav1 upregulation induced apoptosis in MCF7 cells. In contrast, however, line MRC9 had high Cav1 and high Stat3-ptyr705 levels, indicating that high Cav1 is insufficient to reduce Stat3-ptyr705 levels in this line. MCF7 and LuCi6 cells had very low Cav1 and Stat3-ptyr705 levels, indicating that the low Stat3-ptyr705 can be independent from Cav1 levels altogether. Our results reveal a further level of complexity in the relationship between Cav1 and Stat3-ptyr705 than previously thought. In addition, we demonstrate that in a feedback loop, Stat3 inhibition upregulates Cav1 in HeLa cells but not in other lines tested.
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Al Madhoun, Ashraf, Shihab Kochumon, Dania Haddad, Reeby Thomas, Rasheeba Nizam, Lavina Miranda, Sardar Sindhu, Milad S. Bitar, Rasheed Ahmad und Fahd Al-Mulla. „Adipose Tissue Caveolin-1 Upregulation in Obesity Involves TNF-α/NF-κB Mediated Signaling“. Cells 12, Nr. 7 (27.03.2023): 1019. http://dx.doi.org/10.3390/cells12071019.
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Obesity is characterized by chronic low-grade inflammation. Obese people have higher levels of caveolin-1 (CAV1), a structural and functional protein present in adipose tissues (ATs). We aimed to define the inflammatory mediators that influence CAV1 gene regulation and the associated mechanisms in obesity. Using subcutaneous AT from 27 (7 lean and 20 obese) normoglycemic individuals, in vitro human adipocyte models, and in vivo mice models, we found elevated CAV1 expression in obese AT and a positive correlation between the gene expression of CAV1, tumor necrosis factor-alpha (TNF-α), and the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). CAV1 gene expression was associated with proinflammatory cytokines and chemokines and their cognate receptors (r ≥ 0.447, p ≤ 0.030), but not with anti-inflammatory markers. CAV1 expression was correlated with CD163, indicating a prospective role for CAV1 in the adipose inflammatory microenvironment. Unlike wild-type animals, mice lacking TNF-α exhibited reduced levels of CAV1 mRNA/proteins, which were elevated by administering exogenous TNF-α. Mechanistically, TNF-α induces CAV1 gene transcription by mediating NF-κB binding to its two regulatory elements located in the CAV1 proximal regulatory region. The interplay between CAV1 and the TNF-α signaling pathway is intriguing and has potential as a target for therapeutic interventions in obesity and metabolic syndromes.
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Sbenghe, Maria Magdalena, Agnieszka Witkiewicz, Takami Sato, Maria B. Queenan, Matias Emanuel Valsecchi, Kendra J. Feeney und Michael J. Mastrangelo. „Correlation of caveolin 1 expression with disease-free survival in skin melanoma.“ Journal of Clinical Oncology 30, Nr. 15_suppl (20.05.2012): e19016-e19016. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.e19016.
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e19016 Background: As clinical and histological parameters are unable to precisely predict the behavior of skin melanoma, new criteria are required to improve risk assessment. Caveolin 1 (CAV1), a scaffolding membrane protein, has been implicated in cell proliferation, death and transformation. In melanoma cell lines, CAV1 was found to have an antimetastatic role and loss of stromal CAV1 expression in lymph nodes metastases was associated with poor survival. The objectives of this analysis were to correlate CAV1 expression in primary skin melanoma cells with tumor thickness and disease free survival (DFS). Methods: CAV1 immunostaining was performed on the primary skin melanomas of 40 patients. CAV1 expression was scored semi-quantitatively using a 3-point scale: 0 (no staining), 1 (diffuse weak staining or strong staining in less then 30% of the cells) and 2 (strong staining of 30% or more of the cells). For analysis purposes, CAV1 was dichotomized as present (score 1 or 2) or absent (score 0). Primary melanoma was classified based on 2009 AJCC T-stage. DFS was measured from removal of primary skin melanoma to development of loco-regional or systemic recurrence. Pearson Chi-Square, Kaplan Meier, and Cox-Proportional Hazard Ratio were used for data analyses. Results: T-stage distribution was: Cis 12.5%, T1 32.5%, T2 22.5%, T3 17.5%, T4 15.0%. There was a clear inverse relationship between T stage and Cav 1 expression in tumor cells, with higher CAV1 expression in less invasive melanomas (P= 0.01). Fifteen patients experienced either locoregional or distant recurrence (median time to recurrence 14 months; range <1 month -105 months). Twenty-five patients remained disease free for minimum of 3 years (median 77 months; range 36 – 111 months). Presence of CAV1 in primary melanoma tumor cells was correlated with increased DFS (P = 0.05) but this association was not significant when adjusting for T stage (P=0.59). Conclusions: CAV1 expression in melanoma tumor cells correlates with clinical behavior of skin melanoma as its loss is associated with invasiveness and distant recurrence. Whether the loss of CAV1 in primary melanoma tumor cells is just an epiphenomenon or a causal event is to be decided by further work on a larger population sample.
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Mattsson, Charlotte L., Robert I. Csikasz, Irina G. Shabalina, Jan Nedergaard und Barbara Cannon. „Caveolin-1-ablated mice survive in cold by nonshivering thermogenesis despite desensitized adrenergic responsiveness“. American Journal of Physiology-Endocrinology and Metabolism 299, Nr. 3 (September 2010): E374—E383. http://dx.doi.org/10.1152/ajpendo.00071.2010.
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Caveolin-1 (Cav1)-ablated mice display impaired lipolysis in white adipose tissue. They also seem to have an impairment in brown adipose tissue function, implying that Cav1-ablated mice could encounter problems in surviving longer periods in cold temperatures. To investigate this, Cav1-ablated mice and wild-type mice were transferred to cold temperatures for extended periods of time, and parameters related to metabolism and thermogenesis were investigated. Unexpectedly, the Cav1-ablated mice survived in the cold. There were no differences between Cav1-ablated and wild-type mice with regard to food intake, in behavior related to shivering, or in body temperature. The Cav1-ablated mice had a halved total fat content independently of acclimation temperature. There was no difference in brown adipose tissue uncoupling protein-1 (UCP1) protein amount, and isolated brown fat mitochondria were thermogenically competent but displayed 30% higher thermogenic capacity. However, the β3-adrenergic receptor amount was reduced by about one-third in the Cav1-ablated mice at all acclimation temperatures. Principally in accordance with this, a higher than standard dose of norepinephrine was needed to obtain full norepinephrine-induced thermogenesis in the Cav1-ablated mice; the higher dose was also needed for the Cav1-ablated mice to be able to utilize fat as a substrate for thermogenesis. In conclusion, the ablation of Cav1 impairs brown adipose tissue function by a desensitization of the adrenergic response; however, the desensitization is not evident in the animal as it is overcome physiologically, and Cav1-ablated mice can therefore survive in prolonged cold by nonshivering thermogenesis.