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Journal articles on the topic 'Cell proliferation'
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M. Baghdadi, Houry. "Effect of stem cells on genetic mutations and proliferation in squamous cell carcinoma." International Journal of Academic Research 6, no. 1 (January 30, 2014): 192–97. http://dx.doi.org/10.7813/2075-4124.2014/6-1/a.25.
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Chung, Hyunju, and Seungjoon Park. "Ghrelin regulates cell cycle-related gene expression in cultured hippocampal neural stem cells." Journal of Endocrinology 230, no. 2 (August 2016): 239–50. http://dx.doi.org/10.1530/joe-16-0126.
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We have previously demonstrated that ghrelin stimulates the cellular proliferation of cultured adult rat hippocampal neural stem cells (NSCs). However, little is known about the molecular mechanisms by which ghrelin regulates cell cycle progression. The purpose of this study was to investigate the potential effects of ghrelin on cell cycle regulatory molecules in cultured hippocampal NSCs. Ghrelin treatment increased proliferation assessed by CCK-8 proliferation assay. The expression levels of proliferating cell nuclear antigen and cell division control 2, well-known cell-proliferating markers, were also increased by ghrelin. Fluorescence-activated cell sorting analysis revealed that ghrelin promoted progression of cell cycle from G0/G1 to S phase, whereas this progression was attenuated by the pretreatment with specific inhibitors of MEK/extracellular signal-regulated kinase 1/2, phosphoinositide 3-kinase/Akt, mammalian target of rapamycin, and janus kinase 2/signal transducer and activator of transcription 3. Ghrelin-induced proliferative effect was associated with increased expression of E2F1 transcription factor in the nucleus, as determined by Western blotting and immunofluorescence. We also found that ghrelin caused an increase in protein levels of positive regulators of cell cycle, such as cyclin A and cyclin-dependent kinase (CDK) 2. Moreover, p27KIP1 and p57KIP2 protein levels were reduced when cell were exposed to ghrelin, suggesting downregulation of CDK inhibitors may contribute to proliferative effect of ghrelin. Our data suggest that ghrelin targets both cell cycle positive and negative regulators to stimulate proliferation of cultured hippocampal NSCs.
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Fraser, Hamish M., Helen Wilson, Audrey Silvestri, Keith D. Morris, and Stanley J. Wiegand. "The Role of Vascular Endothelial Growth Factor and Estradiol in the Regulation of Endometrial Angiogenesis and Cell Proliferation in the Marmoset." Endocrinology 149, no. 9 (May 22, 2008): 4413–20. http://dx.doi.org/10.1210/en.2008-0325.
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The present studies explore the roles of vascular endothelial growth factor (VEGF) and estradiol on angiogenesis and stromal and epithelial cell proliferation in the marmoset endometrium during the proliferative phase of the ovulatory cycle. At the start of the proliferative phase, marmosets were 1) treated with vehicle, 2) treated with a VEGF inhibitor (VEGF Trap, aflibercept), 3) ovariectomized, 4) ovariectomized and given replacement estradiol, or 5) treated with VEGF Trap and given replacement estradiol. The uterus was examined 10 d later in the late proliferative phase. Changes in endothelial and epithelial cell proliferation were quantified using a volumetric density method after immunohistochemistry for bromodeoxyuridine to localize proliferating cells, CD31 to visualize endothelial cells, and dual staining to distinguish endothelial cell proliferation. Endothelial proliferation was elevated in late proliferative controls but virtually absent after VEGF Trap. Ovariectomy had a similar inhibitory effect, whereas angiogenesis was restored by estrogen replacement. Estradiol replacement in VEGF Trap-treated marmosets resulted in only a small increase in endothelial cell proliferation that remained significantly below control values. VEGF Trap treatment and ovariectomy also markedly reduced stromal cell proliferation but resulted in increased stromal cell density associated with a reduction in overall endometrial volume. Estrogen replacement in both ovariectomized and VEGF Trap-treated animals restored stromal proliferation rates and cell density. These results show that endometrial angiogenesis and stromal proliferation during the proliferative phase are driven by estradiol and that the effect of estrogen on angiogenesis is mediated largely by VEGF.
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Robey, H. L., P. S. Hiscott, and I. Grierson. "Cytokeratins and retinal epithelial cell behaviour." Journal of Cell Science 102, no. 2 (June 1, 1992): 329–40. http://dx.doi.org/10.1242/jcs.102.2.329.
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The expression of cytokeratins 18 and 19 by human retinal pigment epithelial cells (HRPE) has been suspected of being associated with HRPE proliferation. We have investigated the involvement of these cytokeratin subtypes in the proliferative and migratory behaviour of cultured HRPE. Cell proliferation markers (bromodeoxyuridine and proliferating cell nuclear antigen) and the cytokeratins were identified using immunohistochemical techniques. In vitro, cytokeratins 18 and 19, as detected by the monoclonal antibodies RGE 53 and K4.62, were expressed in a subset of HRPE and this subset was significantly less likely to be proliferating. Micro-chemotaxis chambers were used to study migrating cells and immunohistochemical staining for cytokeratins 18 and 19 revealed that actively migrating cells always expressed these two cytokeratins, whereas stationary cells did not label for these cytokeratin subtypes. It was apparent that cytokeratins 18 and 19 were not markers of proliferation, but were involved in the mobility of HRPE in vitro. Cytokeratins 18 and 19 may be useful indicators of simple epithelial cell migration in tissues.
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Kabraji, Sheheryar Kairas, Giorgio Gaglia, Danae Argyropoulou, Yang Dai, Shu Wang, Johann Bergholz, Shannon Coy, et al. "Temporal and spatial topography of cell proliferation in cancer." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 3122. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.3122.
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3122 Background: Tumors are complex ecosystems where exogenous and endogenous cues are integrated to either stimulate or inhibit cancer cell proliferation. However, the nature of these complex cell cycle states, their spatial organization, response to perturbation, and implications for clinical outcomes, are poorly characterized in tumor tissues. Methods: We used multiplexed tissue imaging to develop a robust classifier of proliferation, the multivariate proliferation index (MPI), using 513 unique tumors across five cancer types. Next, we used dimensionality reduction analysis to assess how the patterns of cell cycle protein expression in tumors were altered in response to perturbation. Results: The MPI outperforms single markers, like Ki67, when classifying proliferative index across diverse tumor types and reveals the proliferative architecture of tumors in situ. We find that proliferative and non-proliferative cancer cells are organized across microscopic (cell-to-cell) and macroscopic (tissue-level) scales. Both domains are reshaped by therapy, and local clusters of proliferative and non-proliferative tumor cells preferentially neighbor distinct tumor-infiltrating immune cells. We further phenotyped non-proliferating cancer cells using markers of quiescent cancer cells, cancer stem cells, and dormant cancer cells. We found that these types of non-proliferating cancer cells can occupy distinct regions within the same primary tumor. In high-dimensional marker space, populations of proliferative cancer cells express canonical patterns of cell cycle protein markers, a property we refer to as “cell cycle coherence”. Untreated tumors exist in a continuum of coherence states, ranging from optimal coherence, akin to freely cycling cells in culture, to reduced coherence characterized by either cell cycle polarization or non-canonical marker expression. Coherence can be stereotypically altered by induction and abrogation of mitogen signaling in a HER2-driven model of breast cancer. Cell cycle coherence is modulated by neoadjuvant therapy in patients with localized breast cancer, and coherence is associated with disease-free survival after adjuvant therapy in patients with colorectal cancer, mesothelioma and glioblastoma. Conclusions: The MPI robustly defines proliferating and non-proliferating cells in tissues, with immediate implications for clinical practice and research. The coherence metrics capture the diversity of post-treatment cell cycle states directly in clinical samples, a fundamental step in advancing precision medicine. More broadly, replacing binary metrics with multivariate traits provides a quantitative framework to study temporal processes from fixed static images and to investigate the rich spatial biology of human cancers.
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Chan, Ming Liang, Janka Petravic, Alexandra M. Ortiz, Jessica Engram, Mirko Paiardini, Deborah Cromer, Guido Silvestri, and Miles P. Davenport. "Limited CD4+ T cell proliferation leads to preservation of CD4+ T cell counts in SIV-infected sooty mangabeys." Proceedings of the Royal Society B: Biological Sciences 277, no. 1701 (June 30, 2010): 3773–81. http://dx.doi.org/10.1098/rspb.2010.0972.
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Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infections result in chronic virus replication and progressive depletion of CD4+ T cells, leading to immunodeficiency and death. In contrast, ‘natural hosts’ of SIV experience persistent infection with high virus replication but no severe CD4+ T cell depletion, and remain AIDS-free. One important difference between pathogenic and non-pathogenic infections is the level of activation and proliferation of CD4+ T cells. We analysed the relationship between CD4+ T cell number and proliferation in HIV, pathogenic SIV in macaques, and non-pathogenic SIV in sooty mangabeys (SMs) and mandrills. We found that CD4+ T cell proliferation was negatively correlated with CD4+ T cell number, suggesting that animals respond to the loss of CD4+ T cells by increasing the proliferation of remaining cells. However, the level of proliferation seen in pathogenic infections (SIV in rhesus macaques and HIV) was much greater than in non-pathogenic infections (SMs and mandrills). We then used a modelling approach to understand how the host proliferative response to CD4+ T cell depletion may impact the outcome of infection. This modelling demonstrates that the rapid proliferation of CD4+ T cells in humans and macaques associated with low CD4+ T cell levels can act to ‘fuel the fire’ of infection by providing more proliferating cells for infection. Natural host species, on the other hand, have limited proliferation of CD4+ T cells at low CD4+ T cell levels, which allows them to restrict the number of proliferating cells susceptible to infection.
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Tsunoda, Mikiya, Hiroyasu Aoki, Munetomo Takahashi, Haruka Shimizu, Haru Ogiwara, Shigeyuki Shichino, Kouji Matsushima, and Satoshi Ueha. "Abstract 5180: T cell receptor repertoire analysis revealed tissue tropism of tumor-reactive T-cell clones in cell cycle reporter mice." Cancer Research 83, no. 7_Supplement (April 4, 2023): 5180. http://dx.doi.org/10.1158/1538-7445.am2023-5180.
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Abstract Tumor-reactive T cells are composed of clones with various TCRs, and each clone has different in vivo kinetics. By analyzing TCR repertoire of tumor and tumor-draining lymph node (dLN), we have demonstrated that Tumor-reactive CD8+ T cells can be classified into “dLN Major”, “Tumor Major”, and “Double Major” clones, which exhibited high frequency in the dLN, tumor, or both tissues. To investigate whether this classification was related to the tissue tropism in the proliferation of each clone, we here employed tumor-bearing Fucci transgenic mice expressing a fluorescent cell-cycle indicator to identify the proliferation of T-cell clones in each tissue. We purified proliferating- and resting-CD8+ T cells from the tumors and dLN and analyzed their TCR repertoire in an LLC subcutaneous tumor model. All Tumor Major clones were proliferated in the tumor, while nearly 0% for dLN Major, indicated their different proliferative capacity in the tumor. The percentage of proliferating clones in the dLN was 20% for Tumor Major and 15% for dLN Major, indicating that these clones had equivalent proliferative capacity in the dLN. These proliferating dLN major clones overlapped more with the tumor than the non-proliferating dLN major clones, suggesting that proliferating dLN Major clones had higher tumor migration capacity. Furthermore, these proliferating dLN major clones were more proliferative in the tumor. These results suggested that dLN Major responded to antigen presentation in the dLN but not in the tumor, whereas Tumor Major responded to those in the dLN and tumor. In addition, there are two types of dLN major, “clones that are proliferating in dLN” and “clones that are not proliferating in dLN” indicating that the former may contribute to the anti-tumor response. Immune checkpoint inhibitor (ICI) treatment not only reactivates clones in the tumor but also activates tumor-reactive clones in the dLN. In conformity with these previous studies, the percentage of proliferating clones among dLN Major increased to about 50% and 80% in the dLN in mice with anti-PD-L1 and anti-CD4 treatment, respectively. This result suggests ICI treatment enhances anti-tumor responses mainly by promoting the activation and proliferation of dLN Major clones. This study shows new findings that tumor-reactive T cells differ in the tissue tropism of their proliferation of each clone. In the future, a quantitative understanding of the contribution of each class of clones to the anti-tumor response will hopefully lead to the development of new combined immunotherapies that optimize the anti-tumor T-cell response. Citation Format: Mikiya Tsunoda, Hiroyasu Aoki, Munetomo Takahashi, Haruka Shimizu, Haru Ogiwara, Shigeyuki Shichino, Kouji Matsushima, Satoshi Ueha. T cell receptor repertoire analysis revealed tissue tropism of tumor-reactive T-cell clones in cell cycle reporter mice. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5180.
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Hall, Peter A. "Cell proliferation." Journal of Pathology 165, no. 4 (December 1991): 349–54. http://dx.doi.org/10.1002/path.1711650412.
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Deniz, Özdemir. "KAN0438757: A NOVEL PFKFB3 INHIBITOR THAT INDUCES PROGRAMMED CELL DEATH AND SUPPRESSES CELL MIGRATION IN NON-SMALL CELL LUNG CARCINOMA CELLS." Biotechnologia Acta 16, no. 5 (October 31, 2023): 34–44. http://dx.doi.org/10.15407/biotech16.05.034.
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Aim. PFKFB3 is glycolytic activators that is overexpressed in human lung cancer and plays a crucial role in multiple cellular functions including programmed cell death. Despite the many small molecules described as PFKFB3 inhibitors, some of them have shown disappointing results in vitro and in vivo. On the other hand KAN0438757, selective and potent, small molecule inhibitor has been developed. However, the effects of KAN0438757, in non-small cell lung carcinoma cells remain unknown. Herein, we sought to decipher the effect of KAN0438757 on proliferation, migration, DNA damage, and programmed cell death in non-small cell lung carcinoma cells. Methods. The effects of KAN0438757 on cell viability, proliferation, DNA damage, migration, apoptosis, and autophagy in in non-small cell lung carcinoma cells was tested by WST-1, real-time cell analysis, comet assay, wound-healing migration test, and MMP/JC-1 and AO/ER dual staining assays as well as western blot analysis. Results. Our results revealed that KAN0438757 significantly suppressed the viability and proliferation of A549 and H1299 cells and inhibited migration of A549 cells. More importantly, KAN0438757 caused DNA damage and triggered apoptosis and this was accompanied by the up-regulation of cleaved PARP in A549 cells. Furthermore, treatment with KAN0438757 resulted in increased LC3 II and Beclin1, which indicated that KAN0438757 stimulated autophagy. Conclusions. Overall, targeting PFKFB3 with KAN0438757 may be a promising effective treatment approach, requiring further in vitro and in vivo evaluation of KAN0438757 as a therapy in non-small cell lung carcinoma cells.
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Levine, Richard, Magnus S. Agren, and Patricia M. Mertz. "Effect of Occlusion on Cell Proliferation during Epidermal Healing." Journal of Cutaneous Medicine and Surgery 2, no. 4 (April 1998): 193–98. http://dx.doi.org/10.1177/120347549800200403.
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Background: Occlusive dressings influence epithelization of superficial wounds by some unknown mechanism(s). Objective: The effects of occlusion on epidermal cell proliferation in two types of wounds were examined. Methods: Partial-thickness wounds and tape-stripped skin wounds were compared. An immunohistochemical technique, employing PC10 — a monoclonal antibody against proliferating cell nuclear antigen (PCNA) — was applied to formalin-fixed, paraffin-embedded porcine tissue sections. Results: The number of PC10-positive cells was low during the migratory phase, then increased to a peak of proliferation 2 to 3 days after resurfacing. An overall increased proliferative response (mean = 21%) was seen in occluded compared to control partial-thickness wounds (day 10 postoperatively); an opposite effect of occlusion on epidermal proliferation was seen in tape-stripped skin. Occlusion decreased the proliferative response (mean = 42%) compared to air-exposure. Conclusion: Occlusion increased epidermal cell proliferation in wounds (where the entire surface epithelium and papillary dermis was removed), whereas an opposite effect was seen in tape-stripped skin from which only the stratum corneum had been removed.
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Moorthy, Rajesh Kannan, Chandhru Srinivasan, Sridharan Jayamohan, Mahesh Kumar Kannan, Siva Sankari Thirugnanam, Janaki Sankar Ganesh, and Antony Joseph Velanganni Arockiam. "Knockdown of microRNA-375 suppresses cell proliferation and promotes apoptosis in human breast cancer cells." Indian Journal of Science and Technology 14, no. 43 (November 12, 2021): 3199–209. http://dx.doi.org/10.17485/ijst/v14i43.1719.
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Walter, L. M., P. A. W. Rogers, and J. E. Girling. "272. Progesterone stimulates endothelial cell proliferation, but not stromal cell proliferation, in mouse endometrium." Reproduction, Fertility and Development 17, no. 9 (2005): 112. http://dx.doi.org/10.1071/srb05abs272.
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Previous studies have suggested that progesterone stimulates stromal cell (SC) proliferation in the mouse endometrium1. However, these studies have not differentiated endothelial cells (EC) from other SC. In this study, we investigated the effects of progesterone on cellular proliferation in ovariectomised mouse endometrium. We hypothesised that progesterone would stimulate both SC and EC proliferation. One group of CBA × C57 mice (n = 6) were treated with a single injection of 100 ng of estradiol on day eight following ovariectomy, followed by a day with no treatment and three consecutive daily injections of 1 mg progesterone. Other groups were treated with either the vehicle (n = 5), estradiol (n = 4) or progesterone (n = 5) injections only. All groups were dissected on day 13 after ovariectomy, 4 h following a BrdU injection. CD31/BrdU double staining immunohistochemistry allowed proliferating EC to be differentiated from proliferating SC. Mice treated with progesterone only had significantly higher EC proliferation in comparison to females treated with progesterone following oestrogen priming (P = 0.05) or vehicle only (P = 0.01) (progesterone only: median=97.3 proliferating EC (PEC)/mm2 [range = 60.8–203.4]; oestrogen plus progesterone: 41.0 PEC/mm2 [8.9–86.9]; vehicle only: 0.0 PEC/mm2 [0.0–3.1]). Unexpectedly, there was no significant difference in SC proliferation among the treatment groups (progesterone only: 50.1 PSC/mm2 [39.2–102.6]; oestrogen plus progesterone: 46.1 PSC/mm2 [12.6–120.8]; vehicle only: 44.8 PSC/mm2 [17.3–68.4]). To determine if VEGF had a role in the progesterone-induced EC proliferation, the previous experiment was repeated with the inclusion of mice treated with VEGF anti-serum. The addition of VEGF anti-serum significantly inhibited progesterone-induced EC proliferation (46.8 PEC/mm2 [38.9–128.0]; P = 0.04], but had no effect on SC proliferation (P = 0.3). These results demonstrate that progesterone stimulates endometrial EC proliferation, but not SC proliferation as reported by earlier studies1. Studies are currently underway to further investigate the role of VEGF in mediating progesterone effects on endometrial EC. (1)Clarke, C.L. and Sutherland, R.L. (1990) Endocrine Reviews 11, 266–301.
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Lawrence, Ben, Simon Schimmack, Bernhard Svejda, Ignat Drozdov, Daniele Alaimo, Barton Kenney, Mark Kidd, and Irvin M. Modlin. "Prognostication by multigene proliferative marker panel compared with Ki-67 in small-intestinal NENs." Journal of Clinical Oncology 30, no. 4_suppl (February 1, 2012): 242. http://dx.doi.org/10.1200/jco.2012.30.4_suppl.242.
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242 Background: Ki-67 is the major proliferative marker in clinical use to determine neuroendocrine neoplasm (NEN) prognosis. Ki-67 is unable to predict the outcome of SI-NENs, as the majority have a low (≤2) Ki-67%. Therefore, we aimed to identify a sensitive panel of proliferative markers using qRT-PCR to more accurately define the proliferation of these slow growing tumors. Methods: We identified genes with a mechanistic function in cell cycle progression that were over-expressed in RNA microarrays of SI-NENs (n=8) compared to adjacent normal tissue (n=4) (dCHIP, annotation databases). Timing of marker gene expression (qRT-PCR) in proliferating cell-cycle phases (S, G2, M) was determined in flow-sorted SI-NEN cell lines (KRJ-1, H-STS) after propidium iodide staining. RNA expression of candidate proliferative markers was then investigated using an in vivo model and two independent tumor datasets, and transcript level compared to Ki-67% protein expression (immunohistochemical staining). Results: Twenty genes with a mechanistic role in proliferation were identified and 17 confirmed to be expressed in proliferating cell cycle phases. Each tumor expressed a unique profile of the 17 proliferative markers. Both Ki-67 protein and Ki-67 RNA transcript levels failed to differentiate in vivo SI-NEN models or patient samples despite variable proliferative capacity (e.g., WDNETs versus WDNECs). Although most tumors showed low levels of Ki-67 expression, the tumors expressed high levels of select alternative proliferative markers. Hierarchical clustering provided a novel and clinically meaningful prognostic classification. Conclusions: Proliferation of individual SI-NENs is regulated by unique combinations of multiple genes with a mechanistic role in cell-cycle progression. Regulation of proliferation in SI-NENs is therefore complex and cannot accurately be defined by Ki-67 as a single marker. A panel of proliferative RNA markers has potential to significantly improve prognostication in patients with SI-NENs.
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Stoeber, Kai, Thea D. Tlsty, Lisa Happerfield, Geraldine A. Thomas, Sergei Romanov, Lynda Bobrow, E. Dillwyn Williams, and Gareth H. Williams. "DNA replication licensing and human cell proliferation." Journal of Cell Science 114, no. 11 (June 1, 2001): 2027–41. http://dx.doi.org/10.1242/jcs.114.11.2027.
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The convergence point of growth regulatory pathways that control cell proliferation is the initiation of genome replication, the core of which is the assembly of pre-replicative complexes resulting in chromatin being ‘licensed’ for DNA replication in the subsequent S phase. We have analysed regulation of the pre-replicative complex proteins ORC, Cdc6, and MCM in cycling and non-proliferating quiescent, differentiated and replicative senescent human cells. Moreover, a human cell-free DNA replication system has been exploited to study the replicative capacity of nuclei and cytosolic extracts prepared from these cells. These studies demonstrate that downregulation of the Cdc6 and MCM constituents of the replication initiation pathway is a common downstream mechanism for loss of proliferative capacity in human cells. Furthermore, analysis of MCM protein expression in self-renewing, stable and permanent human tissues shows that the three classes of tissue have developed very different growth control strategies with respect to replication licensing. Notably, in breast tissue we found striking differences between the proportion of mammary acinar cells that express MCM proteins and those labelled with conventional proliferation markers, raising the intriguing possibility that progenitor cells of some tissues are held in a prolonged G1 phase or ‘in-cycle arrest’. We conclude that biomarkers for replication-licensed cells detect, in addition to actively proliferating cells, cells with growth potential, a concept that has major implications for developmental and cancer biology.
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Kurki, P., A. Laasonen, E. M. Tan, and E. Lehtonen. "Cell proliferation and expression of cytokeratin filaments in F9 embryonal carcinoma cells." Development 106, no. 4 (August 1, 1989): 635–40. http://dx.doi.org/10.1242/dev.106.4.635.
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A double immunofluorescence method was developed for the monitoring of proliferation and differentiation of F9 embryonal carcinoma cells. Cytokeratin filament expression was used as a marker for differentiation, and proliferating cell nuclear antigen (PCNA)/cyclin or bromodeoxyuridine labeling were used as markers for proliferation. F9 cells had a high proliferation rate and were cytokeratin-filament-negative. Upon treatment with retinoic acid and dibutyryl cyclic AMP, cytokeratin-filament-positive cells with differentiated phenotype appeared. After 3 days, the extent of proliferation of cytokeratin-filament-positive cells was comparable to, but after 5 days significantly lower than, that of cytokeratin-filament-negative cells in the same culture. In differentiating F9 cells, cytokeratin filament expression is associated with, and even slightly precedes, the dramatic decrease in the rate of proliferation.
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Kallak, Theodora K., and Kerstin Uvnäs-Moberg. "Oxytocin stimulates cell proliferation in vaginal cell line Vk2E6E7." Post Reproductive Health 23, no. 1 (March 2017): 6–12. http://dx.doi.org/10.1177/2053369117693148.
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Objective During and after menopause, the symptoms of vaginal atrophy cause great discomfort and necessitate effective treatment options. Currently, vaginally applied oxytocin is being investigated as a treatment for the symptoms of vaginal atrophy in postmenopausal women. To clarify the mechanisms behind oxytocins effects on vaginal atrophy, the present study investigated the effects of oxytocin on cell proliferation in the cells of the Vk2E6E7 line, a non-tumour vaginal cell line. The study also compared the effects of oxytocin with those of estradiol (E2). Study design The effects of both oxytocin and E2 on the proliferation of Vk2E6E7 cells were investigated using Cell Proliferation ELISA BrdU Colorimetric Assay. The expression of both oxytocin and oxytocin receptor was studied in Vk2E6E7 cells using quantitative real-time polymerase chain reaction and immunofluorescent staining. Main outcome measures Cell proliferation and gene expression. Results Oxytocin increased cell proliferation both time dependently and dose dependently. This differed from the effect pattern observed in cells treated with E2. In addition, in oxytocin-treated cells, the oxytocin receptor was found to be co-localized with caveolin-1, indicating pro-proliferative signalling within the cell. Conclusions Oxytocin stimulates cell proliferation and the co-localization of oxytocin receptor with caveolin-1 in oxytocin-treated cells, supporting the role of oxytocin signalling in cell proliferation. In addition, these findings suggest that increased cell proliferation is one mechanism by which local vaginal oxytocin treatment increases vaginal thickness and relieves vaginal symptoms in postmenopausal women with vaginal atrophy.
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Sakao, Seiichiro, Laimute Taraseviciene-Stewart, Kathy Wood, Carlyne D. Cool, and Norbert F. Voelkel. "Apoptosis of pulmonary microvascular endothelial cells stimulates vascular smooth muscle cell growth." American Journal of Physiology-Lung Cellular and Molecular Physiology 291, no. 3 (September 2006): L362—L368. http://dx.doi.org/10.1152/ajplung.00111.2005.
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We have previously hypothesized that the development of severe angioproliferative pulmonary hypertension is associated with not only initial endothelial cell (EC) apoptosis followed by the emergence of apoptosis-resistant proliferating EC but also with proliferation of vascular smooth muscle cells (VSMC). We have demonstrated that EC death results in the selection of an apoptosis-resistant, proliferating, and phenotypically altered EC phenotype. We postulate here that the initial apoptosis of EC induces the release of mediators that cause VSMC proliferation. We cultured EC in an artificial capillary CellMax system designed to simulate the highly efficient functions of the human capillary system. We induced apoptosis of microvascular EC using shear stress and the combined VEGF receptor (VEGFR-1 and -2) inhibitor SU-5416. Flow cytometry for the proliferation marker bromodeoxyuridine showed that serum-free medium conditioned by apoptosed EC induced proliferation of VSMC, whereas serum-free medium conditioned by nonapoptosed EC did not. We also show that medium conditioned by apoptosed EC is characterized by increased concentrations of transforming growth factor (TGF)-β1 and VEGF compared with medium conditioned by nonapoptosed EC and that TGF-β1 blockade prevented the proliferation of cultured VSMC. In conclusion, EC death induced by high shear stress and VEGFR blockade leads to the production of factors, in particular TGF-β1, that activate VSMC proliferation.
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Sambasiva Rao, M., and Janardan K. Reddy. "The Relevance of Peroxisome Proliferation and Cell Proliferation in Peroxisome Proliferator-Induced Hepatocarcinogenesis." Drug Metabolism Reviews 21, no. 1 (January 1989): 103–10. http://dx.doi.org/10.3109/03602538909029957.
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Potten, Christopher S., and Markus Loeffler. "Epidermal cell proliferation." Virchows Archiv B Cell Pathology Including Molecular Pathology 53, no. 1 (December 1987): 279–85. http://dx.doi.org/10.1007/bf02890254.
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Loeffler, M., C. S. Potten, and H. E. Wichmann. "Epidermal cell proliferation." Virchows Archiv B Cell Pathology Including Molecular Pathology 53, no. 1 (December 1987): 286–300. http://dx.doi.org/10.1007/bf02890255.
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Yuko, Murase, Fesseha Meseret, Abbaspour Nazanin, and Young Hong Mee. "Watermelon Powder Supplementation Reduces Colonic Cell Proliferation by Upregulating p21Waf1/Cip1 Expression." Current Developments in Nutrition 4, Supplement_2 (May 29, 2020): 340. http://dx.doi.org/10.1093/cdn/nzaa044_039.
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Abstract Objectives Watermelon is high in L-citrulline, a precursor for L-arginine, which in turn may reduce the risk of colorectal cancer (CRC). Research has shown that L-arginine inhibits the hyperproliferation of colorectal tumor cells as a marker for CRC. The objective of this study was, therefore, to examine the effects of watermelon powder supplementation on colonic cell proliferation and their gene expression. The hypothesis was that watermelon powder supplementation would reduce CRC risk by regulating colonic expression of genes related to epithelial cell proliferation. Methods Thirty-two 21-day-old, male, Sprague Dawley rats were randomly assigned to one of the following isocaloric diets: 0.5% watermelon powder, 0.36% L-arginine, and control for 9 weeks. All animals were injected with azoxymethane (15 mg/kg body weight). Colonic cell proliferation was measured using ki-67 immunohistochemistry, and colonic gene expression was determined using a quantitative real-time polymerase chain reaction (PCR). Results Both watermelon powder and L-arginine groups exhibited lower proliferating index (P = 0.041) and lower proliferative zone (P = 0.041). In addition, watermelon powder and L-arginine supplementation upregulated p21Waf1/Cip1 gene expression (P = 0.048). There were no significant differences in the expression of Cyclin D1, Cyclin-dependent kinase 2 (CDK2), Cyclin-dependent kinase 4 (CDK4), and Peroxisome proliferator-activated receptor γ (PPARγ). Conclusions These results suggest that watermelon or L-arginine supplementation may decrease the risk of CRC as they both reduced proliferation by upregulating a cyclin-dependent kinase inhibitor. Additional markers for gene expression involving cell proliferation are needed to confirm the present findings. Funding Sources National Watermelon Promotion Board (NWPB 15–16) National Cancer Institutes of Health (U54CA132384 for SDSU and U54132379 for UCSD).
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Zhang, Feixiong, Tiam Feridooni, Adam Hotchkiss, and Kishore B. S. Pasumarthi. "Divergent cell cycle kinetics of midgestation ventricular cells entail a higher engraftment efficiency after cell transplantation." American Journal of Physiology-Cell Physiology 308, no. 3 (February 1, 2015): C220—C228. http://dx.doi.org/10.1152/ajpcell.00319.2014.
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Cardiac progenitor cells (CPCs) in the primary and secondary heart fields contribute to the formation of all major cell types in the mammalian heart. While some CPCs remain undifferentiated in midgestation and postnatal hearts, very little is known about their proliferation and differentiation potential. In this study, using an Nkx2.5 cell lineage-restricted reporter mouse model, we provide evidence that Nkx2.5+ CPCs and cardiomyocytes can be readily distinguished from nonmyocyte population using a combination of Nkx2.5 and sarcomeric myosin staining of dispersed ventricular cell preparations. Assessment of cell number and G1/S transit rates during ventricular development indicates that the proliferative capacity of Nkx2.5+ cell lineage gradually decreases despite a progressive increase in Nkx2.5+ cell number. Notably, midgestation ventricles (E11.5) contain a larger number of CPCs (∼2-fold) compared with E14.5 ventricles, and the embryonic CPCs retain cardiomyogenic differentiation potential. The proliferation rates are consistently higher in embryonic CPCs compared with myocyte population in both E11.5 and E14.5 ventricles. Results from two independent cell transplantation models revealed that E11.5 ventricular cells with a higher percentage of proliferating CPCs can form larger grafts compared with E14.5 ventricular cells. Furthermore, transplantation of embryonic ventricular cells did not cause any undesirable side effects such as arrhythmias. These data underscore the benefits of donor cell developmental staging in myocardial repair.
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Schmidt, T., and C. N. David. "Gland cells in Hydra: cell cycle kinetics and development." Journal of Cell Science 85, no. 1 (September 1, 1986): 197–215. http://dx.doi.org/10.1242/jcs.85.1.197.
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The proliferative capacity of gland cells in Hydra attenuata was investigated. The results indicate that both gland cell proliferation and interstitial cell differentiation to gland cells contribute to the maintenance of the whole population. On the basis of [3H]thymidine incorporation and nuclear DNA measurements, gland cells consist of at least three different populations. One population consists of rapidly proliferating cells with a cell cycle of about 72 h. These cells are distributed throughout the body column. In the lower gastric region there is a population of non-cycling cells in G2 while in the upper gastric region there is a population of non-cycling cells in G1. About half the G1 population becomes a new antigen, SEC 1, which is typical of mucus cells.
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Pabla, Sarabjot, Jason Zhu, Matthew Labriola, Rajan Gupta, Daniel J. George, Shannon McCall, Edwin Yau, et al. "Cell proliferation as a biomarker for response to immune checkpoint inhibitors in highly inflamed renal cell carcinoma." Journal of Clinical Oncology 37, no. 8_suppl (March 10, 2019): 61. http://dx.doi.org/10.1200/jco.2019.37.8_suppl.61.
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61 Background: Cell proliferation is an important marker of survival in many tumors and we hypothesized that this attribute could be related to response to immune checkpoint inhibitors in RCC. Previously we reported (SITC 2018) moderately proliferative lung cancer has a much higher response rate than either poorly or highly proliferative tumors. Methods: 69 FFPE tumor samples of RCC were evaluated by RNA-seq to measure transcript levels of 394 immune related genes, including 10 related to cell proliferation (BUB1, CCNB2, CDK1, CDKN3, FOXM1, KIAA0101, MAD2L1, MELK, MKI67, TOP2A). Cell proliferation, defined as the mean mRNA expression of these 10 genes was evaluated for association with ORR to ICIs by RECIST v1.1 criteria for both PD-L1 IHC positive and negative cases. Cell proliferation for each case was split into 3 tertiles of poorly ( < 33), moderately (33-66) and highly ( > 66) proliferative compared to a reference population. Poorly and highly proliferative were grouped for comparison to moderately proliferative tumors. Tumors were inflamed or non-inflamed based upon RNA‐seq analysis of CD8 compared to a reference population of more than 500 cases of multiple tumors. Non-inflamed, or immune desert tumors, defined as the lower 25th percentile of rank for CD8+ T-cells, and greater than 75th percentile of rank as inflamed. Results: In our cohort of 69 patient the overall ORR was 18.8%. 15.9% of tumors were non-inflamed with an ORR of 9.1%. For 36.2% inflamed tumor the ORR was 32%. For cell proliferation 62.2% were poorly proliferative, 8.7% were highly proliferative, and 29% were moderately. ORR in moderately proliferative tumors was 30% versus 14.2% in poorly/highly proliferative tumors. In inflamed tumors, ORR in moderately proliferative tumors was 37.5% as opposed to 17.6% in poorly/highly proliferative tumors. In 11 non-inflamed tumors, there was only one responder, which was a poorly/highly proliferative tumor. Conclusions: Cell proliferation may play a crucial role in distinguishing RCC patients who may have a clinical benefit to ICI, including the important subgroup of inflamed tumors. Moderately proliferative tumors have a higher ORR than their poorly/highly counterparts.
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Zhu, Su-Ning, Mian Chen, Jenny Jongstra-Bilen, and Myron I. Cybulsky. "GM-CSF regulates intimal cell proliferation in nascent atherosclerotic lesions." Journal of Experimental Medicine 206, no. 10 (September 14, 2009): 2141–49. http://dx.doi.org/10.1084/jem.20090866.
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The contribution of intimal cell proliferation to the formation of early atherosclerotic lesions is poorly understood. We combined 5-bromo-2′-deoxyuridine pulse labeling with sensitive en face immunoconfocal microscopy analysis, and quantified intimal cell proliferation and Ly-6Chigh monocyte recruitment in low density lipoprotein receptor–null mice. Cell proliferation begins in nascent lesions preferentially at their periphery, and proliferating cells accumulate in lesions over time. Although intimal cell proliferation increases in parallel to monocyte recruitment as lesions grow, proliferation continues when monocyte recruitment is inhibited. The majority of proliferating intimal cells are dendritic cells expressing CD11c and major histocompatibility complex class II and 33D1, but not CD11b. Systemic injection of granulocyte/macrophage colony-stimulating factor (GM-CSF) markedly increased cell proliferation in early lesions, whereas function-blocking anti–GM-CSF antibody inhibited proliferation. These findings establish GM-CSF as a key regulator of intimal cell proliferation in lesions, and demonstrate that both proliferation and monocyte recruitment contribute to the inception of atherosclerosis.
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Lozano-Velasco, Estefanía, Daniel Vallejo, Francisco J. Esteban, Chris Doherty, Francisco Hernández-Torres, Diego Franco, and Amelia Eva Aránega. "APitx2-MicroRNA Pathway Modulates Cell Proliferation in Myoblasts and Skeletal-Muscle Satellite Cells and Promotes Their Commitment to a Myogenic Cell Fate." Molecular and Cellular Biology 35, no. 17 (June 8, 2015): 2892–909. http://dx.doi.org/10.1128/mcb.00536-15.
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The acquisition of a proliferating-cell status from a quiescent state as well as the shift between proliferation and differentiation are key developmental steps in skeletal-muscle stem cells (satellite cells) to provide proper muscle regeneration. However, how satellite cell proliferation is regulated is not fully understood. Here, we report that the c-isoform of the transcription factor Pitx2 increases cell proliferation in myoblasts by downregulating microRNA 15b (miR-15b), miR-23b, miR-106b, and miR-503. ThisPitx2c-microRNA (miRNA) pathway also regulates cell proliferation in early-activated satellite cells, enhancing Myf5+satellite cells and thereby promoting their commitment to a myogenic cell fate. This study reveals unknown functions of several miRNAs in myoblast and satellite cell behavior and thus may have future applications in regenerative medicine.
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Fontaine, Romain, Eirill Ager-Wick, Kjetil Hodne, and Finn-Arne Weltzien. "Plasticity of Lh cells caused by cell proliferation and recruitment of existing cells." Journal of Endocrinology 240, no. 2 (February 2019): 361–77. http://dx.doi.org/10.1530/joe-18-0412.
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Luteinizing hormone (Lh) and follicle-stimulating hormone (Fsh) control reproduction in vertebrates. Using a transgenic line of medaka, in which green fluorescent protein expression is controlled by the endogenous lhb promotor, we studied development and plasticity of Lh cells, comparing juveniles and adults of both genders. Confocal imaging and 3D reconstruction revealed hypertrophy and hyperplasia of Lh cells in both genders from juvenile to adult stages. We show that Lh cell hyperplasia may be caused by recruitment of existing pituitary cells that start to produce lhb, as evidenced by time lapse recordings of primary pituitary cell cultures, and/or through Lh cell proliferation, demonstrated through a combination of 5-bromo-2′-deoxyuridine incubation experiments and proliferating cell nuclear antigen staining. Proliferating Lh cells do not belong to the classical type of multipotent stem cells, as they do not stain with anti-sox2. Estradiol exposure in vivo increased pituitary cell proliferation, particularly Lh cells, whereas pituitary lhb and gpa expression levels decreased. RNA-seq and in situ hybridization showed that Lh cells express two estrogen receptors, esr1 and esr2b, and the aromatase gene cyp19a1b, suggesting a direct effect of estradiol, and possibly androgens, on Lh cell proliferation. In conclusion, our study reveals a high degree of plasticity in the medaka Lh cell population, resulting from a combination of recruitment and cell proliferation.
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Collesi, Chiara, Lorena Zentilin, Gianfranco Sinagra, and Mauro Giacca. "Notch1 signaling stimulates proliferation of immature cardiomyocytes." Journal of Cell Biology 183, no. 1 (September 29, 2008): 117–28. http://dx.doi.org/10.1083/jcb.200806091.
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The identification of the molecular mechanisms controlling cardiomyocyte proliferation during the embryonic, fetal, and early neonatal life appears of paramount interest in regard to exploiting this information to promote cardiac regeneration. Here, we show that the proliferative potential of neonatal rat cardiomyocytes is powerfully stimulated by the sustained activation of the Notch pathway. We found that Notch1 is expressed in proliferating ventricular immature cardiac myocytes (ICMs) both in vitro and in vivo, and that the number of Notch1-positive cells in the heart declines with age. Notch1 expression in ICMs paralleled the expression of its Jagged1 ligand on non-myocyte supporting cells. The inhibition of Notch signaling in ICMs blocked their proliferation and induced apoptosis; in contrast, its activation by Jagged1 or by the constitutive expression of its activated form using an adeno-associated virus markedly stimulated proliferative signaling and promoted ICM expansion. Maintenance or reactivation of Notch signaling in cardiac myocytes might represent an interesting target for innovative regenerative therapy.
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Berman, J. E., and S. Zolla-Pazner. "Control of B cell proliferation: inhibition of responses to B cell mitogens induced by plasma cell tumors." Journal of Immunology 134, no. 5 (May 1, 1985): 2872–78. http://dx.doi.org/10.4049/jimmunol.134.5.2872.
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Abstract A multitude of factors has been described that positively and negatively regulate B cell proliferation. A model system for the study of negative control of B cell function is provided by mice bearing plasmacytomas (PC-mice). In PC-mice, the primary immune response, as measured by development of antibody-forming cells (AFC), is severely suppressed. The present report specifically identifies a block in B cell proliferation as the apparent cause of this reduction in AFC production. Thus, the proliferative response of B cells from the spleens of PC-mice (PC-spleens) was significantly impaired when stimulated with four different B cell mitogens (lipopolysaccharide, Salmonella typhimurium mitogen, anti-mu conjugated to Sepharose, and 8-mercaptoguanosine). Nevertheless, the mitogen-responsiveness of these B cells was recovered when they were segregated by various methods from macrophages. These data suggest that the proliferative ability of the B cells in PC-spleens is inherently normal. In concordance with this conclusion, it was shown that suppressor cells from PC-spleens can block the proliferation of normal B cells derived from nontumor-bearing mice. This inhibition does not require direct cell contact and is mediated via soluble factors. The relevance of these results to previous studies of PC-induced immunosuppression and to the control of normal B cell proliferation is discussed.
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Bilodeau, Steve, Audrey Roussel-Gervais, and Jacques Drouin. "Distinct Developmental Roles of Cell Cycle Inhibitors p57Kip2 and p27Kip1 Distinguish Pituitary Progenitor Cell Cycle Exit from Cell Cycle Reentry of Differentiated Cells." Molecular and Cellular Biology 29, no. 7 (January 12, 2009): 1895–908. http://dx.doi.org/10.1128/mcb.01885-08.
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ABSTRACT Patterning and differentiation signals are often believed to drive the developmental program, including cell cycle exit of proliferating progenitors. Taking advantage of the spatial and temporal separation of proliferating and differentiated cells within the developing anterior pituitary gland, we investigated the control of cell proliferation during organogenesis. Thus, we identified a population of noncycling precursors that are uniquely marked by expression of the cell cycle inhibitor p57Kip2 and by cyclin E. In p57Kip2−/− mice, the developing pituitary is hyperplastic due to accumulation of proliferating progenitors, whereas overexpression of p57Kip2 leads to hypoplasia. p57Kip2-dependent cell cycle exit is not required for differentiation, and conversely, blockade of cell differentiation, as achieved in Tpit−/− pituitaries, does not prevent cell cycle exit but rather leads to accumulation of p57Kip2-positive precursors. Upon differentiation, p57Kip2 is replaced by p27Kip1. Accordingly, proliferating differentiated cells are readily detected in p27Kip1−/− pituitaries but not in wild-type or p57Kip2−/− pituitaries. Strikingly, all cells of p57Kip2−/−;p27Kip1−/− pituitaries are proliferative. Thus, during normal development, progenitor cell cycle exit is controlled by p57Kip2 followed by p27Kip1 in differentiated cells; these sequential actions, taken together with different pituitary outcomes of their loss of function, suggest hierarchical controls of the cell cycle that are independent of differentiation.
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Hultsch, T., R. Martin, and R. J. Hohman. "The effect of the immunophilin ligands rapamycin and FK506 on proliferation of mast cells and other hematopoietic cell lines." Molecular Biology of the Cell 3, no. 9 (September 1992): 981–87. http://dx.doi.org/10.1091/mbc.3.9.981.
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The immunosuppressive drugs FK506 and cyclosporin A have an identical spectrum of activities with respect to IgE receptor (Fc epsilon RI)-mediated exocytosis from mast cells and T cell receptor-mediated transcription of IL-2. These findings suggest a common step in receptor-mediated signal transduction leading to exocytosis and transcription and imply that immunosuppressive drugs target specific signal transduction pathways, rather than specific cell types. This hypothesis is supported by studies on the effect of rapamycin on IL-3 dependent proliferation of the rodent mast cell line PT18. Rapamycin inhibits proliferation of PT18 cells, achieving a plateau of 80% inhibition at 1 nM. This inhibition is prevented in a competitive manner by FK506, a structural analogue of rapamycin. Proliferation of rat basophilic leukemia cells and WEHI-3 cells was also inhibited, at doses comparable to those shown previously to inhibit IL-2-dependent proliferation of cytotoxic T lymphocyte line (CTLL) cells. In contrast, proliferation of A-431 cells, a epidermoid cell line, was not affected by rapamycin. DNA histograms indicate that complexes formed between the rapamycin-FK506-binding protein (FKBP) and rapamycin arrest-proliferating PT18 cells in the G0/G1-phase. It is concluded that FKBP-rapamycin complexes may inhibit proliferative signals emanating from IL-3 receptors, resulting in growth arrest of cytokine-dependent, hematopoietic cells.
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Kumar, Kunal, Rana P. Singh, and Jai PN Mishra. "Usnic Acid Inhibits Cell Proliferation Via Downregulation Of PCNA Expression In Gastric Carcinoma AGS Cells." Indian Journal of Pharmaceutical and Biological Research 7, no. 3 (September 25, 2019): 01–04. http://dx.doi.org/10.30750/ijpbr.7.3.1.
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Usnic acid is a secondary metabolite obtained from various species of lichen. Previous studies have shown various biological activities of usnic acid, such as anti-oxidant, anti-microbial, anti-viral, anti-protozoal, anti-inflammatory, and anti-proliferative activities in different models. Its anti-proliferative activities in gastric cancer cells are still unexplored. Herein, we have investigated the effects of usnic acid on cell proliferation and viability and associated molecular alterations in human gastric carcinoma AGS cells. The treatment of usnic acid (2.5-25μM) dose-dependently reduced cell proliferation. The mRNA expression of tumor suppressor gene phosphatase tensin homolog (PTEN)in the usnic acid-treated AGS cells was increased, which may play a role in the inhibition of cell proliferation and induction of cell death. We also observed a decrease in the expression of PCNA that regulates cell proliferation by playing an important role in DNA replication. The expression of cyclin-dependent kinase inhibitor p21, which may play a role in cell cycle and proliferation inhibition was found uninfluenced with usnic acid treatment. Thus, collectively these results revealed that usnic acid inhibits the cell proliferation of AGS cells through downregulating the expression of PCNA and can be further evaluated in vivo models for its therapeutic potentials.
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Burton, G. F., D. H. Conrad, A. K. Szakal, and J. G. Tew. "Follicular dendritic cells and B cell costimulation." Journal of Immunology 150, no. 1 (January 1, 1993): 31–38. http://dx.doi.org/10.4049/jimmunol.150.1.31.
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Abstract Ag-bearing follicular dendritic cells (FDC) are found throughout secondary lymphoid tissues in close association with rapidly proliferating germinal center B lymphocytes. We reasoned that FDC might provide costimulatory signals that would enhance the ability of Ag to stimulate B cell proliferation in the germinal centers. To test this, FDC were cultured with B cells activated by a slg-dependent (goat anti-mouse mu conjugated to dextran (anti-mu-dex)) or -independent (LPS) pathway and their proliferation was measured by using [3H]thymidine incorporation. The addition of FDC markedly augmented B cell proliferation in a dose-dependent fashion. Depletion of FDC from cultures abrogated the increased proliferation. Addition of highly purified FDC obtained from cell sorting resulted in B cell costimulation, whereas addition of other sorted cells was without effect. The FDC accessory activity was apparent over the entire culture period and over a wide range of either polyclonal B cell activator. When B cells and activators were cultured in the absence of FDC, only about one fourth of the cells remained viable after 3 days. In contrast, virtually all cells in cultures containing FDC, B cells, and activator were viable. Cultures containing FDC and B cells from nude mice proliferated normally in the presence of anti-mu-dex plus rIL-4, implying that IL-4 provides adequate T cell help in this system. The costimulatory activity of the FDC could not replace either the anti-mu-dex or IL-4 in this system and was not MHC restricted. These data support the concept that FDC not only provide Ag but also facilitate B cell proliferation by means of other costimulatory interactions that contribute to make the microenvironment in the germinal center favorable for B cells to proliferate.
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Perri, RT. "Impaired expression of cell surface receptors for B cell growth factor by chronic lymphocytic leukemia B cells." Blood 67, no. 4 (April 1, 1986): 943–48. http://dx.doi.org/10.1182/blood.v67.4.943.943.
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Abstract Normal human B cell proliferation is controlled by various immunoregulatory signals including the T cell-derived lymphokine B cell growth factor (BCGF). The role of BCGF in the regulation of malignant B cell proliferation is unclear. Therefore, we studied the proliferative response of purified chronic lymphocytic leukemia (CLL) B cells to BCGF. For all CLL patients studied, CLL B cells showed a decreased proliferative response as compared with control B cells for BCGF- induced B cell proliferation (patient 291 +/- 59 cpm v control 3,942 +/- 622, mean +/- SEM). This impaired proliferative response appeared to be intrinsic to CLL B cells since it was not corrected by incubation with increasing concentrations of BCGF. Attainment of normal B cell responsiveness to BCGF requires the processing of an initial activation signal which results in the expression of cell surface receptors for BCGF. Increasing concentrations of the B cell activation signal (the F(ab')2 fragment of goat anti-human mu chain) did not improve CLL B cell responsiveness to BCGF. Three-day activated CLL B cells compared with activated control B cells demonstrated a marked impairment in their ability to absorb out the BCGF activity present in the BCGF preparation (BCGF activity absorbed out, patient 12.8% v control 53%). Pretreatment of CLL B cells with neuraminidase failed to improve either the proliferative response to BCGF or the expression of cell surface receptors for BCGF by the CLL B cells. This study suggests that the impaired responsiveness to BCGF by CLL B cells is the result of impaired expression of cell surface receptors for BCGF when CLL B cells are exposed to activation signals.
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Perri, RT. "Impaired expression of cell surface receptors for B cell growth factor by chronic lymphocytic leukemia B cells." Blood 67, no. 4 (April 1, 1986): 943–48. http://dx.doi.org/10.1182/blood.v67.4.943.bloodjournal674943.
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Normal human B cell proliferation is controlled by various immunoregulatory signals including the T cell-derived lymphokine B cell growth factor (BCGF). The role of BCGF in the regulation of malignant B cell proliferation is unclear. Therefore, we studied the proliferative response of purified chronic lymphocytic leukemia (CLL) B cells to BCGF. For all CLL patients studied, CLL B cells showed a decreased proliferative response as compared with control B cells for BCGF- induced B cell proliferation (patient 291 +/- 59 cpm v control 3,942 +/- 622, mean +/- SEM). This impaired proliferative response appeared to be intrinsic to CLL B cells since it was not corrected by incubation with increasing concentrations of BCGF. Attainment of normal B cell responsiveness to BCGF requires the processing of an initial activation signal which results in the expression of cell surface receptors for BCGF. Increasing concentrations of the B cell activation signal (the F(ab')2 fragment of goat anti-human mu chain) did not improve CLL B cell responsiveness to BCGF. Three-day activated CLL B cells compared with activated control B cells demonstrated a marked impairment in their ability to absorb out the BCGF activity present in the BCGF preparation (BCGF activity absorbed out, patient 12.8% v control 53%). Pretreatment of CLL B cells with neuraminidase failed to improve either the proliferative response to BCGF or the expression of cell surface receptors for BCGF by the CLL B cells. This study suggests that the impaired responsiveness to BCGF by CLL B cells is the result of impaired expression of cell surface receptors for BCGF when CLL B cells are exposed to activation signals.
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Xing, Yiding, Shobha H. Ganji, Jung W. Noh, and Vaijinath S. Kamanna. "Cell density-dependent expression of EDG family receptors and mesangial cell proliferation: role in lysophosphatidic acid-mediated cell growth." American Journal of Physiology-Renal Physiology 287, no. 6 (December 2004): F1250—F1257. http://dx.doi.org/10.1152/ajprenal.00342.2003.
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Lysophosphatidic acid (LPA), a major member of the bioactive lysophospholipids in serum, possesses diverse physiological activities including cell proliferation. Recently, three endothelial differentiation gene (EDG) family receptors, including EDG-2 (LPA1), EDG-4 (LPA2), and EDG-7 (LPA3), have been identified as LPA receptors. The role of LPA and their receptors in mesangial cell physiology is not clearly understood. This study examined the expression profile of EDG receptors as a function of cell density and the participation of EDG receptors in human mesangial cell proliferation by LPA. We showed that mesangial cells express all three EDG family LPA receptors in a cell density-dependent manner. EDG-7 maximally expressed at sparse cell density and minimally expressed in dense cell population. The EDG-2 expression pattern was opposite to the EDG-7. No changes in EDG-4 expression as a function of cell density were noted. DNA synthetic rate was greater in sparse cell density compared with dense cell population and followed a similar pattern with EDG-7 expression. Comparative studies in sparse and dense cell density indicated that EDG-7 was positively associated, whereas EDG-2 was negatively associated with cell proliferation rate. LPA induced mesangial cell proliferation by 1.5- to 3.5-fold. Dioctanoylglycerol pyrophosphate, an antagonist for EDG-7, almost completely inhibited mesangial cell proliferation induced by LPA. We suggest that EDG-7 regulates LPA-mediated mesangial cell proliferation. Additionally, these data suggest that EDG-7 and EDG-2 LPA receptors play a diverse role as proliferative and antiproliferative, respectively, in mesangial cells. Regulation of EDG family receptors may be importantly linked to mesangial cell-proliferative processes.
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Nadasdy, T., Z. Laszik, K. E. Blick, L. D. Johnson, and F. G. Silva. "Proliferative activity of intrinsic cell populations in the normal human kidney." Journal of the American Society of Nephrology 4, no. 12 (June 1994): 2032–39. http://dx.doi.org/10.1681/asn.v4122032.
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The proliferative activity of various normal human renal cell populations is unknown. Recently, antibodies to cell proliferation-associated nuclear proteins, such as proliferating cell nuclear antigen (PCNA) and KI-67, which are applicable to archival paraffin sections, became available. With antibodies to PCNA and Ki-67 after microwave pretreatment of the paraffin sections, the proliferation indexes (ratio of positive nuclei with PCNA and Ki-67 antibodies/all nuclei counted x 100, i.e. percentage of positive cells) of 12 different intrinsic renal cell populations in 20 normal human kidneys have been determined. The following proliferation indexes (percentages of positive cells) were found with the PCNA and the Ki-67 antibodies, respectively: proximal tubular epithelium, 0.22, 0.24; thin limb of Henle, 0.29, 0.30; thick ascending limb of Henle, 0.32, 0.29; distal tubular epithelium (distal convoluted tubules and cortical collecting ducts, 0.33, 0.44; medullary collecting ducts, 0.32, 0.3; glomerular mesangial cells, 0.07, 0.12; glomerular visceral epithelial cells, 0.04, 0.08; glomerular parietal epithelial cells, 0.07, 0.1; glomerular capillary endothelium, 0.42, 0.47; peritubular capillary endothelial cells, 0.38, 0.43; endothelium of large intrarenal vessels (arteries and veins), 0.09, 0.12. Thus, normally capillary endothelium (glomerular and peritubular) appears to have the highest proliferation index in the human kidney by these techniques. These results indicate major variation in the proliferative activity of normal human renal cell populations, along with a significant correlation between PCNA and Ki-67 staining. Furthermore, this study provides normal values for the proliferative activity of different human renal cell populations.(ABSTRACT TRUNCATED AT 250 WORDS)
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Passegue, Emmanuelle, Amy J. Wagers, Sylvie Giuriato, Wade C. Anderson, and Irving L. Weissman. "Cell Cycle Regulation and Cell Fate Decisions in Hematopoietic Stem Cells." Blood 106, no. 11 (November 16, 2005): 1349. http://dx.doi.org/10.1182/blood.v106.11.1349.1349.
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Abstract The blood is a perpetually renewing tissue seeded by a rare population of adult bone marrow hematopoietic stem cells (HSC). During steady-state hematopoiesis, the HSC population is relatively quiescent but constantly maintains a low numbers of cycling cells that differentiate to produce the various lineage of mature blood cells. However, in response to hematological stress, the entire HSC population can be recruited into cycle to self-renew and regenerate the blood-forming system. HSC proliferation is therefore highly adaptative and requires appropriate regulation of cell cycle progression to drive both differentiation-associated and self-renewal-associated proliferation, without depletion of the stem cell pool. Although the molecular events controlling HSC proliferation are still poorly understood, they are likely determined, at least in part, by regulated expression and/or function of components and regulators of the cell cycle machinery. Here, we demonstrate that the long-term self-renewing HSC (defined as Lin−/c-Kit+/Sca-1+/Thy1.1int/Flk2−) exists in two distinct states that are both equally important for their in vivo functions as stem cells: a numerically dominant quiescent state, which is critical for HSC function in hematopoietic reconstitution; and a proliferative state, which represents almost a fourth of this population and is essential for HSC functions in differentiation and self-renewal. We show that when HSC exit quiescence and enter G1 as a prelude to cell division, at least two critical events occur: first, during the G1 and subsequent S-G2/M phases, they temporarily lose efficient in vivo engraftment activity, while retaining in vitro differentiation potential; and second, they select the particular cell cycle proteins that are associated with specific developmental outcomes (self-renewal vs. differentiation) and developmental fates (myeloid vs. lymphoid). Together, these findings provide a direct link between HSC proliferation, cell cycle regulation and cell fate decisions that have critical implications for both the therapeutic use of HSC and the understanding of leukemic transformation.
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Wadham, C., J. R. Gamble, M. A. Vadas, and Y. Khew-Goodall. "Translocation of protein tyrosine phosphatase Pez/PTPD2/PTP36 to the nucleus is associated with induction of cell proliferation." Journal of Cell Science 113, no. 17 (September 1, 2000): 3117–23. http://dx.doi.org/10.1242/jcs.113.17.3117.
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Pez is a non-transmembrane tyrosine phosphatase with homology to the FERM (4.1, ezrin, radixin, moesin) family of proteins. The subcellular localisation of Pez in endothelial cells was found to be regulated by cell density and serum concentration. In confluent monolayers Pez was cytoplasmic, but in cells cultured at low density Pez was nuclear, suggesting that it is a nuclear protein in proliferating cells. This notion is supported by the loss of nuclear Pez when cells are serum-starved to induce quiescence, and the rapid return of Pez to the nucleus upon refeeding with serum to induce proliferation. Vascular endothelial cells normally exist as a quiescent confluent monolayer but become proliferative during angiogenesis or upon vascular injury. Using a ‘wound’ assay to mimic these events in vitro, Pez was found to be nuclear in the cells that had migrated and were proliferative at the ‘wound’ edge. TGFbeta, which inhibits cell proliferation but not migration, inhibited the translocation of Pez to the nucleus in the cells at the ‘wound’ edge, further strengthening the argument that Pez plays a role in the nucleus during cell proliferation. Together, the data presented indicate that Pez is a nuclear tyrosine phosphatase that may play a role in cell proliferation.
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Z, Ding. "Concentration Polarization of Ox-LDL and Its Effect on Cell Proliferation and Apoptosis in Human Endothelial Cells." Journal of Cardiology and Cardiovascular Medicine 1, no. 1 (2016): 011–18. http://dx.doi.org/10.29328/journal.jccm.1001003.
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Hernández-Núñez, Ismael, Ana Quelle-Regaldie, Laura Sánchez, Fátima Adrio, Eva Candal, and Antón Barreiro-Iglesias. "Decline in Constitutive Proliferative Activity in the Zebrafish Retina with Ageing." International Journal of Molecular Sciences 22, no. 21 (October 28, 2021): 11715. http://dx.doi.org/10.3390/ijms222111715.
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It is largely assumed that the teleost retina shows continuous and active proliferative and neurogenic activity throughout life. However, when delving into the teleost literature, one finds that assumptions about a highly active and continuous proliferation in the adult retina are based on studies in which proliferation was not quantified in a comparative way at the different life stages or was mainly studied in juveniles/young adults. Here, we performed a systematic and comparative study of the constitutive proliferative activity of the retina from early developing (2 days post-fertilisation) to aged (up to 3–4 years post-fertilisation) zebrafish. The mitotic activity and cell cycle progression were analysed by using immunofluorescence against pH3 and PCNA, respectively. We observed a decline in the cell proliferation in the retina with ageing despite the occurrence of a wave of secondary proliferation during sexual maturation. During this wave of secondary proliferation, the distribution of proliferating and mitotic cells changes from the inner to the outer nuclear layer in the central retina. Importantly, in aged zebrafish, there is a virtual disappearance of mitotic activity. Our results showing a decline in the proliferative activity of the zebrafish retina with ageing are of crucial importance since it is generally assumed that the fish retina has continuous proliferative activity throughout life.
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Green, S. E., P. Chapman, J. Burn, A. D. Burt, M. Bennett, D. R. Appleton, J. S. Varma, and J. C. Mathers. "Colonic epithelial cell proliferation in hereditary non-polyposis colorectal cancer." Gut 43, no. 1 (July 1, 1998): 85–92. http://dx.doi.org/10.1136/gut.43.1.85.
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Background—Despite the recent discovery of four genes responsible for up to 90% of all cases of hereditary non-polyposis colorectal cancer (HNPCC), there will still be families in whom predictive testing is not possible. A phenotypic biomarker would therefore be useful. An upwards shift of the proliferative compartment in colonic crypts is reported to be one of the earliest changes in premalignant mucosa.Aims—To assess the role of crypt cell proliferation as a phenotypic biomarker in HNPCC.Patients—Thirty five patients at 50% risk of carrying the HNPCC gene (21 of whom subsequently underwent predictive testing and hence gene carrier status was known) and 18 controls.Methods—Crypt cell proliferation was measured at five sites in the colon using two different techniques. Labelling index was determined using the monoclonal antibody MIB1 and whole crypt mitotic index was measured using the microdissection and crypt squash technique. The distribution of proliferating cells within the crypts was also assessed.Results—There were no significant differences in the total labelling index or mean number of mitoses per crypt, nor in the distribution of proliferating cells within the crypt, between the study and control groups at any site. When the 21 patients in whom gene carrier status was known were analysed separately there were no significant differences in the measured indices of proliferation between the HNPCC gene carriers and non-gene carriers.Conclusion—Crypt cell proliferation is not a discriminative marker of gene carriage in HNPCC.
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Lee, Junho. "Ghrelin stimulates cell proliferation in T cells (109.22)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 109.22. http://dx.doi.org/10.4049/jimmunol.186.supp.109.22.
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Abstract Ghrelin is a 28 amino acid acylated peptide, which is produced and secreted by X/A-like enteroendocrine cells of the stomach. We have recently demonstrated that ghrelin is expressed by various immune cells including T- and B-lymphocytes, monocytes and neutrophils. These immune cells have also been shown to express the ghrelin receptor, namely the growth hormone secretagogue receptor (GHS-R). In the present study, we have investigated the effects of ghrelin on T cell proliferation and its signaling through its cell surface receptor. We have found that ghrelin induces a modest increase in the proliferation of murine CD4+ T cells and T-cell lines. Western blot experiments have demonstrated that GHS-R ligation activates the external receptor activated kinases (ERK1/2) and Akt signaling pathways in a dose-dependent fashion. Moreover, we have also revealed the involvement of the PKC pathway in the phosphorylation of ERK1/2. The pro-proliferative effects of ghrelin through ERK1/2 appears to be mediated through the regulation of the expression of cell cycle proteins, cyclin D1, CDK4, cyclin E and CDK2 as well as Rb. Together, these data suggest that ghrelin promotes the cell proliferation of T cell via the activation of the PKC, PI-3-K, Akt and Erk1/2 signaling pathways and that this GHS-R signal appears to be essential but not sufficient for cell cycle progression.
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Murad, Kari L., Edmund J. Gosselin, John W. Eaton, and Mark D. Scott. "Stealth Cells: Prevention of Major Histocompatibility Complex Class II-Mediated T-Cell Activation by Cell Surface Modification." Blood 94, no. 6 (September 15, 1999): 2135–41. http://dx.doi.org/10.1182/blood.v94.6.2135.
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Abstract Transfusion or transplantation of T lymphocytes into an allogeneic recipient can evoke potent immune responses including, in immunocompromised patients, graft-versus-host disease (GVHD). As our previous studies demonstrated attenuated immunorecognition of red blood cells covalently modified with methoxy(polyethylene glycol) (mPEG), we hypothesized that T-cell activation by foreign antigens might similarly be prevented by mPEG modification. Mixed lymphocyte reactions (MLR) using peripheral blood mononuclear cells (PBMC) from HLA class II disparate donors demonstrate that mPEG modification of PBMC effectively inhibits T-cell proliferation (measured by 3H-thymidine incorporation) in a dose-dependent manner. Even slight derivatization (0.4 mmol/L mPEG per 4 × 106 cells) resulted in a ≥75% decrease, while higher concentrations caused ≥96% decrease in proliferation. Loss of PBMC proliferation was not due to either mPEG-induced cytotoxicity, as viability was normal, or cellular anergy, as phytohemagglutinin (PHA)-stimulated mPEG-PBMC demonstrated normal proliferative responses. Addition of exogenous interleukin (IL)-2 also had no proliferative effect, suggesting that the mPEG-modified T cells were not antigen primed. Flow cytometric analysis demonstrates that mPEG-modification dramatically decreases antibody recognition of multiple molecules involved in essential cell:cell interactions, including both T-cell molecules (CD2, CD3, CD4, CD8, CD28, CD11a, CD62L) and antigen-presenting cell (APC) molecules (CD80, CD58, CD62L) likely preventing the initial adhesion and costimulatory events necessary for immune recognition and response.
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Murad, Kari L., Edmund J. Gosselin, John W. Eaton, and Mark D. Scott. "Stealth Cells: Prevention of Major Histocompatibility Complex Class II-Mediated T-Cell Activation by Cell Surface Modification." Blood 94, no. 6 (September 15, 1999): 2135–41. http://dx.doi.org/10.1182/blood.v94.6.2135.418k08_2135_2141.
Full textAbstract:
Transfusion or transplantation of T lymphocytes into an allogeneic recipient can evoke potent immune responses including, in immunocompromised patients, graft-versus-host disease (GVHD). As our previous studies demonstrated attenuated immunorecognition of red blood cells covalently modified with methoxy(polyethylene glycol) (mPEG), we hypothesized that T-cell activation by foreign antigens might similarly be prevented by mPEG modification. Mixed lymphocyte reactions (MLR) using peripheral blood mononuclear cells (PBMC) from HLA class II disparate donors demonstrate that mPEG modification of PBMC effectively inhibits T-cell proliferation (measured by 3H-thymidine incorporation) in a dose-dependent manner. Even slight derivatization (0.4 mmol/L mPEG per 4 × 106 cells) resulted in a ≥75% decrease, while higher concentrations caused ≥96% decrease in proliferation. Loss of PBMC proliferation was not due to either mPEG-induced cytotoxicity, as viability was normal, or cellular anergy, as phytohemagglutinin (PHA)-stimulated mPEG-PBMC demonstrated normal proliferative responses. Addition of exogenous interleukin (IL)-2 also had no proliferative effect, suggesting that the mPEG-modified T cells were not antigen primed. Flow cytometric analysis demonstrates that mPEG-modification dramatically decreases antibody recognition of multiple molecules involved in essential cell:cell interactions, including both T-cell molecules (CD2, CD3, CD4, CD8, CD28, CD11a, CD62L) and antigen-presenting cell (APC) molecules (CD80, CD58, CD62L) likely preventing the initial adhesion and costimulatory events necessary for immune recognition and response.
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Marinos, Rebecca S., Wei Zhang, Guoyao Wu, Katherine A. Kelly, and Cynthia J. Meininger. "Tetrahydrobiopterin levels regulate endothelial cell proliferation." American Journal of Physiology-Heart and Circulatory Physiology 281, no. 2 (August 1, 2001): H482—H489. http://dx.doi.org/10.1152/ajpheart.2001.281.2.h482.
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Vascular abnormalities, including altered angiogenesis, are major factors contributing to the morbidity and mortality of diabetes. We hypothesized that impaired angiogenesis in diabetes results from decreased tetrahydrobiopterin (BH4)-dependent synthesis of nitric oxide (NO) by endothelial cells (EC). To test this hypothesis, we utilized EC from spontaneously diabetic BB (BBd) and nondiabetes-prone BB (BBn) rats to investigate the link between BH4 and EC proliferation. There were significant decreases in the proliferation rate and expression of proliferating cell nuclear antigen in BBd versus BBn EC, with no evidence of apoptosis in either group. Sepiapterin (a precursor of BH4 via the salvage pathway) increased BH4 synthesis and enhanced proliferation of BBd EC. The stimulating effect of sepiapterin on EC proliferation was attenuated by N G-monomethyl-l-arginine, a NO synthase inhibitor. Reducing BH4 concentrations in BBn EC caused a decrease in proliferation, which was attenuated by a long-acting NO donor. Our results suggest that BH4 levels regulate proliferation of normal EC and that a BH4deficiency impairs NO-dependent proliferation of BBd EC.
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Molochkova, Yu V., A. N. Khlebnikova, V. A. Molochkov, L. E. Gurevich, and A. V. Molochkov. "Comparative study of Ki67 protein expression in oral lichen planus and leukoplakia." Vestnik dermatologii i venerologii 94, no. 4 (December 7, 2018): 15–20. http://dx.doi.org/10.25208/0042-4609-2018-94-4-15-20.
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Oral lichen planus (OLP) is included in the category of potentially malignant diseases. Benign processes are differentiated from malignant ones by the nature of cell proliferative activity. The aim of the present study was the comparative study of proliferative activity in OLP and leuk oplakia cells, as well as the cells of oral squamous cell carcinoma.Materials and methods. Biopsy specimens from 16 patients with OPL, 13 with leukoplakia, and 7 with oral squamous cell carcinoma were investigated. Immunohistochemical studies were performed using Ki67 monoclonal antibodies.Results. The average Ki67 index in OPL cells was 9.3 ± 2.3 %. Proliferating cells were located exclusively in the basal epidermis layer. In leukoplakia cells, the average Ki67 index was 20.5 ± 6.1 %; the proliferating cells were located in the basal layer and lower parts of the spinous (suprabasal) layer of the epidermis. In squamous cell carcinoma, the average Ki67 index was 57.4 ± 2.04 %. Proliferating cells were located diffusely over all cell complexes from the lower to the highest layers of the epidermis. Differences in the proliferation level were significant for the leukoplakia/OPL pair (p = 0.003) and squamous cell carcinoma/OPL pair (p < 0.001), while for squamous cell carcinoma/leukoplakia pair the difference was not significant (p = 0.211).Conclusion. The differences in the proliferation level and in the nature of the proliferating cell distributionin through the epidermis can be applied in the differential diagnosis of OPL and leuk oplakia.
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Yoshimura, A., K. Inui, T. Nemoto, S. Uda, Y. Sugenoya, S. Watanabe, N. Yokota, T. Taira, S. Iwasaki, and T. Ideura. "Simvastatin suppresses glomerular cell proliferation and macrophage infiltration in rats with mesangial proliferative nephritis." Journal of the American Society of Nephrology 9, no. 11 (November 1998): 2027–39. http://dx.doi.org/10.1681/asn.v9112027.
Full textAbstract:
Inhibition of 3-hydro-3-methylglutaryl coenzyme A reductase inhibits the production of mevalonate and has been shown to suppress proliferation in many cell types. Therefore, 3-hydro-3-methylglutaryl coenzyme A reductase inhibitors may have a beneficial effect in glomerular disease, because glomerular cell proliferation is a central feature in the active glomerular injury. This study examines the effect of simvastatin on glomerular pathology in a rat mesangial proliferative glomerulonephritis (GN) induced by anti-thymocyte antibody (anti-Thy 1.1 GN). There was no difference in the degree of the antibody and complement-mediated initial injuries between simvastatin-treated and control GN rats. The most pronounced feature of simvastatin-treated GN was the suppression of the early glomerular cell proliferation. The proliferative activity was maximal at day 4 after disease induction (26.5+/-7.0 of proliferating cell nuclear antigen-positive cells/glomerulus); however, approximately 70% of proliferation was suppressed by simvastatin treatment. At day 4 after disease induction, simvastatin administration also decreased alpha-smooth muscle actin expression in the glomerulus, which is a marker for mesangial cell activation. Inhibition of monocyte/macrophage recruitment into glomeruli by simvastatin was also a prominent feature. There was a 30% decrease in the number of glomerular ED-1+ cells by simvastatin treatment at day 2 after disease induction. Furthermore, simvastatin remarkably suppressed subsequent mesangial matrix expansion and type IV collagen accumulation in glomeruli. We also found that the platelet-derived growth factor expression was reduced in simvastatin-treated nephritic rats, which might simply reflect the reduction in mesangial cell proliferation and mesangial cellularity. There was no significant difference in plasma cholesterol or triglyceride levels between simvastatin- and vehicle-treated nephritic rats at day 2 and day 4, which corresponded to the times when simvastatin treatment resulted in a reduction in mesangial cell proliferation. In conclusion, this is the first report to find that mesangial cell proliferation and matrix expansion have been blocked by simvastatin in vivo. The protective effect of simvastatin in the matrix expansion in anti-Thy1.1 GN was partly by inhibition of mesangial cell proliferation and monocyte/ macrophage recruitment into glomeruli, which were independent of a change in circulating lipids.
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Franceschi, Claudio. "Cell proliferation, cell death and aging." Aging Clinical and Experimental Research 1, no. 1 (September 1989): 3–15. http://dx.doi.org/10.1007/bf03323871.
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Metz, Ethan P., Phillip J. Wilder, Tessa M. Popay, Jing Wang, Qi Liu, Achyuth Kalluchi, M. Jordan Rowley, William P. Tansey, and Angie Rizzino. "Elevating SOX2 Downregulates MYC through a SOX2:MYC Signaling Axis and Induces a Slowly Cycling Proliferative State in Human Tumor Cells." Cancers 14, no. 8 (April 12, 2022): 1946. http://dx.doi.org/10.3390/cancers14081946.
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Slowly cycling/infrequently proliferating tumor cells present a clinical challenge due to their ability to evade treatment. Previous studies established that high levels of SOX2 in both fetal and tumor cells restrict cell proliferation and induce a slowly cycling state. However, the mechanisms through which elevated SOX2 levels inhibit tumor cell proliferation have not been identified. To identify common mechanisms through which SOX2 elevation restricts tumor cell proliferation, we initially performed RNA-seq using two diverse tumor cell types. SOX2 elevation in both cell types downregulated MYC target genes. Consistent with these findings, elevating SOX2 in five cell lines representing three different human cancer types decreased MYC expression. Importantly, the expression of a dominant-negative MYC variant, omomyc, recapitulated many of the effects of SOX2 on proliferation, cell cycle, gene expression, and biosynthetic activity. We also demonstrated that rescuing MYC activity in the context of elevated SOX2 induces cell death, indicating that the downregulation of MYC is a critical mechanistic step necessary to maintain survival in the slowly cycling state induced by elevated SOX2. Altogether, our findings uncover a novel SOX2:MYC signaling axis and provide important insights into the molecular mechanisms through which SOX2 elevation induces a slowly cycling proliferative state.