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- Title
Dexamethasone-mediated protection from drug cytotoxicity: association with p21<sup>WAF1/CIP1</sup> protein accumulation?
- Authors
Naumann, Ulrike; Durka, Silke; Weller, Michael
- Abstract
Dexamethasone (DEX)-mediated inhibition of drug-induced, but not CD95 ligand-induced, apoptosis in malignant glioma cells correlates with wild-type p53 status. Here, we examined mechanisms underlying DEX-mediated protection from apoptosis. DEX did not induce p53 expression in two p53 wild-type cell lines (U87MG, LN-229) and did not alter drug-induced p53 accumulation. Forced expression of temperature-sensitive p53val135 in mutant conformation failed to prevent accumulation of endogenous wild-type p53 but acted in a transdominant negative manner to inhibit p53-mediated, camptothecin-induced p21WAF1/CIP1 expression. p53val135-transfected cells retained responsiveness to DEX at restrictive temperature, suggesting that p53 activity is not required for cytoprotection. Forced expression of wild-type p53val135 abrogated the protective effect of DEX, suggesting redundant cytoprotective effects of DEX and p53. Indeed, DEX induced moderate accumulation of p21WAF1/CIP1 in U87MG, LN-229 and p53 mutant LN-18 cells, but not in p53 mutant LN-308 or T98G cells. LN-18 is also the p53 mutant cell line with the best cytoprotective response to DEX. p21WAF1/CIP1 accumulation occurred in the absence of changes in p21WAF1/CIP1 mRNA expression. Wild-type p53 was not required for this DEX effect since DEX induced p21WAF1/CIP1 accumulation in p53val135-transfected LN-229 cells, too. DEX failed to induce p21WAF1/CIP1 expression or cytoprotection in untransformed rat astrocytes. The same lack of modulation of p21WAF1/CIP1 expression and drug toxicity was observed in p21+/+, p21+/- and p21-/- human colon carcinoma cells. Paradoxically, while only p21+/+ and p21+/- mouse embryonic fibroblasts showed enhance p21WAF1/CIP1 levels after exposure to DEX, only p21-/- fibroblasts were protected from...
- Subjects
CELL-mediated cytotoxicity; APOPTOSIS; CELL cycle; GLIOMAS; DRUG therapy
- Publication
Oncogene, 1998, Vol 17, Issue 12, p1567
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/sj.onc.1202071