Induction of p21 by p65 in p53 null cells treated with Doxorubicin.
NFkappaB/p65 is a transcription factor that can protect or contribute to cell death. Here we show that knockdown of p65 by IkappaBSR or p65 siRNA decreased the cytotoxic effect of DOX on HCT116 (p53+/+) cells, correlating with increased induction of p21. In previous work, we demonstrated that p21 suppressed cell death via its CDK-inhibitory activity. Thus, we propose that the p65 activity is required for p53-dependent cell death through limitation of p53-induced p21 expression. In HCT116 (p53-/-) cells, downregulation of p65 expression enhanced the cytotoxic effect of DOX, due to decreased p21 expression levels. We present evidence that in p53-null tumor cells treated with DOX, p65 was involved in induction of p21 expression by directly binding to the p21 promoter. Our data suggested that both p53 and p65 limited each other's ability to stimulate p21 induction and this mutual repression mechanism was consistent with a model in which both factors were competing for limiting pool of p300/CBP coactivator protein complexes. These findings indicate an association between p21 expression and resistance to cell death through p65, a novel regulatory mechanism in which p21 bridges a transcriptional crosstalk between p53 and p65.
Ma
Shenglin
S
Zhejiang Tumor Hospital, Banshanqiao,Hangzhou, Zhejiang Province, China.
Tang
Juanjuan
J
Feng
Jianguo
J
Xu
Yaping
Y
Yu
Xinmin
X
Deng
Qinghua
Q
Lu
Yanjun
Y
D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D016923:Cell Death; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis* / Q000235:genetics; D004317:Doxorubicin / Q000633:toxicity*; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53; D006801:Humans; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D050880:p300-CBP Transcription Factors / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D050759:Cyclin-Dependent Kinase Inhibitor p21; D051996:Transcription Factor RelA; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D050880:p300-CBP Transcription Factors