Stability of p21Waf1/Cip1 CDK inhibitor protein is responsive to RhoA-mediated regulation of the actin cytoskeleton

Coleman, Mathew L.; Densham, Ruth M; Croft, Daniel R.; Olson, Michael F.

doi:10.1038/sj.onc.1209322

Cited by 36 publications

(29 citation statements)

References 57 publications

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“…3G and H) protects Y1 cells from AVPinduced senescence. Our results apparently contradict other reports stating that RhoA activity is important in the initiation of malignant transformation (Coleman et al 2006). At present, it is difficult to reconcile these disparate results mainly because there are no recognizable patterns of alteration in the organization and Figure 5 AVP does not inhibit the G 0 /G 1 /S cell cycle transition induced by FCS in G 0 /G 1 -arrested Y1 parental cells and clonal sub-lines Y1-RhoAN19-2.1 and RhoAv14-1.1.…”

Section: Discussioncontrasting

confidence: 57%

Vasopressin triggers senescence in K-ras transformed cells via RhoA-dependent downregulation of cyclin D1

Forti¹,

Armelin²

2007

Endocrine Related Cancer

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Arginine vasopressin (AVP), a vasoactive peptide hormone that binds to three G-protein coupled receptors (V 1 R, V 2 R, and V 3 R), has long been known to activate V 1 R and elicit mitogenesis in several cell types, including adrenal glomerulosa cells. However, in the mouse Y1 adrenocortical malignant cell line, AVP triggers not only a canonical mitogenic response but also novel RhoA-GTP-dependent mechanisms which downregulate cyclin D1, irreversibly inhibiting K-ras oncogene-driven proliferation. In Y1 cells, AVP blocks cyclin D1 expression, induces senescence-associated b-galactosidase (SAb-Gal) and inhibits proliferation. However, ectopic expression of cyclin D1 renders Y1 cells resistant to both SAb-Gal induction and proliferation inhibition by AVP. In addition, ectopic expression of the dominant negative RhoAN19 mutant blocks RhoA activation, yielding Y1 cell sub-lines which are no longer susceptible to cyclin D1 downregulation, SAb-Gal induction, or proliferation inhibition by AVP. Furthermore, inhibiting RhoA with C3 exoenzyme protects Y1 cells from AVP proliferation inhibition and SAb-Gal induction. On the other hand, AVP treatment does not activate caspases 3 and 7, and the caspase inhibitor Ac-DEVD-CMK does not protect Y1 cells from proliferation inhibition by AVP, implying that AVP does not trigger apoptosis. These results underline a pivotal survival activity of cyclin D1 that protects K-ras oncogene-dependent malignant cells from senescence.

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Section: Discussioncontrasting

confidence: 57%

Vasopressin triggers senescence in K-ras transformed cells via RhoA-dependent downregulation of cyclin D1

Forti¹,

Armelin²

2007

Endocrine Related Cancer

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“…Given that MDA-MB-453 cells express mutant p53 protein and that SKOV3.ip1 cells are p53 null, however, it is reasonable to deduce that the increased p21 level is through a p53-independent mechanism. It has been shown that inhibition of Rho GTPases contributes to p21 elevation through both increased transcription and protein stabilization (47). Notably, InB kinase h overexpression is able to up-regulate Akt phosphorylation and its expression is highly associated with the expression of total and cytoplasmic p21 in primary breast cancers (48).…”

Section: Discussionmentioning

confidence: 94%

Sensitizing HER2-overexpressing cancer cells to luteolin-induced apoptosis through suppressing p21WAF1/CIP1 expression with rapamycin

Chiang

Way

Lin

2007

Molecular Cancer Therapeutics

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HER2 overexpression, which confers resistance to various therapeutic regimens, correlates with a poor clinical prognosis. In this study, we showed that luteolin, a naturally occurring flavonoid, is a potent stimulator of HER2 degradation. Luteolin effectively inhibited cell proliferation and induced apoptosis in HER2-overexpressing cancer cells. Furthermore, we found that low doses of luteolin up-regulated p21 expression and high doses of luteolin down-regulated its expression. Examination of the Akt/mammalian target of rapamycin (mTOR) signaling revealed that this signaling was only transiently inhibited by low doses of luteolin, which suggested that the inability to cause sustained Akt/mTOR inhibition may contribute to p21 induction and provide a survival advantage to HER2-overexpressing cancer cells. To test this hypothesis, we showed that the combined use of luteolin and mTOR inhibitor rapamycin prevented low doses of luteolin from inducing p21 expression, and HER2-overexpressing cancer cells would be sensitized toward luteolin-induced apoptosis. In addition, p21 small interfering RNA also increased the luteolin-induced cell death. In nude mice with xenografted SKOV3.ip1-induced tumors, luteolin significantly inhibited HER2 expression and tumor growth in a dose-dependent manner, and rapamycin further enhanced the effect of luteolin with a concomitant p21 inhibition. These results reveal an intriguing finding that suppressing p21 expression might have therapeutic implications and further suggest that combination of mTOR inhibitors may be a promising strategy to help increase the efficacy of preventive or therapeutic compounds against HER2-overexpressing tumors.

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“…Activation of the ERK subfamily of MAPKs is mediated by receptor protein tyrosine kinases or G-protein-coupled receptors (41). JNK subfamily of MAPK is activated by osmotic stress (42) and physical stress (43). It is possible that abnormalities in the nuclear lamina lead to activation of G-protein-coupled or other receptors via an unknown mechanism ( Figure 9).…”

Section: Discussionmentioning

confidence: 99%

Activation of MAPK pathways links LMNA mutations to cardiomyopathy in Emery-Dreifuss muscular dystrophy

Muchir¹,

Pavlidis²,

Decostre³

et al. 2007

J. Clin. Invest.

269

343

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Stability of p21Waf1/Cip1 CDK inhibitor protein is responsive to RhoA-mediated regulation of the actin cytoskeleton

Cited by 36 publications

References 57 publications

Vasopressin triggers senescence in K-ras transformed cells via RhoA-dependent downregulation of cyclin D1

Vasopressin triggers senescence in K-ras transformed cells via RhoA-dependent downregulation of cyclin D1

Sensitizing HER2-overexpressing cancer cells to luteolin-induced apoptosis through suppressing p21WAF1/CIP1 expression with rapamycin

Activation of MAPK pathways links LMNA mutations to cardiomyopathy in Emery-Dreifuss muscular dystrophy

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