scholarly journals Decreased IRS Signaling Impairs β-Cell Cycle Progression and Survival in Transgenic Mice Overexpressing S6K in β-Cells

Diabetes ◽  
2010 ◽  
Vol 59 (10) ◽  
pp. 2390-2399 ◽  
Author(s):  
Lynda Elghazi ◽  
Norman Balcazar ◽  
Manuel Blandino-Rosano ◽  
Corentin Cras-Méneur ◽  
Szabolcs Fatrai ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Transgenic Mice ◽  
Cell Cycle Progression ◽  
Β Cells ◽  
Β Cell ◽  
Cycle Progression

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 Three-dimensional analysis of β-cell proliferation by a novel mouse model

2019 ◽  
Author(s):  
Shinsuke Tokumoto ◽  
Daisuke Yabe ◽  
Hisato Tatsuoka ◽  
Ryota Usui ◽  
Muhammad Fauzi ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Cycle Progression ◽  
Three Dimensional ◽  
Spatiotemporal Analysis ◽  
Mouse Line ◽  
Β Cells ◽  
Β Cell ◽  
Insulin Promoter ◽  
Novel Method

SummaryInducing β-cell proliferation could inhibit diabetes progression. Many factors have been suggested as potential β-cell mitogens, but their impact on β-cell replication has not been confirmed due to the lack of a standardized β-cell proliferation assay. In this study, we developed a novel method that specifically labels replicating β cells and yields more reproducible results than current immunohistochemical assays. We established a mouse line expressing the fluorescent ubiquitination-based cell cycle indicator (Fucci2a) reporter only in β cells through Cre-mediated recombination under the control of the rat insulin promoter (RIP-Cre;Fucci2aR). Three-dimensional imaging of optically cleared pancreas tissue from these mice enabled the quantification of replicating β cells in islets and morphometric analysis of islets following mitogen treatment. Intravital imaging of RIP-Cre;Fucci2aR mice revealed cell cycle progression of β cells. Thus, this novel mouse line is a powerful tool for spatiotemporal analysis of β-cell proliferation in response to mitogen stimulation.

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 Molecular Control of Cell Cycle Progression in the Pancreatic β-Cell

2006 ◽  
Vol 27 (4) ◽  
pp. 356-370 ◽  
Author(s):  
Irene Cozar-Castellano ◽  
Nathalie Fiaschi-Taesch ◽  
Todd A. Bigatel ◽  
Karen K. Takane ◽  
Adolfo Garcia-Ocaña ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Cycle Progression ◽  
Molecular Control

scholarly journals The Murine Gammaherpesvirus 68 v-Cyclin Gene Is an Oncogene That Promotes Cell Cycle Progression in Primary Lymphocytes

1999 ◽  
Vol 73 (6) ◽  
pp. 5110-5122 ◽  
Author(s):  
Linda F. van Dyk ◽  
Jay L. Hess ◽  
Jonathan D. Katz ◽  
Meagan Jacoby ◽  
Samuel H. Speck ◽  
...  
Keyword(s):  
Cell Cycle ◽  
T Cell ◽  
Transgenic Mice ◽  
Cell Cycle Progression ◽  
Proximal Promoter ◽  
Cycle Progression ◽  
Murine Gammaherpesvirus ◽  
Cyclin Gene ◽  
Gammaherpesvirus 68 ◽  
Murine Gammaherpesvirus 68

ABSTRACT Several gammaherpesviruses contain open reading frames encoding proteins homologous to mammalian D-type cyclins. In this study, we analyzed the expression and function of the murine gammaherpesvirus 68 (γHV68) viral cyclin (v-cyclin). The γHV68 v-cyclin gene was expressed in lytically infected fibroblasts as a leaky-late mRNA of approximately 0.9 kb encoding a protein of approximately 25 kDa. To evaluate the effect of the γHV68 v-cyclin on cell cycle progression in primary lymphocytes and to determine if the γHV68 v-cyclin gene is an oncogene, we generated transgenic mice by using the lckproximal promoter to express the γHV68 v-cyclin in early T cells. Expression of the γHV68 v-cyclin significantly increased the number of thymocytes in cell culture, as determined by measuring both DNA content and incorporation of 5-bromo-2-deoxyuridine following in vivo pulse-labeling. Expression of the γHV68 v-cyclin interfered with normal thymocyte maturation, as shown by increased numbers of CD4+ CD8+ double-positive thymocytes and decreased numbers of CD4+ or CD8+single-positive and T-cell-receptor-bright thymocytes and splenocytes in transgenic mice. Despite increased numbers of cycling thymocytes, γHV68–v-cyclin–transgenic mice did not have proportionately increased thymocyte numbers, and staining by terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling demonstrated increased apoptosis in the thymi of v-cyclin-transgenic mice. Fifteen of 38 γHV68–v-cyclin–transgenic mice developed high-grade lymphoblastic lymphoma between 3 and 12 months of age. We conclude that (i) the γHV68 v-cyclin is expressed as a leaky-late gene in lytically infected cells, (ii) expression of the γHV68 v-cyclin in thymocytes promotes cell cycle progression and inhibits normal T-cell differentiation, and (iii) the γHV68 v-cyclin gene is an oncogene.

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