scholarly journals Involvement of the STAT5-cyclin D/CDK4-pRb pathway in β-cell proliferation stimulated by prolactin during pregnancy

2019 ◽  
Vol 316 (1) ◽  
pp. E135-E144 ◽  
Author(s):  
Xin Zhao ◽  
Yili Xu ◽  
Ya Wu ◽  
Hui Zhang ◽  
Houxia Shi ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Cycle Progression ◽  
Cell Mass ◽  
Cyclin D ◽  
Β Cell ◽  
Cycle Progression ◽  
Rb Phosphorylation ◽  
Insulinoma Cells

During pregnancy, maternal pancreatic β-cells undergo a compensatory expansion in response to the state of insulin resistance, where prolactin (PRL) plays a major role. Retinoblastoma protein (Rb) has been shown to critically regulate islet proliferation and function. The aim of the study was to explore the role of Rb in β-cell mass expansion during pregnancy. Expression of pocket protein family and E2Fs were examined in mouse islets during pregnancy and in insulinoma cells (INS-1) stimulated by PRL. PRL-stimulated INS-1 cells were used to explore the signaling pathway that regulates Rb downstream of the PRL receptor. Pancreas-specific Rb-knockout (Rb-KO) mice were assessed to evaluate the in vivo function of Rb in β-cell proliferation during pregnancy. During pregnancy, expression of Rb, phospho-Rb (p-Rb), p107, and E2F1 increased, while p130 decreased in maternal islets. With PRL stimulation, induction of Rb expression occurred mainly in the nucleus, while p-Rb was predominantly in the cytoplasm. Inhibition of STAT5 significantly restrained the expression of CDK4, Rb, p-Rb, and E2F1 in PRL-stimulated INS-1 cells with attenuation in cell cycle progression. Reduction of Rb phosphorylation by CDK4 inhibition blocked PRL-mediated proliferation of INS-1 cells. On the other hand, knockdown of Rb using siRNA led to an induction in E2F1 leading to cell cycle progression from G1 to S and G2/M phase, similar to the effects of PRL-mediated induction of p-Rb that led to cell proliferation. With Rb knockdown, PRL did not lead to further increase in cell cycle progression. Similarly, while Rb-KO pregnant mice displayed better glucose tolerance and higher insulin secretion, they had similar β-cell mass and proliferation to wild-type pregnant controls, supporting the essential role of Rb suppression in augmenting β-cell proliferation during pregnancy. Rb-E2F1 regulation plays a pivotal role in PRL-stimulated β-cell proliferation. PRL promotes Rb phosphorylation and E2F1 upregulation via STAT5-cyclin D/CDK4 pathway during pregnancy.

scholarly journals Role of AKT/mTORC1 pathway in pancreatic β-cell proliferation

2012 ◽  
pp. 235-243 ◽  
Author(s):  
Norman Balcazar Morales ◽  
Cecilia Aguilar de Plata
Keyword(s):  
Cell Cycle ◽  
Growth Factors ◽  
Cell Cycle Progression ◽  
Cell Mass ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Cycle Progression ◽  
Mtorc1 Signaling

Growth factors, insulin signaling and nutrients are important regulators of β-cell mass and function. The events linking these signals to regulation of β-cell mass are not completely understood. Recent findings indicate that mTOR pathway integrates signals from growth factors and nutrients with transcription, translation, cell size, cytoskeleton remodeling and mitochondrial metabolism. mTOR is a part of two distinct complexes; mTORC1 and mTORC2. The mammalian TORC1 is sensitive to rapamycin and contains Raptor, deptor, PRAS40 and the G protein β-subunit-like protein (GβL). mTORC1 activates key regulators of protein translation; ribosomal S6 kinase (S6K) and eukaryote initiation factor 4E-binding protein 1. This review summarizes current findings about the role of AKT/mTORC1 signaling in regulation of pancreatic β cell mass and proliferation. mTORC1 is a major regulator of β-cell cycle progression by modulation of cyclins D2, D3 and cdk4/cyclin D activity. These studies uncovered key novel pathways controlling cell cycle progression in β-cells in vivo. This information can be used to develop alternative approaches to expand β-cell mass in vivo and in vitro without the risk of oncogenic transformation. The acquisition of such knowledge is critical for the design of improved therapeutic strategies for the treatment and cure of diabetes as well as to understand the effects of mTOR inhibitors in β-cell function.

scholarly journals A Non-Cell-Autonomous Role of BEC-1/BECN1/Beclin1 in Coordinating Cell-Cycle Progression and Stem Cell Proliferation during Germline Development

2017 ◽  
Vol 27 (6) ◽  
pp. 905-913 ◽  
Author(s):  
Kristina Ames ◽  
Dayse S. Da Cunha ◽  
Brenda Gonzalez ◽  
Marina Konta ◽  
Feng Lin ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Stem Cell ◽  
Cell Cycle Progression ◽  
Germline Development ◽  
Cycle Progression ◽  
Stem Cell Proliferation

Effects of Aqueous Extract of Sophora flavescens on the Expression of Cell Cycle Regulatory Proteins in Human Oral Mucosal Fibroblasts

2003 ◽  
Vol 31 (04) ◽  
pp. 563-572 ◽  
Author(s):  
Hyun-A Kim ◽  
Hyung-Keun You ◽  
Hyung-Shik Shin ◽  
Youn-Chul Kim ◽  
Tai-Hyun Kang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Cycle Progression ◽  
Cyclin E ◽  
Regulatory Proteins ◽  
Cyclin D ◽  
Sophora Flavescens ◽  
Cycle Progression ◽  
Cell Cycle Regulatory Proteins ◽  
Cycle Regulation

Sophorae Radix, the dried roots of Sophora flavescens AITON (Leguminosae), has been used in Oriental traditional medicine for treatment of skin and mucosal ulcers, sores, gastrointestinal hemorrhage, diarrhea, inflammation and arrhythmia. In the present study, we examine the effect of the aqueous extract of Sophorae Radix (AESR) on cell proliferation and cell cycle regulation in human oral mucosal fibroblasts (HOMFs). To study the molecular mechanisms of cell cycle regulation by AESR, we also measured the intracellular levels of cell cycle regulatory proteins such as cyclin D, cyclin-dependent kinases (CDK)-4, CDK-6, cyclin E, CDK-2, p53, p21WAF1/CIP1 and p16INK4 . Cell proliferation was increased in the presence of 10~500 μg/ml of AESR. Maximal growth stimulation was observed in those cells exposed to 100 μg/ml of AESR. Exposure of HOMFs to 100 μg/ml of AESR resulted in an increase of cell cycle progression. The levels of cyclin E and CDK-2 were increased in HOMFs after 100 μg/ml of AESR treatment, but the levels of cyclin D, CDK-4, and CDK-6 were unchanged. After exposure to 100 μg/ml of AESR, the protein levels of p16INK4A and p53 were decreased as compared to that of the control group, but the level of p21WAF1/CIP1 was similar in the cells treated with 100 μg/ml of AESR and untreated cells. The results suggest that AESR may increase cell proliferation and cell cycle progression in HOMFs, which is linked to increased cellular levels of cyclin E and CDK-2 and decreased cellular levels of p53 and p16INK4A . Further studies are necessary to clarify the active constituents of AESR responsible for such biomolecular activities.

scholarly journals Disruption of the Pelota Gene Causes Early Embryonic Lethality and Defects in Cell Cycle Progression

2003 ◽  
Vol 23 (4) ◽  
pp. 1470-1476 ◽  
Author(s):  
Ibrahim M. Adham ◽  
Mahmoud A. Sallam ◽  
Gerd Steding ◽  
Monika Korabiowska ◽  
Ulrich Brinck ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Inner Cell Mass ◽  
Cell Mass ◽  
Homologous Gene ◽  
Mouse Development ◽  
Cycle Progression ◽  
Early Embryonic Lethality ◽  
Cellular Dna

ABSTRACT Mutations in either the Drosophila melanogaster pelota or pelo gene or the Saccharomyces cerevisiae homologous gene, DOM34, cause defects of spermatogenesis and oogenesis in Drosophila, and delay of growth and failure of sporulation in yeast. These phenotypes suggest that pelota is required for normal progression of the mitotic and meiotic cell cycle. To determine the role of the pelota in mouse development and progression of cell cycle, we have established a targeted disruption of the mouse Pelo. Heterozygous animals are variable and fertile. Genotyping of the progeny of heterozygous intercrosses shows the absence of Pelo −/− pups and suggests an embryo-lethal phenotype. Histological analyses reveal that the homozygous Pelo deficient embryos fail to develop past day 7.5 of embryogenesis (E7.5). The failure of mitotic active inner cell mass of the Pelo −/− blastocysts to expand in growth after 4 days in culture and the survival of mitotic inactive trophoplast indicate that the lethality of Pelo-null embryos is due to defects in cell proliferation. Analysis of the cellular DNA content reveals the significant increase of aneuploid cells in Pelo −/− embryos at E7.5. Therefore, the percent increase of aneuploid cells at E7.5 may be directly responsible for the arrested development and suggests that Pelo is required for the maintenance of genomic stability.

On the role of TRPC1 in control of Ca2+ influx, cell volume, and cell cycle

2012 ◽  
Vol 303 (6) ◽  
pp. C625-C634 ◽  
Author(s):  
C. P. Madsen ◽  
T. K. Klausen ◽  
A. Fabian ◽  
B. J. Hansen ◽  
S. F. Pedersen ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Volume ◽  
Volume Regulation ◽  
Cell Cycle Progression ◽  
Regulatory Volume Decrease ◽  
Cell Volume Regulation ◽  
S Phase ◽  
Cycle Progression

Ca+ signaling plays a crucial role in control of cell cycle progression, but the understanding of the dynamics of Ca2+ influx and release of Ca2+ from intracellular stores during the cell cycle is far from complete. The aim of the present study was to investigate the role of the free extracellular Ca2+ concentration ([Ca2+]o) in cell proliferation, the pattern of changes in the free intracellular Ca2+ concentration ([Ca2+]i) during cell cycle progression, and the role of the transient receptor potential (TRP)C1 in these changes as well as in cell cycle progression and cell volume regulation. In Ehrlich Lettré Ascites (ELA) cells, [Ca2+]i decreased significantly, and the thapsigargin-releasable Ca2+ pool in the intracellular stores increased in G1 as compared with G0. Store-depletion-operated Ca2+ entry (SOCE) and TRPC1 protein expression level were both higher in G1 than in G0 and S phase, in parallel with a more effective volume regulation after swelling [regulatory volume decrease (RVD)] in G1 as compared with S phase. Furthermore, reduction of [Ca2+]o, as well as two unspecific SOCE inhibitors, 2-APB (2-aminoethyldiphenyl borinate) and SKF96365 (1-(β-[3-(4-methoxy-phenyl)propoxyl-4-methoxyphenethyl)1H-imidazole-hydrochloride), inhibited ELA cell proliferation. Finally, Madin-Darby canine kidney cells in which TRPC1 was stably silenced [TRPC1 knockdown (TRPC1-KD) MDCK] exhibited reduced SOCE, slower RVD, and reduced cell proliferation compared with mock controls. In conclusion, in ELA cells, SOCE and TRPC1 both seem to be upregulated in G1 as compared with S phase, concomitant with an increased rate of RVD. Furthermore, TRPC1-KD MDCK cells exhibit decreased SOCE, decreased RVD, and decreased proliferation, suggesting that, at least in certain cell types, TRPC1 is regulated during cell cycle progression and is involved in SOCE, RVD, and cell proliferation.

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