p53 Deficiency leads to compensatory up-regulation of p16INK4a.
p53-p21-cyclin-dependent kinase and p16(INK4a)-cyclin-dependent kinase pathways have parallel functions in preventing tumorigenesis. In cancer patients, tumor suppressor p53 is frequently inactivated through mutations, whereas p16(INK4a) is silenced through promoter methylation. However, the interaction between these two pathways is less well understood. Here, we report that p53 controls p16(INK4a) expression in a unique way. p53 deficiency led to up-regulation of p16(INK4a) in primary mouse embryonic fibroblasts, osteoblasts, and various mouse organs, and an increase in the p16(INK4a) promoter activity, without affecting the half-life of p16(INK4a). Reconstitution of p53, but not mutant p53, restored the proper expression of p16(INK4a). These results indicate that p53 is necessary in repressing p16(INK4a) expression. However, up-regulation of p53 in response to genotoxic stress or nutlin-3 treatment did not down-regulate p16(INK4a). p53 did not repress the p16(INK4a) promoter activity either. These findings suggest that p53 has a necessary but not sufficient role in repressing p16(INK4a) expression. p16(INK4a) elevation in p53(-/-) cells is, at least partially, mediated by Ets1, a known positive regulator of p16(INK4a), as p53 deficiency up-regulated Ets1 through protein stabilization and knockdown of Ets1 down-regulated p16(INK4a) expression in p53(-/-) mouse embryonic fibroblasts. These studies uncover a compensatory mechanism for the loss of p53 and provide a basis for targeting both p53 and p16(INK4a) in cancer therapy.
Leong
Wai Fook
WF
Cancer and Developmental Biology Division, The Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research, Singapore.
Chau
Jenny Fung Ling
JF
Li
Baojie
B
D000818:Animals; D015153:Blotting, Western; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism / Q000502:physiology; D051379:Mice; D050784:Proto-Oncogene Protein c-ets-1 / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction; D014158:Transcription, Genetic; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
D019941:Cyclin-Dependent Kinase Inhibitor p16; D050784:Proto-Oncogene Protein c-ets-1; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53