Academic literature on the topic 'Dickkopf-3 (DKK3)'
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Journal articles on the topic "Dickkopf-3 (DKK3)":
1
Suwa, T., M. Chen, CL Hawks, and PJ Hornsby. "Zonal expression of dickkopf-3 and components of the Wnt signalling pathways in the human adrenal cortex." Journal of Endocrinology 178, no. 1 (July 1, 2003): 149–58. http://dx.doi.org/10.1677/joe.0.1780149.
Abstract:
The mechanisms underlying the differentiation of the adrenal cortex into zones are unclear. Microarray studies on RNA from microdissected zona reticularis (ZR) and zona fasciculata/zona glomerulosa (ZF/ZG) derived from adult human adrenal glands showed that a gene of the dickkopf family (DKK), DKK3, is differentially expressed in the zones. The Dickkopf proteins are morphogens involved in Wnt signalling. Northern blotting showed higher DKK3 transcript levels in ZF/ZG than ZR samples. In situ hybridization on adult human adrenal gland sections showed that DKK3 expression was much higher in the ZG than in the ZF or ZR. DKK3 expression was also higher in the medulla. We screened for expression of other members of the DKK family and the related Wingless-type mouse mammary tumor virus integration site gene family (WNT), frizzled (FZD), and dishevelled (DVL) gene families. Among dickkopf family members, only DKK3 was expressed at a detectable level in both human and mouse adrenocortical RNA samples. Consistent with previously published data on the effects of Wnt4 gene disruption in the mouse, we found only WNT4 expression within the WNT family in both human and mouse RNA. Northern blotting showed that WNT4 was expressed at a higher level in ZF/ZG cells than in ZR. The higher level of DKK3 and WNT4 expression in ZF/ZG cells was confirmed by real-time PCR. In the frizzled and dishevelled families we found FZD1, FZD2 and DVL3 transcripts in human adrenocortical RNA, and FZD2 and DVL3 in mouse adrenocortical RNA. These data show that a variety of genes of the Wnt signalling pathways are expressed in the adrenal cortex. The zonal distribution of DKK3 expression suggests that it could be involved in zonal differentiation or growth.
2
Zewinger, Stephen, Thomas Rauen, Michael Rudnicki, Giuseppina Federico, Martina Wagner, Sarah Triem, Stefan J. Schunk, et al. "Dickkopf-3 (DKK3) in Urine Identifies Patients with Short-Term Risk of eGFR Loss." Journal of the American Society of Nephrology 29, no. 11 (October 2, 2018): 2722–33. http://dx.doi.org/10.1681/asn.2018040405.
Abstract:
BackgroundThe individual course of CKD may vary, and improved methods for identifying which patients will experience short-term eGFR loss are needed. Assessing urinary Dickkopf-3 (DKK3), a stress-induced tubular epithelia–derived profibrotic glycoprotein, may provide information about ongoing tubulointerstitial fibrosis and short-term eGFR loss.MethodsTo investigate urinary DKK3’s potential as a biomarker of short-term eGFR loss (over 12 months), we prospectively assessed eGFR and urinary DKK3 levels in patients with CKD of various etiologies at baseline and annual follow-ups. We also measured urinary DKK3 in a general population sample and patients with diagnostic kidney biopsies or IgA nephropathy under treatment.ResultsMedian urinary DKK3-to-creatinine concentration at baseline was significantly higher in patients with CKD than the general population sample (431 versus 33 pg/mg). In the CKD cohort, having a urinary DKK3-to-creatinine level >4000 pg/mg was independently and significantly associated after multiple adjustments with mean annual decline in eGFR of 7.6% over 12 months. Urinary DKK3 significantly improved prediction of kidney function decline compared with eGFR or albuminuria alone. Urinary DKK3-to-creatinine levels were related to the extent of tubulointerstitial fibrosis in kidney biopsies. In patients with IgA nephropathy, a rise in urinary DKK3 was associated with significant eGFR decline within 6 months, whereas stable or decreasing urinary DKK3 indicated a more favorable course.ConclusionsUrinary DKK3 levels identify patients at high risk for eGFR decline over the next 12 months regardless of the cause of kidney injury and beyond established biomarkers, potentially providing a tool to monitor CKD progression and assess effects of interventions.
3
Sciascia, Savino, Alice Barinotti, Massimo Radin, Irene Cecchi, Elisa Menegatti, Edoardo Terzolo, Daniela Rossi, Simone Baldovino, Roberta Fenoglio, and Dario Roccatello. "Dickkopf Homolog 3 (DKK3) as a Prognostic Marker in Lupus Nephritis: A Prospective Monocentric Experience." Journal of Clinical Medicine 11, no. 11 (May 25, 2022): 2977. http://dx.doi.org/10.3390/jcm11112977.
Abstract:
Background: The gold standard for diagnosis of lupus nephritis (LN) is still represented by renal biopsy, and serological prognostic biomarkers are still lacking. Dickkopf homolog-3 (DKK3) has been suggested as a marker of tissue fibrosis in different conditions; however, its role in autoimmune diseases needs to be elucidated. Here, we investigated the prognostic role of DKK3 in systemic lupus erythematosus (SLE) patients with and without LN, assessing its changes in relation to kidney function, flares, and interstitial fibrosis. Methods: Overall, 132 SLE patients (57 with LN) were included and prospectively followed up for at least 36 months. DKK3 was measured in serum at baseline. Biopsies were evaluated for glomerular involvement, interstitial fibrosis, and tubular atrophy. Results: Patients with biopsy-proven LN had significantly higher levels of DKK3 than those without (median [min–max]: 215 ng/mL [81–341] vs. 21.1 ng/mL [1–69], p < 0.01). DKK3 levels were associated with prevalent chronic kidney diseases (OR: 4.31 [C.I. 2.01–6.61] per DKK3 doubling, p < 0.01), higher chronicity index at biopsy (1.75 [1.51–2.77] per DKK3 doubling, p < 0.01), and flares rate (OR: 1.45 [C.I. 1.1–5.71] per DKK3 doubling, p < 0.044). Conclusions: While kidney biopsy still represents the gold standard for diagnostic and prognostic assessment in LN, DKK3 could represent an additional prognostic tool to monitor SLE patients and guide therapeutic choices.
4
Dziamałek-Macioszczyk, Paulina, Agata Winiarska, Anna Pawłowska, Paweł Wojtacha, and Tomasz Stompór. "Patterns of Dickkopf-3 Serum and Urine Levels at Different Stages of Chronic Kidney Disease." Journal of Clinical Medicine 12, no. 14 (July 15, 2023): 4705. http://dx.doi.org/10.3390/jcm12144705.
Abstract:
Dickkopf 3 (Dkk3) is a WNT/β-catenin signaling pathway regulator secreted by tubular epithelial cells upon the influence of different stressors. Recently Dkk3 was described as a biomarker of tubular cell injury and a tool that may estimate the risk of chronic kidney disease (CKD) progression. The data about Dkk3 concentrations at particular stages of CKD are lacking. The aim of this study was to measure serum and urine Dkk3 levels in patients with different ‘renal status’ and evaluate its role as a biomarker of renal damage. One hundred individuals, aged between 24 and 85 years (mean 53.1 ± 17.1), were enrolled in the study. Five groups of 20 subjects each were recruited based on their kidney function. Serum and urine Dkk3 levels were measured by ELISA. The highest median urinary Dkk3 normalized to urinary creatinine was found in patients with established CKD (7051 pg/mg). It was two times higher in renal transplant patients (5705 pg/mg) than in healthy individuals (2654 pg/mg) and the glomerulonephritis group (2470 pg/mg). Urinary Dkk3 was associated with serum creatinine in participants with established CKD and following transplantation. Our results confirm the potential role of Dkk3 as a biomarker of an ongoing renal injury.
5
Zhang, Yingjie, Huibo Li, Rongyi Cao, Lili Sun, Yan Wang, Shengjin Fan, Yanqiu Zhao, et al. "Suppression of Mir-708 Promotes DKK3 to Inhibit Wnt/β-Catenin Signaling Pathway in Adult B-ALL." Blood 128, no. 22 (December 2, 2016): 5090. http://dx.doi.org/10.1182/blood.v128.22.5090.5090.
Abstract:
Abstract Dickkopf-3 (DKK-3) is a Wnt signaling antagonist, and DKK3 inactivation is associated with poor prognosis in various solid tumors and hematologic malignancies. Epigenetic hypermethylation has been implicated in downregulation of DKK3, but other regulatory mechanisms remain to be investigated. In this study, we examined DKK3 expression and the role of microRNA in the regulation of DKK3 in adult B-ALL. Our results showed low levels of DKK3 expression in Nalm-6 and BALL-1 cell lines, and leukemia cells from adult B-ALL patients. DKK3 expression was remarkably lower in the initial diagnosis and relapse samples than in the matched samples during remission. In addition to hypermethylation, low levels of DKK3 were associated with high expression of miR-708. This finding was similar to that in childhood ALL. The miR-708 was predicted to bind to the 3'-UTR of DKK3. By using miR-708 mimics, we found that miR-708 targets DKK3 to promote B-ALL cell proliferation through cell cycle promotion and apoptosis inhibition. The treatment with 5-aza-2'-deoxycytidine significantly increased DKK3 and decreased p-GSK3β, cyclin D1 and nuclear and cytoplasmic β-catenin protein expression. A synergistic effect was seen when the miR-708 inhibitor and 5-aza were used simultaneously. Although miR-708 was reported to either promote or suppress tumorigenecity in some solid tumors, our findings indicate that suppression of miR-708 increases DKK3 expression to inhibit the Wnt/β- catenin signaling pathway in B-ALL. Disclosures No relevant conflicts of interest to declare.
6
Inamoto, Yoshihiro, Paul J. Martin, Stephanie J. Lee, Amin A. Momin, Laura Tabellini, Lynn E. Onstad, Joseph Pidala, et al. "Dickkopf-related protein 3 is a novel biomarker for chronic GVHD after allogeneic hematopoietic cell transplantation." Blood Advances 4, no. 11 (June 3, 2020): 2409–17. http://dx.doi.org/10.1182/bloodadvances.2020001485.
Abstract:
Abstract To identify plasma biomarkers associated with fibrotic mechanisms of chronic graft-versus-host disease (GVHD), we used multiplex mass spectrometry with pooled samples for biomarker discovery in comparing proteomic profiles between patients with newly diagnosed sclerotic chronic GVHD (n = 21), those with newly diagnosed nonsclerotic chronic GVHD (n = 33), and those without chronic GVHD (n = 20). Immunoassay was used to measure protein concentrations of individual discovery samples and 186 independent verification samples. The discovery mass spectrometry analysis identified 2 candidate proteins with at least 1.5-fold difference in sclerotic GVHD: Dickkopf-related protein 3 (DKK3) and interleukin-1 receptor accessory protein (IL1RAP). Analysis of individual discovery samples by immunoassay showed that DKK3, a modulator of the Wnt signaling pathway, was a biomarker for both sclerotic and nonsclerotic chronic GVHD. Verification analysis of 186 patients confirmed that elevated plasma DKK3 concentrations were associated with chronic GVHD, regardless of the presence or absence of sclerosis, and that the area under the receiver operating characteristic curve was 0.85 for association of DKK3 concentrations with chronic GVHD. Multiple linear regression analysis showed that chronic GVHD with or without steroid treatment and patient age were independently associated with DKK3 concentrations. Patients with high DKK3 concentrations had a higher nonrelapse mortality than those with low concentrations. The lower IL1RAP concentrations in patients with sclerotic GVHD compared with other conditions in the discovery cohort were not confirmed in the verification cohort. DKK3 is a novel biomarker for chronic GVHD. Further studies are needed to determine the biological functions of DKK3 in the pathogenesis of chronic GVHD.
7
Zhou, Liran, Hongmei Husted, Todd Moore, Mason Lu, Defeng Deng, Yan Liu, Vijaya Ramachandran, et al. "Suppression of stromal-derived Dickkopf-3 (DKK3) inhibits tumor progression and prolongs survival in pancreatic ductal adenocarcinoma." Science Translational Medicine 10, no. 464 (October 24, 2018): eaat3487. http://dx.doi.org/10.1126/scitranslmed.aat3487.
Abstract:
Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis, and it is unclear whether its stromal infiltrate contributes to its aggressiveness. Here, we demonstrate that Dickkopf-3 (DKK3) is produced by pancreatic stellate cells and is present in most human PDAC. DKK3 stimulates PDAC growth, metastasis, and resistance to chemotherapy with both paracrine and autocrine mechanisms through NF-κB activation. Genetic ablation of DKK3 in an autochthonous model of PDAC inhibited tumor growth, induced a peritumoral infiltration of CD8+ T cells, and more than doubled survival. Treatment with a DKK3-blocking monoclonal antibody inhibited PDAC progression and chemoresistance and prolonged survival. The combination of DKK3 inhibition with immune checkpoint inhibition was more effective in reducing tumor growth than either treatment alone and resulted in a durable improvement in survival, suggesting that DKK3 neutralization may be effective as a single targeted agent or in combination with chemotherapy or immunotherapy for PDAC.
8
Sciascia, S., M. Radin, A. Barinotti, I. Cecchi, D. Rossi, R. Fenoglio, and D. Roccatello. "POS1448 DICKKOPF HOMOLOG 3 (DKK3) AS A PROGNOSTIC MARKER IN LUPUS NEPHRITIS: A PROSPECTIVE MONOCENTRIC EXPERIENCE." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 1069.1–1069. http://dx.doi.org/10.1136/annrheumdis-2022-eular.1254.
Abstract:
BackgroundLupus nephritis (LN) is a major cause of mortality/morbidity in patients affected by systemic lupus erythematosus (SLE). Reliable prognostic markers, especially related to the degree of interstitial fibrosis, are still lacking and renal biopsy still represents the gold standard. Recent data suggests a role of Dickkopf homolog 3 (DKK3) as a marker of tissue fibrosis in different diseases, however its role in autoimmune diseases still needs to be elucidated.ObjectivesTo investigate DKK3 serum levels in SLE patients with and without LN, assessing its changes in relation to kidney function, flares and interstitial renal fibrosis, as well as its association with the IFN signature.Methods132 SLE patients, 57 of whom diagnosed with LN, were included in this study, as well as 50 healthy donors. DKK3 and Myxovirus resistance protein 1 (MxA) were measured in serum samples, using enzyme-linked immunosorbent assays. Biopsies were evaluated for glomerular involvement, interstitial renal fibrosis and tubular atrophy according to 2003 International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification and the revised 2018 version. Patients were followed-up for at least 36 months.ResultsDKK3 serum levels were significantly higher in patients with biopsy-proven LN when compared to those without (median[min-max]: 215ng/ml [81-341] vs 21.1ng/ml [1-69], p<0.01). When focusing on patients with LN, DKK3 levels resulted to be associated with the presence of chronic kidney disease (OR: 4.31[C.I. 2.01-6.61] per DKK3 doubling, p<0.01), higher chronicity index at biopsy (OR: 1.75[C.I. 1.59-2.13] per DKK3 doubling, p<0.01) and flares rate (OR: 1.45[C.I. 1.1-5.71] per DKK3 doubling, p<0.044). DKK3 levels correlated with the IFN signature as expressed by MxA (correlation coefficient: 0.71, p<0.037).ConclusionWhile kidney biopsy remains the gold standard for diagnostic and prognostic assessment in LN, DKK3 could represent an additional useful prognostic tool to monitor SLE patients and eventually to guide therapeutic choices.Disclosure of InterestsNone declared
9
Lim, Xinhong, Si Hui Tan, Ka Lou Yu, Sophia Beng Hui Lim, and Roeland Nusse. "Axin2 marks quiescent hair follicle bulge stem cells that are maintained by autocrine Wnt/β-catenin signaling." Proceedings of the National Academy of Sciences 113, no. 11 (February 22, 2016): E1498—E1505. http://dx.doi.org/10.1073/pnas.1601599113.
Abstract:
How stem cells maintain their identity and potency as tissues change during growth is not well understood. In mammalian hair, it is unclear how hair follicle stem cells can enter an extended period of quiescence during the resting phase but retain stem cell potential and be subsequently activated for growth. Here, we use lineage tracing and gene expression mapping to show that the Wnt target gene Axin2 is constantly expressed throughout the hair cycle quiescent phase in outer bulge stem cells that produce their own Wnt signals. Ablating Wnt signaling in the bulge cells causes them to lose their stem cell potency to contribute to hair growth and undergo premature differentiation instead. Bulge cells express secreted Wnt inhibitors, including Dickkopf (Dkk) and secreted frizzled-related protein 1 (Sfrp1). However, the Dickkopf 3 (Dkk3) protein becomes localized to the Wnt-inactive inner bulge that contains differentiated cells. We find that Axin2 expression remains confined to the outer bulge, whereas Dkk3 continues to be localized to the inner bulge during the hair cycle growth phase. Our data suggest that autocrine Wnt signaling in the outer bulge maintains stem cell potency throughout hair cycle quiescence and growth, whereas paracrine Wnt inhibition of inner bulge cells reinforces differentiation.
10
Nguyen, Que Thanh Thanh, Hwang Shin Park, Tae Jin Lee, Kyung-Mi Choi, Joong Yull Park, Daehan Kim, Jae Hyung Kim, Junsoo Park, and Eun-Ju Lee. "DKK3, Downregulated in Invasive Epithelial Ovarian Cancer, Is Associated with Chemoresistance and Enhanced Paclitaxel Susceptibility via Inhibition of the β-Catenin-P-Glycoprotein Signaling Pathway." Cancers 14, no. 4 (February 12, 2022): 924. http://dx.doi.org/10.3390/cancers14040924.
Abstract:
Dickkopf-3 (DKK3), a tumor suppressor, is frequently downregulated in various cancers. However, the role of DKK3 in ovarian cancer has not been evaluated. This study aimed to assess aberrant DKK3 expression and its role in epithelial ovarian carcinoma. DKK3 expression was assessed using immunohistochemistry with tissue blocks from 82 patients with invasive carcinoma, and 15 normal, 19 benign, and 10 borderline tumors as controls. Survival data were analyzed using Kaplan–Meier and Cox regression analysis. Paclitaxel-resistant cells were established using TOV-21G and OV-90 cell lines. Protein expression was assessed using Western blotting and immunofluorescence analysis. Cell viability was assessed using the MT assay and 3D-spheroid assay. Cell migration was determined using a migration assay. DKK3 was significantly downregulated in invasive carcinoma compared to that in normal, benign, and borderline tumors. DKK3 loss occurred in 56.1% invasive carcinomas and was significantly associated with disease-free survival and chemoresistance in serous adenocarcinoma. DKK3 was lost in paclitaxel-resistant cells, while β-catenin and P-glycoprotein were upregulated. Exogenous secreted DKK3, incorporated by cells, enhanced anti-tumoral effect and paclitaxel susceptibility in paclitaxel-resistant cells, and reduced the levels of active β-catenin and its downstream P-glycoprotein, suggesting that DKK3 can be used as a therapeutic for targeting paclitaxel-resistant cancer.
Dissertations / Theses on the topic "Dickkopf-3 (DKK3)":
1
Mourtada, Jana. "Mécanismes d’activation de la réponse immunitaire par DNp63 dans les cancers des voies aérodigestives supérieures HPV-positifs." Electronic Thesis or Diss., Strasbourg, 2023. http://www.theses.fr/2023STRAJ127.
Abstract:
Les tumeurs HPV+ de l’oropharynx sont hétérogènes d’un point de vue pronostic et moléculaire. Le pronostic des tumeurs se distinguent respectivement par la présence ou l’absence d’une signature moléculaire dépendante du facteur de transcription ΔNp63. Nous avions démontré que ΔNp63 inhibe les capacités migratoires et invasives des lignées cellulaires de cancer ORL HPV+, et augmente leur sensibilité aux chimiothérapies à base de sel de platine, suggérant son rôle dans la progression tumorale. Une analyse fonctionnelle de ΔNp63 nous a permis de montrer que son expression stimule la phagocytose de cellules cancéreuses par des macrophages in vitro. De manière cohérente, l’analyse du transcriptome de notre même modèle cellulaire met en évidence que ΔNp63 régule l’expression de facteurs diffusibles comme des chimiokines et des interleukines, parmi lesquels la protéine DKK3. Nos résultats montrent que la sécrétion de DKK3 par les cellules cancéreuses active la voie NF-kB dans les macrophages, et mimique les effets de ΔNp63 dans la régulation de la phagocytose. L’induction de la voie NF-kB par DKK3 dans les macrophages est réalisée par l’intermédiaire de son récepteur CKAP4. Enfin, nos analyses suggèrent que ∆Np63 régule l’expression de facteurs impliqués dans l’inflammasome, ainsi que celles d’autres cytokines comme TNFRSF11B, CCL26, CCL11, TIMP1 et TIMP2. L’ensemble de nos résultats montrent que ΔNp63 joue un rôle original dans le pronostic des patients HPV+ à travers la régulation de molécules sécrétées, impliquées dans le recrutement et l’activation de cellules immunitairesHPV+ oropharyngeal tumors display both prognostic and molecular heterogeneity. Patients prognosis can be distinguished by the presence or absence of a molecular signature that depends on the ΔNp63 transcription factor. We demonstrated that ΔNp63 inhibits the migratory and invasive capabilities of HPV+ HNSCC cell lines and increases their sensitivity to platinum-based chemotherapy, implying its role in tumor progression. A functional analysis of ΔNp63 revealed its ability to stimulate the phagocytosis of cancer cells by macrophages in vitro. Consistently, a transcriptomic analysis of the same cellular model highlighted that ΔNp63 regulates the expression of secreted factors, including chemokines and interleukins, among which is the DKK3protein. Our findings indicate that DKK3 secretion by cancer cells activates the NF-κB pathway in macrophages, mimicking ΔNp63's effects on phagocytosis regulation. Induction of the NF-κB pathway by DKK3 in macrophages is mediated by its receptor CKAP4. Finally, our analyses suggest that ∆Np63 regulates the expression of factors involved in the inflammasome, as well as those of other cytokines such as TNFRSF11B, CCL26, CCL11, TIMP1 and TIMP2. Altogether, our results show that ΔNp63 plays a unique role in the prognosis of HPV+ patients by regulating secreted molecules involved in the recruitment and immune cell activation
2
Zheng, Shu-Kai, and 鄭舒凱. "Dickkopf -3 protein ( Dkk3), a novel target gene of zebrafish myf5 intronic microRNA, is involved in the myf5 expression during myogenesis." Thesis, 2007. http://ndltd.ncl.edu.tw/handle/86794154837362841582.
Abstract:
碩士臺灣大學
分子與細胞生物學研究所
95
Myf5, one of myogenesis regulatory factors (MRFs), plays roles in the specification and differentiation of muscular cells during myogenesis. The expression of myf5 is in a somite- and stage-specific manner under a fine-tuned regulation mechanism. Hoi (2006) identified an intronic motif (miR-In, +610/+632) within intron I (+502/+835, I300) of zebrafish myf5. The miR-In can inhibit myf5 expression and regulate muscle development through repressing the expression of myf5. However, the target gene of miR-In is totally unknown. In this study, we found a putative EST sequence of target gene of miR-In by using pull-down assay. Then, the full length of miR-In-putative target gene was identified by using 5’ and 3’ rapid amplification of cDNA ends. The sequence of this clone was blasted with NCBI database and found that it was similar to a Dickkopf 3 protein (dkk3) sequence, named dkk3. Whole mount in situ hybridization showed that the dkk3 transcripts appeared at somites in the 10 hpf zebrafish embryos. The signals of dkk3 at somites were progressively increased and were up to maximum at 16 hpf. But the dkk3 transcripts were gradually decreased after 16 hpf and became quite low after 24 hpf. This expression pattern of dkk3 gene was consistent with that of myf5, suggesting that dkk3 might be involved in the myf5 expression at somites. Knocking down dkk3 with morpholino oligonucleotie (MO) resulted in a down-regulation of myf5 in somites but not in presomitic mesoderm. The phenotype of dkk3-MO injected embryos was similar to the myf5 morphant. At the same time, the embryos of myf5-GFP transgenic zebrafish were injected dkk3 morphant and were observed that fluorescence of GFP was down expression in somites. Co-injection of myf5 mRNA and dkk3-MO could rescue the expression of myogenin in somites, suggesting that dkk3 might influence myf5 expression in somites. The dual-luciferase assay revealed that miR-In enabled to inhibit dkk3 expression through binding to 3’UTR target sequences of dkk3. This is the first report by using pull-down assay to find that dkk3 is a target gene of the miR-In and demonstrate that miR-In could inhibit myf5 expression through repressing dkk3 protein expression during myogenesis in zebrafish.
3
Fu, Chuan-Yang, and 傅傳揚. "Zebrafish Dickkopf-3-related gene (Dkk3a) regulates thepromoter activity of myf5 through interaction with membranereceptor Integrinα6b." Thesis, 2012. http://ndltd.ncl.edu.tw/handle/56bwx4.
Abstract:
博士國立臺灣大學
分子與細胞生物學研究所
101
Myogenic regulatory factor Myf5 plays important roles in muscle development. In zebrafish myf5, a microRNA (miR), termed miR-3906 or miR-In300, was reported to silence dickkopf-3-related gene (dkk3r or dkk3a), resulting in repressing myf5 promoter activity. However, the membrane receptor which interacts with ligand Dkk3a to control myf5 expression through signal transduction remains unknown. To address this question, we applied immunoprecipitation and LC-MS/MS mass spectrometry to screen putative membrane receptors of Dkk3a, and Integrin α6b (Itgα6b) was finally identified. To further confirm this, we employed cell-surface binding assays which showed that Dkk3a and Itgα6b co-expressed at the cell membrane of HEK-293T cells. Crosslinking immunoprecipitation data also showed high affinity of Itgα6b for Dkk3a. We further proved that the β-propeller repeated domains of Itgα6b are key segments bound by Dkk3a. Moreover, when dkk3a and itgα6b mRNAs were co-injected into embryos, luciferase activity was upregulated four-fold greater than that of control embryos. In contrast, the luciferase activities of dkk3a-knockdown embryos co-injected with itgα6b mRNA and itgα6b-knockdown embryos co-injected with dkk3a mRNA were decreased in a manner similar to control embryos, respectively. Knockdown of itgα6b resulted in abnormal somite shape, fewer somitic cells, weaker, or absent, myf5 expression, and reduced protein level of phosphorylated p38a in somites. These defective phenotypes of trunk muscular development were similar to those of dkk3a-knockdown embryos. We demonstrated that the secreted ligand Dkk3a binds to the membrane receptor Itgα6b, which increases the protein level of phosphorylated p38a and activates myf5 promoter activity of zebrafish embryos during myogenesis.
4
Su, Ying-Fang, and 蘇盈方. "Zebrafish Dickkopf-3-related gene (Dkk3r) regulates the promoter activity of myogenic regulatory factor myf5 gene through interaction with membrane receptor of Integrin alpha 6b." Thesis, 2011. http://ndltd.ncl.edu.tw/handle/59233074383649141970.
Abstract:
碩士國立臺灣大學
分子與細胞生物學研究所
99
Myf5, one of the myogenic regulatory factors, plays important roles in the specification and differentiation of muscular cells during myogenesis. In zebrafish, an intronic microRNA (miR), miR-3906, located within myf5 intron I, has been reported to silence the translation of its target gene, dickkopf-3-related (dkk3r) gene. Dkk3r, a secretory protein, regulates the phosporylation of p38a to maintain Smad4 stability, which, in turn, enabling the Smad2/Smad3a/Smad4 complex to form and to activate the myf5 promoter in nucleus. However, the membrane receptor(s) bound by Dkk3r to control signal transduction is still unknown. After recombinant zebrafish Dkk3r tagged with Flag was produced by insect cells, we applied protein immunoprecipitation and mass spectromotry to screen the putative receptors of Dkk3r. We found that Integrin alpha 6b (Itga6b) might be one of receptors to interact with Dkk3r. To further confirm this hypothesis, we used whole-mount in situ hybridization and found that the transcripts of both dkk3r and itga6b were presented in somites at 16 hpf during myogenesis. By in vitro cell surface binding assay, we also observed that Dkk3r and Itga6b were co-expressed at the cell membrane of HEK-293T, indicating that the temporal and spatial expressions of dkk3r and itga6b are co-localized. Furthermore, in vivo luciferase assay demonstrated that the luciferase activity driven by myf5 promoter was 223% and 217% greater than that of control when the excessive dkk3r and itga6b mRNAs were injected into embryos, respectively. Interestingly, when we co-injected dkk3r and itga6b mRNAs into embryos, the luciferase activity was up-regulated as high as 397% greater than that of control embryos. This up-regulation of myf5 promoter activity mediated by interaction between dkk3r and itga6b was dosage-dependent. In contrast, when dkk3r was knockdown and co-injected with itga6b mRNA, the luciferase activity was down-regulated to 69% of control embryos, suggesting that the regulatory effect of Itga6b on the downstream activity is dependent on Dkk3r signal pathway. In addition, knockdown of itga6b by injection of itga6b-morpholinos resulted in abnormal shape of somites and weak or even absent expression of myf5 in somites at 16 hpf. Furthermore, knockdown of itga6b reduced the protein level of the phosphorylated p38a. Taken together, we concluded that it is highly likely that Itga6b functions as a receptor of Dkk3r. Their interactions drive the downstream signal transduction to regulate myf5 promoter activity in somites during the development of zebrafish embryos.
Conference papers on the topic "Dickkopf-3 (DKK3)":
1
Zhou, Liran, Hongmei Husted, Todd Moore, Mason Lu, Defeng Deng, Yan Liu, Vijaya Ramachandran, et al. "Abstract 2961: Targeting stromal-derived Dickkopf-3 (DKK3) for the treatment of pancreatic ductal adenocarcinoma (PDAC)." In Proceedings: AACR Annual Meeting 2017; April 1-5, 2017; Washington, DC. American Association for Cancer Research, 2017. http://dx.doi.org/10.1158/1538-7445.am2017-2961.
2
Ueno, Koji, Hiroshi Hirata, Soichiro Yamamura, Sharanjot Saini, Shahana Majid, Peter R. Carroll, and Rajvir Dahiya. "Abstract 5002: Functional significance and mechanisms of inactivation of Secreted Wnt antagonist DICKKOPF-3 (DKK-3) gene in human renal cell carcinoma." In Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC. American Association for Cancer Research, 2010. http://dx.doi.org/10.1158/1538-7445.am10-5002.