|
| ||
|
|
||
Cell Cycle Inhibitor (cell + cycle_inhibitor)
Selected AbstractsTSC-box is essential for the nuclear localization and antiproliferative effect of XTSC-22DEVELOPMENT GROWTH & DIFFERENTIATION, Issue 3 2007Akiko Hashiguchi Transforming growth factor- ,1-stimulated clone 22 (TSC-22) encodes a leucine zipper-containing protein that is highly conserved among various species. Mammalian TSC-22 is a potential tumor suppressor gene. It translocates into nuclei and suppresses cell division upon antiproliferative stimuli. In human colon carcinoma cells, TSC-22 inhibits cell growth by upregulating expression of the p21 gene, a cyclin-dependent kinase (Cdk) inhibitor. We previously showed that the Xenopus laevis homologue of the TSC-22 gene (XTSC-22) is required for cell movement during gastrulation through cell cycle regulation. In this report, we investigated the molecular mechanism of the antiproliferative effect of XTSC-22. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis suggested that XTSC-22 did not affect the expression levels of the p21 family of Cdk inhibitors or other cell cycle regulators. Analysis of deletion mutants of XTSC-22 revealed that nuclear localization of the N-terminal TSC-box is necessary for cell cycle inhibition by XTSC-22. Further experiments suggested that p27Xic1, a key Cdk inhibitor in Xenopus, interacts with XTSC-22. Because p27Xic1 is a cell cycle inhibitor with a nuclear localization signal, it is possible that XTSC-22 suppresses cell division by translocating into the nucleus with p27Xic1, where it may potentiate the intranuclear action of p27Xic1. [source] Cardiac ankyrin repeat protein is a marker of skeletal muscle pathological remodellingFEBS JOURNAL, Issue 3 2009Lydie Laure In an attempt to identify potential therapeutic targets for the correction of muscle wasting, the gene expression of several pivotal proteins involved in protein metabolism was investigated in experimental atrophy induced by transient or definitive denervation, as well as in four animal models of muscular dystrophies (deficient for calpain 3, dysferlin, ,-sarcoglycan and dystrophin, respectively). The results showed that: (a) the components of the ubiquitin,proteasome pathway are upregulated during the very early phases of atrophy but do not greatly increase in the muscular dystrophy models; (b) forkhead box protein O1 mRNA expression is augmented in the muscles of a limb girdle muscular dystrophy 2A murine model; and (c) the expression of cardiac ankyrin repeat protein (CARP), a regulator of transcription factors, appears to be persistently upregulated in every condition, suggesting that CARP could be a hub protein participating in common pathological molecular pathway(s). Interestingly, the mRNA level of a cell cycle inhibitor known to be upregulated by CARP in other tissues, p21WAF1/CIP1, is consistently increased whenever CARP is upregulated. CARP overexpression in muscle fibres fails to affect their calibre, indicating that CARP per se cannot initiate atrophy. However, a switch towards fast-twitch fibres is observed, suggesting that CARP plays a role in skeletal muscle plasticity. The observation that p21WAF1/CIP1 is upregulated, put in perspective with the effects of CARP on the fibre type, fits well with the idea that the mechanisms at stake might be required to oppose muscle remodelling in skeletal muscle. [source] MicroRNAs control hepatocyte proliferation during liver regeneration,HEPATOLOGY, Issue 5 2010Guisheng Song MicroRNAs (miRNAs) constitute a new class of regulators of gene expression. Among other actions, miRNAs have been shown to control cell proliferation in development and cancer. However, whether miRNAs regulate hepatocyte proliferation during liver regeneration is unknown. We addressed this question by performing 2/3 partial hepatectomy (2/3 PH) on mice with hepatocyte-specific inactivation of DiGeorge syndrome critical region gene 8 (DGCR8), an essential component of the miRNA processing pathway. Hepatocytes of these mice were miRNA-deficient and exhibited a delay in cell cycle progression involving the G1 to S phase transition. Examination of livers of wildtype mice after 2/3 PH revealed differential expression of a subset of miRNAs, notably an induction of miR-21 and repression of miR-378. We further discovered that miR-21 directly inhibits Btg2, a cell cycle inhibitor that prevents activation of forkhead box M1 (FoxM1), which is essential for DNA synthesis in hepatocytes after 2/3 PH. In addition, we found that miR-378 directly inhibits ornithine decarboxylase (Odc1), which is known to promote DNA synthesis in hepatocytes after 2/3 PH. Conclusion: Our results show that miRNAs are critical regulators of hepatocyte proliferation during liver regeneration. Because these miRNAs and target gene interactions are conserved, our findings may also be relevant to human liver regeneration. (HEPATOLOGY 2010) [source] Role of insulin-like growth factor binding protein-3 in breast cancer cell growthMICROSCOPY RESEARCH AND TECHNIQUE, Issue 1 2002Lynette J. Schedlich Abstract The mitogenic effects of insulin-like growth factors (IGFs) are regulated by a family of insulin-like growth factor binding proteins (IGFBPs). One member of this family, IGFBP-3, mediates the growth-inhibitory and apoptosis-inducing effects of a number of growth factors and hormones such as transforming growth factor-,, retinoic acid, and 1,25-dihydroxyvitamin D3. IGFBP-3 may act in an IGF-dependent manner by attenuating the interaction of pericellular IGFs with the type-I IGF receptor. It may also act in an IGF-independent manner by initiating intracellular signaling from a cell surface receptor, or by direct nuclear action, or both. The possibility of a membrane-bound receptor is strengthened by recent studies which have identified members of the transforming growth factor-, receptor family as having a role, either directly or indirectly, in signaling from the cell surface by IGFBP-3. A number of growth factors and hormones stimulate the expression and secretion of cellular IGFBP-3, which then signals from the cell surface to bring about some of the effects attributed to the primary agents. Within the cell, the apoptosis-inducing tumor suppressor, p53, can also induce IGFBP-3 expression and secretion. Since IGFBP-3 upregulates the cell cycle inhibitor, p21Waf1, and increases the ratio of proapoptotic to antiapoptotic members of the Bcl family, it appears to exert the same effects on major downstream targets of cell signaling as p53 does. The nuclear localization of IGFBP-3 has been described in a number of cell types. IGFBP-3 may act to import IGFs or other nuclear localization signal-deficient signaling molecules into the nucleus. It may also act directly in the nucleus by enhancing the activity of retinoid X receptor-, and thereby promote apoptosis. All of the above phenomena will be discussed with particular emphasis on the growth of breast cancer cells. Microsc. Res. Tech. 59:12,22, 2002. © 2002 Wiley-Liss, Inc. [source] Increased Expression of Senescence-Associated Cell Cycle Inhibitor p16INK4a in Deteriorating Renal Transplants and Diseased Native KidneyAMERICAN JOURNAL OF TRANSPLANTATION, Issue 6 2005Anette Melk Some features of kidney transplants with dysfunction overlap the lesions of aging, such as tubular atrophy and interstitial fibrosis (TA/IF) without major glomerular abnormalities. Somatic cell limitations could contribute to deterioration in aging and disease states. Since expression of p16INK4a, a cell cycle inhibitor associated with somatic cell senescence in vitro, is induced in aged kidney, we studied whether kidneys with dysfunction and TA/IF manifested increased p16INK4a expression. We performed p16INK4a immunostaining on transplanted kidneys and native kidneys with chronic renal diseases. At implantation, transplants manifested little TA/IF, and nuclear p16INK4a immunostaining was consistent with age. However, transplants biopsied for abnormal function displaying TA/IF showed strong nuclear and cytoplasmic p16INK4a staining, beyond the amount predicted for age. Both atrophic and non-atrophic nephrons displayed increased p16INK4a, suggesting that it was not simply a feature of atrophy. Epithelial p16INK4a staining was not increased in transplants with good function, but was increased in diseased native kidneys. The finding of increased p16INK4a expression in renal transplants and diseased kidneys with TA/IF and impaired function supports the concept that some cell senescence changes that accompany aging are also induced by injury and disease stresses. Thus, aging, injury and disease may share common pathways involving somatic cell senescence. [source] INK4 proteins, a family of mammalian CDK inhibitors with novel biological functionsIUBMB LIFE, Issue 7 2007Eduardo T. Cánepa Abstract The cyclin D-Cdk4-6/INK4/Rb/E2F pathway plays a key role in controlling cell growth by integrating multiple mitogenic and antimitogenic stimuli. The members of INK4 family, comprising p16INK4a, p15INK4b, p18INK4c, and p19INK4d, block the progression of the cell cycle by binding to either Cdk4 or Cdk6 and inhibiting the action of cyclin D. These INK4 proteins share a similar structure dominated by several ankyrin repeats. Although they appear to be structurally redundant and equally potent as inhibitors, the INK4 family members are differentially expressed during mouse development. The striking diversity in the pattern of expression of INK4 genes suggested that this family of cell cycle inhibitors might have cell lineage-specific or tissue-specific functions. The INK4 proteins are commonly lost or inactivated by mutations in diverse types of cancer, and they represent established or candidate tumor suppressors. Apart from their capacity to arrest cells in the G1-phase of the cell cycle they have been shown to participate in an increasing number of cellular processes. Given their emerging roles in fundamental physiological as well as pathological processes, it is interesting to explore the diverse roles for the individual INK4 family members in different functions other than cell cycle regulation. Extensive studies, over the past few years, uncover the involvement of INK4 proteins in senescence, apoptosis, DNA repair, and multistep oncogenesis. We will focus the discussion here on these unexpected issues. iubmb Life, 59: 419-426, 2007 [source] NDRG2, a novel regulator of myoblast proliferation, is regulated by anabolic and catabolic factorsTHE JOURNAL OF PHYSIOLOGY, Issue 7 2009Victoria C. Foletta Skeletal muscle tissue undergoes adaptive changes in response to stress and the genes that control these processes are incompletely characterised. NDRG2 (N-myc downstream-regulated gene 2), a stress- and growth-related gene, was investigated in skeletal muscle growth and adaption. While NDRG2 expression levels were found to be up-regulated in both differentiated human and mouse myotubes compared with undifferentiated myoblasts, the suppression of NDRG2 in C2C12 myoblasts resulted in slowed myoblast proliferation. The increased expression levels of the cell cycle inhibitors, p21 Waf1/Cip1 and p27 Kip1, and of various muscle differentiation markers in NDRG2-deficient myoblasts indicate that a lack of NDRG2 promoted cell cycle exiting and the onset of myogenesis. Furthermore, the analysis of NDRG2 regulation in C2C12 myotubes treated with catabolic and anabolic agents and in skeletal muscle from human subjects following resistance exercise training revealed NDRG2 gene expression to be down-regulated during hypertrophic conditions, and conversely, up-regulated during muscle atrophy. Together, these data demonstrate that NDRG2 expression is highly responsive to different stress conditions in skeletal muscle and suggest that the level of NDRG2 expression may be critical to myoblast growth and differentiation. [source] | |||||||||||||