The p21WAF1/CIP1 Promoter Is Methylated in Rat-1 Cells: Stable Restoration of p53-Dependent p21WAF1/CIP1 Expression after Transfection of a Genomic Clone Containing the p21WAF1/CIP1 Gene

Allan, Lindsey A.; Duhig, Trevor; Read, Moira; Fried, Mike

doi:10.1128/mcb.20.4.1291-1298.2000

Cited by 64 publications

(43 citation statements)

References 33 publications

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“…Figure 5f shows that the abundance of p27 Kip1 and p57 Kip2 inhibitors is comparable throughout G1 in the two cell populations. The other member of the family, p21 Cip1 , is not expressed in Rat1 fibroblasts (Allan et al, 2000). We conclude from these results that the lower Cdk2 activity observed in Rat1-AT 2 cells is likely attributable to a decrease in cyclin E expression.…”

Section: At 2 Receptor Downregulates Cdk4 and Cyclin E Expressionsupporting

confidence: 47%

Expression of angiotensin type II receptor downregulates Cdk4 synthesis and inhibits cell-cycle progression

et al. 2003

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Accumulating evidence suggests that angiotensin II type II (AT 2 ) receptor subtype negatively regulates cell proliferation in pathophysiological conditions associated with tissue remodeling. However, the mechanisms through which AT 2 receptor achieves this effect remain poorly understood. In this study, we demonstrate that expression of AT 2 receptor inhibits the proliferation of rat fibroblasts in a ligand-independent manner. The antiproliferative action of AT 2 is dependent on the density of surface receptors. We show that AT 2 receptor expression negatively regulates G1 phase progression in both cycling cells and G0-arrested cells stimulated to re-enter the cell cycle, but has no detectable effect on apoptosis. The delay in cell-cycle progression of AT 2 -expressing cells is associated with downregulation of cyclin E expression, decreased assembly of cyclin E-Cdk2 complexes, and the resulting attenuation of Cdk2 activation. The induction of Cdk4 expression and activity is also markedly attenuated, which likely contributes to the inhibition of cyclin E expression. Ectopic expression of Cdk4 alleviates the proliferation defect of AT 2 -expressing cells. These findings suggest that the growth-inhibitory effects of the AT 2 receptor are attributable in part to its spontaneous inhibitory action on the cell cycle machinery.

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Section: At 2 Receptor Downregulates Cdk4 and Cyclin E Expressionsupporting

confidence: 47%

Expression of angiotensin type II receptor downregulates Cdk4 synthesis and inhibits cell-cycle progression

et al. 2003

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“…Conversely, in Rat1a-onzin cells grown in 1% serum, p53 and p27 Kip1 levels were both reduced. We were unable to detect p21 Waf1 in Rat1a-puro or Rat1a-onzin cells, most likely as a consequence of methylationmediated silencing of the p21 Waf1 promoter (Allan et al, 2000). In other experiments we have shown that IMR90-onzin cells (Figure 3) also contain 2-3-fold lower levels of p21 and p27 than control cells (not shown).…”

Section: Onzin Overexpression Promotes Growth Survival and Transformentioning

confidence: 58%

Onzin, a c-Myc-repressed target, promotes survival and transformation by modulating the Akt–Mdm2–p53 pathway

et al. 2005

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The c-Myc oncoprotein is a general transcription factor whose target genes dictate the c-Myc phenotype. One such target of c-Myc, 'onzin', is normally expressed at high levels in myeloid cells and is dramatically downregulated in response to c-Myc overexpression. We show here that short hairpin interfering RNA-mediated knockdown of endogenous onzin results in a reduced growth rate and a proapoptotic phenotype. In contrast, onzin overexpression in fibroblasts is associated with an increased growth rate, resistance to apoptotic stimuli, loss of the G2/M checkpoint, and tumorigenic conversion. Onzin-overexpressing cells fail to induce p53 in response to apoptotic stimuli and contain higher levels of the active, phosphorylated forms of Akt1 and, more strikingly, of Mdm2. Using yeast two-hybrid and coimmunoprecipitation assays, we show that onzin directly interacts with both proteins. Green fluorescent protein tagging also confirms directly that Akt1 and Mdm2 colocalize with onzin, although the precise subcellular distribution of each protein is dependent on its relative abundance. Collectively, our results identify onzin as a novel regulator of several p53-dependent aspects of the c-Myc phenotype via its dramatic effect on Mdm2. This is reminiscent of the c-Mycp19 ARF -| Mdm2 pathway and might function as a complementary arm to ensure the proper cellular response to oncogenic and/or apoptotic stimuli.

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“…Regardless of the mechanism for p21 CIP1 upregulation, several observations lead us to suggest that p21 CIP1 is not absolutely required for the G 2 arrest or even the inhibition of CDK2 and CDK1 observed upon activation of DMEKK3:ER*. First, both a sustained G 2 arrest and loss of CDK activity were observed in RM3 cells, which fail to express p21 CIP1 due to methylation of the p21 CIP1 promoter (Allan et al, 2000). Second, even in CM3 cells, activation of DMEKK3:ER* could be delayed until just prior to mitosis and still elicit a G 2 block, implying a more direct effect, perhaps independent of de novo induction of regulators such as p21 CIP1 .…”

Section: Discussionmentioning

confidence: 99%

ΔMEKK3:ER* activation induces a p38α/β2-dependent cell cycle arrest at the G2 checkpoint

et al. 2002

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The p21^WAF1/CIP1 Promoter Is Methylated in Rat-1 Cells: Stable Restoration of p53-Dependent p21^WAF1/CIP1 Expression after Transfection of a Genomic Clone Containing the p21^WAF1/CIP1 Gene

Cited by 64 publications

References 33 publications

Expression of angiotensin type II receptor downregulates Cdk4 synthesis and inhibits cell-cycle progression

Expression of angiotensin type II receptor downregulates Cdk4 synthesis and inhibits cell-cycle progression

Onzin, a c-Myc-repressed target, promotes survival and transformation by modulating the Akt–Mdm2–p53 pathway

ΔMEKK3:ER* activation induces a p38α/β2-dependent cell cycle arrest at the G2 checkpoint

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