p21Waf1/Cip1 protects against p53-mediated apoptosis of human melanoma cells

Gorospe, Myriam; Cirielli, Corrado; Wang, Xiantao; Seth, Prem; Capogrossi, Maurizio C.; Holbrook, Nikki J.

doi:10.1038/sj.onc.1200897

Cited by 283 publications

(210 citation statements)

References 18 publications

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“…The anti-cytotoxic e ect of p21 waf in cases of radiation and doxorubicin treatment is consistent with results with cells de®cient for p21 waf , which show increased sensitivity to radiation and various anti-cancer drugs (Brugardas et al, 1995;Waldman et al, 1996;Wouters et al, 1997). These results are also in line with the observation that p21 waf protects against apoptosis (Gorospe et al, 1996(Gorospe et al, , 1997Polyak et al, 1996) and that loss of p21 waf enhances the apoptotic e ect of ionising radiation . Our results are also consistent with a previous study showing that p21 waf expression increases the clonogenic survival after irradiation (Waldman et al, 1997).…”

Section: Discussionsupporting

confidence: 88%

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Induced p21waf expression in H1299 cell line promotes cell senescence and protects against cytotoxic effect of radiation and doxorubicin

1999

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The CDK inhibitor p21 waf is a principal mediator of p53 function but can also be transactivated by many p53-independent stimuli leading to cell growth arrest or di erentiation. In order to study the function of p21 waf in a p53-de®cient environment, we established an inducible expression of p21 waf in the p53-null lung cancer cell line H1299, based on the muristerone-regulated system. Overexpression of p21 waf led cells to growth arrest which after several days became irreversible and the arrested cells acquired a senescent phenotype as judged by cell shape, the senescence-associated b-gal marker and inhibition of colony formation. The e ect of p21 waf overexpression, in the absence of p53, on the cytotoxicity caused by irradiation, doxorubicin and taxol was studied. Expression of p21 waf provided protection against the cytotoxic e ect of radiation and doxorubicin but not of taxol. These results are relevant to treatment of cancer when p53 is inactive.

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Section: Discussionsupporting

confidence: 88%

“…In several studies upregulation of p21 waf was observed in cases of p53-dependent apoptosis (Kondo et al, 1997;Waldman et al, 1996), whereas in other cases p21 waf was found to protect cells from apoptosis or drug cytotoxicity (Poluha et al, 1996;Gorospe et al, 1996Gorospe et al, , 1997.…”

Section: Introductionmentioning

confidence: 99%

Induced p21waf expression in H1299 cell line promotes cell senescence and protects against cytotoxic effect of radiation and doxorubicin

1999

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“…Suppression of apoptosis due to the expression of p21 has recently been reported (Wang and Walsh., 1996;Gorospe et al, 1996Gorospe et al, , 1997Waldman et al, 1996;Attard et al, 1996). From our ®ndings, we can conclude that CDK-binding or CDK-inhibiting activity of p21 is required to suppress apoptotic cell death and the cells with the mutated p21 lacking the CDKbinding or CDK-inhibiting activity undergo apoptosis.…”

Section: Discussionmentioning

confidence: 51%

“…Recent ®ndings, however, have shown that an increase in p21 blocks cell growth and inhibits apoptosis (Gorospe et al, 1996(Gorospe et al, , 1997Attard et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Mutated p21WAF1/CIP1/SDI1 lacking CDK-inhibitory activity fails to prevent apoptosis in human colorectal carcinoma cells

Yamagishi

Yagi

et al. 1998

Oncogene

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Human colorectal tumor cell lines were established which express wildtype p21 or p21 with a mutation at codon 46 (Cys) or 140 (Gly) on IPTG treatment (LacSwitch). The IPTG-induced wildtype p21 bound to CDK2 and PCNA and inhibited CDK activity in the cells and reduced cell growth rate; whereas, both IPTG-induced mutated p21 proteins neither bound to CDK2 nor a ected the CDK activity but did bind to PCNA, and they did not a ect the cell growth rate. Wildtype p21 suppressed apoptosis and enhanced survival of X-ray-irradiated or adriamycintreated cells; but, mutated p21 neither suppressed apoptosis nor a ected cell survival. When cells were treated with mimosine, a p53-independent p21-inducer, or butyrolactone I, a speci®c inhibitor of CDK, cellular endogenous p21 was induced and X-ray or adriamycininduced apoptosis was blocked. These results suggest that CDK-binding or CDK-inhibitory activity of p21 is required to prevent apoptosis, i.e., CDK is required for apoptosis in human tumor cells.

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“…Marked upregulation of endogenous p21 has been demonstrated in various cell types during the apoptotic response to several agents, including taxol, okadaic acid, etoposide, and interferon gamma (Kano et al, 1997, Sheikh et al, 1997. On the other hand, ectopic overexpression of p21 and studies using p21 de®cient cancer cells, suggest a role for p21 in protection from apoptosis in colon and other types of cancer cells McDonald et al, 1996;Sheikh et al, 1997;Gorospe et al, 1996Gorospe et al, , 1997. To our knowledge, however, the comparative e ects of increased expression of p27 or p21 on the growth and di erentiation of human colon cancer cells have not been examined in the same cell line.…”

Section: Introductionmentioning

confidence: 99%

Comparative effects of overexpression of p27Kip1 and p21Cip1/Waf1 on growth and differentiation in human colon carcinoma cells

et al. 1999

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Recent studies have shown that decreased expression of p27 Kip1 is associated with high grade tumors and an unfavorable prognosis in several types of human cancer. To clarify the role of p27 Kip1 in colon cancer, we have overexpressed this protein in the HT29 colon cancer cell line. The derivatives displayed an increase in the p27 Kip1 protein in cyclin E/CDK2 immunoprecipitates and a decrease in cyclin E-associated kinase activity when compared to vector control clones, providing evidence that the overexpressed protein was functional. Clones with a high level of p27 Kip1 displayed partial growth inhibition in monolayer culture and a decrease in plating e ciency, even though they expressed increased levels of the cyclin D1 protein. Using alkaline phosphatase expression as a marker, we found that the p27 Kip1 overexpressor clones displayed a 2 ± 3-fold increase in sensitivity to induction of di erentiation by 2 mM sodium butyrate. In contrast to these results, derivatives of HT29 cells that stably overexpressed p21 Cip1/Waf1 displayed decreased sensitivity to the induction of di erentiation. These ®ndings may explain why decreased levels of p27 Kip1 in certain human cancers is associated with high grade (poorly di erentiated) tumors, and suggest that strategies that increase the level of p27 Kip1 may be useful in cancer therapy.

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p21Waf1/Cip1 protects against p53-mediated apoptosis of human melanoma cells

Cited by 283 publications

References 18 publications

Induced p21waf expression in H1299 cell line promotes cell senescence and protects against cytotoxic effect of radiation and doxorubicin

Induced p21waf expression in H1299 cell line promotes cell senescence and protects against cytotoxic effect of radiation and doxorubicin

Mutated p21WAF1/CIP1/SDI1 lacking CDK-inhibitory activity fails to prevent apoptosis in human colorectal carcinoma cells

Comparative effects of overexpression of p27Kip1 and p21Cip1/Waf1 on growth and differentiation in human colon carcinoma cells

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