Abstract
In response to stimuli that activate p53, cells can undergo either apoptosis or cell cycle arrest, depending on the precise pattern of p53 target genes that is activated. We show here that Zbtb4, a transcriptional repressor protein, associates with the Sin3/histone deacetylase co-repressor and represses expression of P21CIP1 as part of a heterodimeric complex with Miz1. In vivo, expression of ZBTB4 is downregulated in advanced stages of multiple human tumours. In cell culture, depletion of ZBTB4 promotes cell cycle arrest in response to activation of p53 and suppresses apoptosis through regulation of P21CIP1, thereby promoting long-term cell survival. Our data suggest that Zbtb4 is a critical determinant of the cellular response to p53 activation and reinforce the notion that p21Cip1 can provide an essential survival signal in cells with activated p53.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis
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Cell Cycle
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Child
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Cyclin-Dependent Kinase Inhibitor p21 / genetics*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Down-Regulation
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Gene Expression Regulation*
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Humans
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Kruppel-Like Transcription Factors / metabolism
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Neoplasms / genetics
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Neoplasms / metabolism
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Promoter Regions, Genetic
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Repressor Proteins / genetics
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Repressor Proteins / metabolism*
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Sin3 Histone Deacetylase and Corepressor Complex
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Transcription Factors / metabolism
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Transcription, Genetic
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Tumor Cells, Cultured
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Tumor Suppressor Protein p53 / metabolism*
Substances
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CDKN1A protein, human
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Cyclin-Dependent Kinase Inhibitor p21
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DNA-Binding Proteins
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Kruppel-Like Transcription Factors
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Repressor Proteins
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SIN3A transcription factor
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SIN3B protein, human
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Transcription Factors
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Tumor Suppressor Protein p53
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ZBTB17 protein, human
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ZBTB4 protein, human
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Sin3 Histone Deacetylase and Corepressor Complex