KAISO, a critical regulator of p53-mediated transcription of CDKN1A and apoptotic genes.

Koh DI, Han D, Ryu H, Choi WI, Jeon BN, Kim MK, Kim Y, Kim JY, Parry L, Clarke AR, Reynolds AB, Hur MW
Proc Natl Acad Sci U S A. 2014 111 (42): 15078-83

PMID: 25288747 · PMCID: PMC4210320 · DOI:10.1073/pnas.1318780111

An unresolved issue in genotoxic stress response is identification of induced regulatory proteins and how these activate tumor suppressor p53 to determine appropriate cell responses. Transcription factor KAISO was previously described to repress transcription following binding to methylated DNA. In this study, we show that KAISO is induced by DNA damage in p53-expressing cells and then interacts with the p53-p300 complex to increase acetylation of p53 K320 and K382 residues, although decreasing K381 acetylation. Moreover, the p53 with this particular acetylation pattern shows increased DNA binding and potently induces cell cycle arrest and apoptosis by activating transcription of CDKN1A (cyclin-dependent kinase inhibitor 1) and various apoptotic genes. Analogously, in Kaiso KO mouse embryonic fibroblast cells, p53-to-promoter binding and up-regulation of p21 and apoptosis gene expression is significantly compromised. KAISO may therefore be a critical regulator of p53-mediated cell cycle arrest and apoptosis in response to various genotoxic stresses in mammalian cells.

MeSH Terms (24)

Acetylation Animals Apoptosis Cell Cycle Cell Line Cell Proliferation Cyclin-Dependent Kinase Inhibitor p21 DNA DNA Damage DNA Methylation E1A-Associated p300 Protein Female Fibroblasts HCT116 Cells HEK293 Cells Humans Mice Mice, Inbred C57BL Mice, Knockout Promoter Regions, Genetic Protein Binding Response Elements Transcription Factors Tumor Suppressor Protein p53

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