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 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 The Drosophila F-box protein dSkp2 regulates cell proliferation by targeting Dacapo for degradation

2013 ◽  
Vol 24 (11) ◽  
pp. 1676-1687 ◽  
Author(s):  
Wen Dui ◽  
Bin Wei ◽  
Feng He ◽  
Wei Lu ◽  
Changqing Li ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Functional Relationship ◽  
Kinase Inhibitors ◽  
Cycle Progression ◽  
Cell Doubling Time ◽  
F Box Protein ◽  
Negative Factors

Cell cycle progression is controlled by a complex regulatory network consisting of interacting positive and negative factors. In humans, the positive regulator Skp2, an F-box protein, has been a subject of intense investigation in part because of its oncogenic activity. By contrast, the molecular and developmental functions of its Drosophila homologue, dSkp2, are poorly understood. Here we investigate the role of dSkp2 by focusing on its functional relationship with Dacapo (Dap), the Drosophila homologue of the cyclin-dependent kinase inhibitors p21cip1/p27kip1/p57kip2. We show that dSkp2 interacts physically with Dap and has a role in targeting Dap for ubiquitination and proteasome-mediated degradation. We present evidence that dSkp2 regulates cell cycle progression by antagonizing Dap in vivo. dSkp2 knockdown reduces cell density in the wing by prolonging the cell doubling time. In addition, the wing phenotype caused by dSkp2 knockdown resembles that caused by dap overexpression and can be partially suppressed by reducing the gene dose of dap. Our study thus documents a conserved functional relationship between dSkp2 and Dap in their control of cell cycle progression, suggesting the possibility of using Drosophila as a model system to study Skp2-mediated tumorigenesis.

scholarly journals CUL4B promotes replication licensing by up-regulating the CDK2–CDC6 cascade

2013 ◽  
Vol 200 (6) ◽  
pp. 743-756 ◽  
Author(s):  
Yongxin Zou ◽  
Jun Mi ◽  
Wenxing Wang ◽  
Juanjuan Lu ◽  
Wei Zhao ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Positive Regulation ◽  
Cycle Progression ◽  
Developmental Abnormalities ◽  
Replication Complex ◽  
Cellular Processes ◽  
Cell Cycle Reentry

Cullin-RING ubiquitin ligases (CRLs) participate in the regulation of diverse cellular processes including cell cycle progression. Mutations in the X-linked CUL4B, a member of the cullin family, cause mental retardation and other developmental abnormalities in humans. Cells that are deficient in CUL4B are severely selected against in vivo in heterozygotes. Here we report a role of CUL4B in the regulation of replication licensing. Strikingly, CDC6, the licensing factor in replication, was positively regulated by CUL4B and contributed to the loading of MCM2 to chromatin. The positive regulation of CDC6 by CUL4B depends on CDK2, which phosphorylates CDC6, protecting it from APCCDH1-mediated degradation. Thus, aside being required for cell cycle reentry from quiescence, CDK2 also contributes to pre-replication complex assembly in G1 phase of cycling cells. Interestingly, the up-regulation of CDK2 by CUL4B is achieved via the repression of miR-372 and miR-373, which target CDK2. Our findings thus establish a CUL4B–CDK2–CDC6 cascade in the regulation of DNA replication licensing.

Cdkn3 Knockout Mice Develop Hematopoietic Malignancies

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1537-1537 ◽  
Author(s):  
Zejin Sun ◽  
Donna Cerabona ◽  
Ying He ◽  
Grzegorz Nalepa
Keyword(s):  
Cell Cycle ◽  
Tumor Suppressor ◽  
Cell Cycle Progression ◽  
Conditional Knockout ◽  
Cycle Progression ◽  
Mitotic Kinase ◽  
Risk Of Death

Abstract Cyclin dependent kinase inhibitor 3 (CDKN3) is a dual-specificity cell cycle regulatory phosphatase. In interphase, CDKN3 prevents premature G1/S transition by dephosphorylating interphase cyclin-dependent kinases (CDKs) to prevent premature inactivation of the RB pathway. During cell division, CDKN3 dephosphorylates the key mitotic kinase CDK1 at threonine-161 to extinguish CDK1 activity at the exit from mitosis. CDKN3 knockdown in cultured cells impairs the spindle assembly checkpoint (SAC), accelerates cell cycle progression and causes chromosomal instability, suggesting that it may function as a tumor suppressor. However, since CDKN3 has been reported as overexpressed in some malignancies and mutated or silenced in others, it is unclear whether it functions as an oncogene or a tumor suppressor. To understand the in vivo role of CDKN3 in carcinogenesis, we generated the first Cdkn3 conditional knockout mouse model. We found that Cdkn3-/- mice were viable, non-dysmorphic and born at expected Mendelian ratios, indicating that this gene is dispensable for normal embryonic development. In agreement with the postulated role of this phosphatase in cell cycle progression and regulation of CDKs, we found that Cdkn3-/- cells had increased CDK1, CDK2 and CDK4 activity; increased inhibitory phosphorylation of Rb; increased DNA replication and proliferation; and impaired SAC. Increased CDK activity and accelerated cell cycle progression caused genomic instability reflected by increased frequency of in vivo micronucleation during hematopoiesis as well as higher frequency of aneuploidy and multinucleation and accumulation of supernumerary centrosomes in Cdkn3-/- cells cultured ex vivo. Cdkn3-/- mice had increased myeloid colony-forming units in progenitor assays. Long-term observation of Cdkn3-/- mice revealed an increased risk of death from a variety of hematopoietic (leukemia and lymphoma) and non-hematopoietic (lung, prostate and ovarian) malignancies. Our findings establish Cdkn3 as an in vivo tumor suppressor in bone marrow and a variety of other tissues. In the long term, Cdkn3-/- mice will serve as a tool to dissect the function of this phosphatase in cell cycle control in more detail, and may prove useful in preclinical studies of chemotherapy of CDK-hyperactive, genomically unstable leukemia and lymphoma. Disclosures No relevant conflicts of interest to declare.

scholarly journals The Ubc3 (Cdc34) ubiquitin-conjugating enzyme is ubiquitinated and phosphorylated in vivo.

1994 ◽  
Vol 14 (5) ◽  
pp. 3022-3029 ◽  
Author(s):  
M G Goebl ◽  
L Goetsch ◽  
B Byers
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Protein S ◽  
S Phase ◽  
Cycle Progression ◽  
Endogenous Protein ◽  
Ubiquitin Conjugating Enzyme ◽  
Conjugating Enzyme

The transition from G1 to S phase of the cell cycle in Saccharomyces cerevisiae requires the activity of the Ubc3 (Cdc34) ubiquitin-conjugating enzyme. S. cerevisiae cells lacking a functional UBC3 (CDC34) gene are able to execute the Start function that initiates the cell cycle but fail to form a mitotic spindle or enter S phase. The Ubc3 (Cdc34) enzyme has previously been shown to catalyze the attachment of multiple ubiquitin molecules to model substrates, suggesting that the role of this enzyme in cell cycle progression depends on its targeting an endogenous protein(s) for degradation. In this report, we demonstrate that the Ubc3 (Cdc34) protein is itself a substrate for both ubiquitination and phosphorylation. Immunochemical localization of the gene product to the nucleus renders it likely that the relevant substrates similarly reside within the nucleus.

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 Circular RNA-DPP4 serves an oncogenic role in prostate cancer progression through regulating miR-195/cyclin D1 axis

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Deping Yang ◽  
Bo Yang ◽  
Yanjun Zhu ◽  
Qianlin Xia ◽  
Yan Zhang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Tumor Growth ◽  
Cyclin D1 ◽  
Microarray Analysis ◽  
Cell Cycle Progression ◽  
Normal Prostate ◽  
Cycle Progression

Abstract Background Recently, more and more studies have highlighted the critical regulatory roles of circular RNAs (circRNAs), a class of non-coding RNAs, in the progression of many human cancers, including prostate cancer (PCa). circRNA microarray analysis was performed to identify circRNAs that are differentially expressed in PCa tissues. Methods 104 pairs of PCa tissues and matched adjacent normal prostate tissues (at least 2 cm distal to the tumor margin) were obtained. circRNA microarray analysis was performed on four pairs of PCa tissues and matched adjacent normal prostate tissues to investigate the potential involvement of circRNAs in PCa. Flow cytometric analysis was performed to investigate whether the effect of circDPP4 on PCa cell proliferation was associated with the alteration in cell cycle progression. The role of circDPP4 in PCa tumor growth was further explored in vivo. Results We found that circDPP4 was overexpressed in PCa tissues and cell lines, and its expression was closely associated with Gleason score and clinical stage of PCa patients. In vitro loss- and gain-of-function experiments demonstrated that circDPP4 knockdown inhibited, whereas circDPP4 overexpression promoted the proliferation, migration, invasion and cell cycle progression of PCa cells. Knockdown of circDPP4 also suppressed PCa tumor growth in vivo. We further found that circDPP4 functioned as a competing endogenous RNA (ceRNA) for miR-195 in PCa cells, and miR-195 negatively regulated the expression of oncogenic cyclin D1. Rescue experiments suggested that restoration of miR-195 blocked the oncogenic role of circDPP4 in PCa cells. Conclusions Taken together, our findings revealed a novel regulatory mechanism between circDPP4 and miR-195/cyclin D1 axis, and offered novel strategies for the treatment of PCa.

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.

scholarly journals A Circular RNA from the MDM2 Locus Controls Cell Cycle Progression by Suppressing p53 Levels

2020 ◽  
Vol 40 (9) ◽  
Author(s):  
Ritu Chaudhary ◽  
Bruna R. Muys ◽  
Ioannis Grammatikakis ◽  
Supriyo De ◽  
Kotb Abdelmohsen ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
P53 Protein ◽  
Circular Rnas ◽  
Small Interfering Rnas ◽  
Cycle Progression ◽  
Protein Levels

ABSTRACT Circular RNAs (circRNAs) are a class of noncoding RNAs produced by a noncanonical form of alternative splicing called back-splicing. To investigate a potential role of circRNAs in the p53 pathway, we analyzed RNA sequencing (RNA-seq) data from colorectal cancer cell lines (HCT116, RKO, and SW48) that were untreated or treated with a DNA-damaging agent. Surprisingly, unlike the strong p53-dependent induction of hundreds of p53-induced mRNAs upon DNA damage, only a few circRNAs were upregulated from p53-induced genes. circ-MDM2, an annotated circRNA from the MDM2 locus, was one of the handful of circRNAs that originated from a p53-induced gene. Given the central role of MDM2 in suppressing p53 protein levels and p53 activity, we investigated the function of circ-MDM2. Knocking down circ-MDM2 with small interfering RNAs (siRNAs) that targeted circ-MDM2 did not alter MDM2 mRNA or MDM2 protein levels but resulted in increased basal p53 levels and growth defects in vitro and in vivo. Consistent with these results, transcriptome profiling showed increased expression of several direct p53 targets, reduced retinoblastoma protein (Rb) phosphorylation, and defects in G1-S progression upon silencing circ-MDM2. Our results on the initial characterization of circ-MDM2 identify a new player from the MDM2 locus that suppresses p53 levels and cell cycle progression.

scholarly journals Polar Localization Hub Protein PopZ Restrains Adaptor-Dependent ClpXP Proteolysis in Caulobacter crescentus

2018 ◽  
Vol 200 (20) ◽  
Author(s):  
Kamal Kishore Joshi ◽  
Christine M. Battle ◽  
Peter Chien
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Caulobacter Crescentus ◽  
Cycle Progression ◽  
Content Type ◽  
Polar Localization ◽  
Subsequent Degradation ◽  
Data Point

ABSTRACT In Caulobacter crescentus, timely degradation of several proteins by the ClpXP protease is critical for proper cell cycle progression. During the cell cycle, the ClpXP protease, the substrate CtrA, and many other proteins are localized to the stalked pole dependent on a polar interaction hub composed of PopZ protein oligomers. Prior work suggests that the localization of ClpXP, protease substrates, and cofactors is needed for recognition of substrates, such as CtrA, by ClpXP. Here, we formally test this hypothesis by examining the role of PopZ in ClpXP activity and find, surprisingly, that CtrA degradation is enhanced in cells lacking polar localization due to loss of PopZ. The ClpXP adaptor CpdR is required for this enhanced degradation of CtrA and other adaptor-dependent substrates, but adaptor-independent substrate degradation is not affected upon loss of PopZ. We find that overexpression of PopZ also leads to faster degradation of CtrA but is likely due to nonphysiologically relevant recognition of CtrA by ClpXP alone, as loss of CpdR does not affect this enhancement. Our main conclusion is that loss of PopZ, and therefore loss of polar localization, does not result in the loss of ClpXP-regulated proteolysis, as would be predicted from a model which requires polar localization of ClpXP for its activation. Rather, our data point to a model where PopZ normally restrains ClpXP proteolysis by promoting the inactivation of the CpdR adaptor, perhaps through the activity and localization of the CckA kinase. IMPORTANCE Regulated proteolysis is critical for the cell cycle progression of bacteria, such as Caulobacter crescentus. According to one model, this regulated proteolysis requires localization of the ClpXP protease at the stalked pole for its subsequent degradation of substrates, such as CtrA. This study offers evidence that supports an alternative model to explain how localization might influence protein degradation. Using a delocalized in vivo system created by the deletion of a polar organizing protein, PopZ, we show that activation of the ClpXP protease is independent of its polar localization. The data point to a role for PopZ in restraining ClpXP activity, likely by controlling the activity of upstream regulators of protease activity, such as CckA, though changes in its localization.

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