FOXO target gene CTDSP2 inhibits cell cycle progression through regulation of p21-Cip1/Waf1
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE58987 | GEO | 2015/05/29
SECONDARY ACCESSION(S): PRJNA254054
REPOSITORIES: GEO
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Project description:Activity of Forkhead box O (FOXO) transcription factors is inhibited by PI3K-PKB/Akt signalling to control a variety of cellular processes including cell cycle progression. Through comparative analysis of a number of microarray datasets, we identified a set of genes commonly regulated by FOXO and PI3K/PKB, which includes Carboxyl-Terminal Domain Small Phosphatase 2 (CTDSP2). We validated CTDSP2 as a genuine FOXO target gene and show that ectopic CTDSP2 can induce cell cycle arrest. We analysed transcriptional regulation after CTDSP2 expression and identified extensive regulation of genes involved in cell cycle progression, which depends on the phosphatase activity of CTDSP2. Most notably regulated genes are p21Cip1/Waf1 and E2F1, both implicated in S-phase entry. We show that p21Cip1/Waf1 is regulated by CTDSP2 in a p53-independent manner and that p21Cip1/Waf1 upregulation results in decreased cyclin/CDK2 and cyclin/CDK6 activity. Thus, we identify FOXO-dependent CTDSP2 regulation as a novel regulatory mechanism for inhibiting proliferation in the absence of growth factor/PI3K signalling.
2015-05-29 | GSE58945 | GEO
Project description:Activity of Forkhead box O (FOXO) transcription factors is inhibited by PI3K-PKB/Akt signalling to control a variety of cellular processes including cell cycle progression. Through comparative analysis of a number of microarray datasets, we identified a set of genes commonly regulated by FOXO and PI3K/PKB, which includes Carboxyl-Terminal Domain Small Phosphatase 2 (CTDSP2). We validated CTDSP2 as a genuine FOXO target gene and show that ectopic CTDSP2 can induce cell cycle arrest. We analysed transcriptional regulation after CTDSP2 expression and identified extensive regulation of genes involved in cell cycle progression, which depends on the phosphatase activity of CTDSP2. Most notably regulated genes are p21Cip1/Waf1 and E2F1, both implicated in S-phase entry. We show that p21Cip1/Waf1 is regulated by CTDSP2 in a p53-independent manner and that p21Cip1/Waf1 upregulation results in decreased cyclin/CDK2 and cyclin/CDK6 activity. Thus, we identify FOXO-dependent CTDSP2 regulation as a novel regulatory mechanism for inhibiting proliferation in the absence of growth factor/PI3K signalling.
2015-05-29 | GSE58909 | GEO
Project description:Activity of Forkhead box O (FOXO) transcription factors is inhibited by PI3K-PKB/Akt signalling to control a variety of cellular processes including cell cycle progression. Through comparative analysis of a number of microarray datasets, we identified a set of genes commonly regulated by FOXO and PI3K/PKB, which includes Carboxyl-Terminal Domain Small Phosphatase 2 (CTDSP2). We validated CTDSP2 as a genuine FOXO target gene and show that ectopic CTDSP2 can induce cell cycle arrest. We analysed transcriptional regulation after CTDSP2 expression and identified extensive regulation of genes involved in cell cycle progression, which depends on the phosphatase activity of CTDSP2. Most notably regulated genes are p21Cip1/Waf1 and E2F1, both implicated in S-phase entry. We show that p21Cip1/Waf1 is regulated by CTDSP2 in a p53-independent manner and that p21Cip1/Waf1 upregulation results in decreased cyclin/CDK2 and cyclin/CDK6 activity. Thus, we identify FOXO-dependent CTDSP2 regulation as a novel regulatory mechanism for inhibiting proliferation in the absence of growth factor/PI3K signalling.
2015-05-29 | GSE58986 | GEO
Project description:Activity of Forkhead box O (FOXO) transcription factors is inhibited by PI3K-PKB/Akt signalling to control a variety of cellular processes including cell cycle progression. Through comparative analysis of a number of microarray datasets, we identified a set of genes commonly regulated by FOXO and PI3K/PKB, which includes Carboxyl-Terminal Domain Small Phosphatase 2 (CTDSP2). We validated CTDSP2 as a genuine FOXO target gene and show that ectopic CTDSP2 can induce cell cycle arrest. We analysed transcriptional regulation after CTDSP2 expression and identified extensive regulation of genes involved in cell cycle progression, which depends on the phosphatase activity of CTDSP2. Most notably regulated genes are p21Cip1/Waf1 and E2F1, both implicated in S-phase entry. We show that p21Cip1/Waf1 is regulated by CTDSP2 in a p53-independent manner and that p21Cip1/Waf1 upregulation results in decreased cyclin/CDK2 and cyclin/CDK6 activity. Thus, we identify FOXO-dependent CTDSP2 regulation as a novel regulatory mechanism for inhibiting proliferation in the absence of growth factor/PI3K signalling.
2015-05-29 | GSE58947 | GEO
Project description:Background & aimsMist1 is a basic helix-loop-helix (bHLH) transcription factor that is important to the proper development of the exocrine pancreas. The aim of this study was to investigate the role of Mist1 in modulating acinar cell proliferation.MethodsDuctal and acinar pancreatic cell lines were engineered to express an inducible Mist1 complementary DNA or to express a short hairpin RNA that targeted endogenous Mist1. Alterations in RNA and protein levels were detected by real-time reverse-transcription polymerase chain reaction and immunoblots. Chromatin immunoprecipitation and reporter gene assays were performed to map Mist1-responsive elements on target genes; the overall proliferation index of acinar cells from Mist1 null pancreata was evaluated by immunohistochemistry.ResultsExpression of Mist1 resulted in a significant decrease in the proliferative potential of cells that was associated with induced expression of p21(CIP1/WAF1). Short hairpin RNA-directed knockdown of p21(CIP1/WAF1) generated cells that were refractory to Mist1 expression, whereas knockdown of Mist1 transcripts or deletion of Mist1 from the mouse genome led to increased cell proliferation and a concomitant decrease in p21(CIP1/WAF1) protein levels. Surprisingly, Mist1-dependent activation of the p21(CIP1/WAF1) promoter was independent of classic basic helix-loop-helix protein binding sites. Instead, Sp1 binding sites were essential for Mist1-dependent transcription, suggesting that Mist1 activates p21(CIP1/WAF1) expression through a unique Sp1 pathway. Indeed, coimmunoprecipitation studies demonstrated that Mist1 and Sp1 were found within the same transcription complex.ConclusionsOur results show that Mist1 has a dual role in the development of the exocrine pancreas: controlling cell proliferation and promoting terminal differentiation.
| S-EPMC2853247 | biostudies-literature
Project description:Rat-1 cells are used in many studies on transformation, cell cycle, and apoptosis. Whereas UV treatment of Rat-1 cells results in apoptosis, X-ray treatment does not induce either apoptosis or a cell cycle block. X-ray treatment of Rat-1 cells results in both an increase of p53 protein and expression of the p53-inducible gene MDM2 but not the protein or mRNA of the p53-inducible p21(WAF1/CIP1) gene, which in other cells plays an important role in p53-mediated cell cycle block. The lack of p21(WAF1/CIP1) expression appears to be the result of hypermethylation of the p21(WAF1/CIP1) promoter region, as p21(WAF1/CIP1) protein expression could be induced by growth of Rat-1 cells in the presence of 5-aza-2-deoxycytidine. Furthermore, sequence analysis of bisulfite-treated DNA demonstrated extensive methylation of cytosine residues in CpG dinucleotides in a CpG-rich island in the promoter region of the p21(WAF1/CIP1) gene. Stable X-ray-induced p53-dependent p21(WAF1/CIP1) expression and cell cycle block were restored to a Rat-1 clone after transfection with a P1 artificial chromosome (PAC) DNA clone containing a rat genomic copy of the p21(WAF1/CIP1) gene. The absence of expression of the p21(WAF1/CIP1) gene may contribute to the suitability of Rat-1 cells for transformation, cell cycle, and apoptosis studies.
| S-EPMC85267 | biostudies-literature
Project description:Backgroundp300 functions as a transcriptional co-activator to regulate many cellular responses such as cell growth, transformation, development and differentiation. It has been shown to affect the transcriptional activity of p53 which regulates p21(Waf1/CIP1) expression, however, the role of p300 in differentiation remains unclear.Methodology and principal findingsKnockdown of p300 protein with short hairpin RNA (shRNA) molecules delays human neonatal foreskin keratinocyte (HFKs) differentiation. Moreover, depletion of p300 increases the proliferative capacity of HFKs, extends the life span of cells and allows differentiated HFKs to re-enter the cell cycle. Studies indicate that depletion of p300 down-regulates the acetylation and expression of p53, and chromatin immunoprecipitation (ChIP) analysis shows that induction of p21(Waf1/CIP1) in early differentiation is a result of p300 dependent activation of p53 and that depletion of p21(Waf1/CIP1) results in the delay of differentiation and a phenotype similar to p300 depletion.Conclusionsp300 has a direct role in the control of cell growth and differentiation in primary epithelial cells, and p21(Waf1/CIP1) is an important mediator of these p300 functions.
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Project description:Loss of hSNF5 function is usually observed in malignant rhabdoid tumor (MRT), a highly aggressive pediatric neoplasm. Previous studies have shown that reexpression of hSNF5 in MRT cell lines causes G1 cell cycle arrest with p16(INK4A), p21(CIP1/WAF1), and cyclin D1 playing key roles in MRT cell growth control. However, we have shown that reexpression of hSNF5 induced cell cycle arrest in the absence of p16(INK4A) expression. These results indicate that the mechanism of hSNF5-induced cell cycle arrest is context dependent. Here, we investigated the relationship between p21(CIP1/WAF1) and hSNF5 in the regulation of growth using several MRT cell lines. We found that G1 cell cycle arrest occurred concomitant with an increase in p21(CIP1/WAF1) mRNA and protein levels and preceded p16(INK4A) mRNA and protein upregulation. Chromatin immunoprecipitation data confirmed that hSNF5 appeared at both p21(CIP1/WAF1) and p16(INK4A) promoters after reexpression. We further showed that p21(CIP1/WAF1) induction showed both p53-dependent and p53-independent mechanisms. We also showed that reduction of p21(CIP1/WAF1) expression by RNAi significantly inhibited hSNF5-induced G(1) arrest. Our results show that both p21(CIP1/WAF1) and p16(INK4A) are targets for hSNF5 and that p21(CIP1/WAF1) upregulation during hSNF5-induced G(1) arrest precedes p16(INK4A) upregulation. These findings indicate that SNF5 mediates a temporally controlled program of cyclin-dependent kinase inhibition to restrict aberrant proliferation in MRT cells.
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Project description:BackgroundThe glomerular podocyte is a highly specialized cell type with the ability to ultrafilter blood and support glomerular capillary pressure. However, little is known about the genetic programs leading to this functionality or the final phenotype.ResultsIn the current study, we found that the expression of a myocardin/MKL family member, MKL1, was significantly upregulated during cell cycle arrest induced by a temperature switch in murine podocyte clone 5 (MPC5) cells. Further investigation demonstrated that overexpression of MKL1 led to inhibition of cell proliferation by decreasing the number of cells in S phase of the cell cycle. In contrast, MKL1 knockdown by RNA interference had the opposite effect, highlighting a potential role of MKL1 in blocking G1/S transition of the cell cycle in MPC5 cells. Additionally, using an RT(2) Profiler PCR Array, p21 was identified as a direct target of MKL1. We further revealed that MKL1 activated p21 transcription by recruitment to the CArG element in its promoter, thus resulting in cell cycle arrest. In addition, the expression of MKL1 is positively correlated with that of p21 in podocytes in postnatal mouse kidney and significantly upregulated during the morphological switch of podocytes from proliferation to differentiation.ConclusionsOur observations demonstrate that MKL1 has physiological roles in the maturation and development of podocytes, and thus its misregulation might lead to glomerular and renal dysfunction.
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Project description:The Fragile X-Related 1 gene (FXR1) is a paralog of the Fragile X Mental Retardation 1 gene (FMR1), whose absence causes the Fragile X syndrome, the most common form of inherited intellectual disability. FXR1P plays an important role in normal muscle development, and its absence causes muscular abnormalities in mice, frog, and zebrafish. Seven alternatively spliced FXR1 transcripts have been identified and two of them are skeletal muscle-specific. A reduction of these isoforms is found in myoblasts from Facio-Scapulo Humeral Dystrophy (FSHD) patients. FXR1P is an RNA-binding protein involved in translational control; however, so far, no mRNA target of FXR1P has been linked to the drastic muscular phenotypes caused by its absence. In this study, gene expression profiling of C2C12 myoblasts reveals that transcripts involved in cell cycle and muscular development pathways are modulated by Fxr1-depletion. We observed an increase of p21--a regulator of cell-cycle progression--in Fxr1-knocked-down mouse C2C12 and FSHD human myoblasts. Rescue of this molecular phenotype is possible by re-expressing human FXR1P in Fxr1-depleted C2C12 cells. FXR1P muscle-specific isoforms bind p21 mRNA via direct interaction with a conserved G-quadruplex located in its 3' untranslated region. The FXR1P/G-quadruplex complex reduces the half-life of p21 mRNA. In the absence of FXR1P, the upregulation of p21 mRNA determines the elevated level of its protein product that affects cell-cycle progression inducing a premature cell-cycle exit and generating a pool of cells blocked at G0. Our study describes a novel role of FXR1P that has crucial implications for the understanding of its role during myogenesis and muscle development, since we show here that in its absence a reduced number of myoblasts will be available for muscle formation/regeneration, shedding new light into the pathophysiology of FSHD.
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