Identification of p53 Regulators by Genome-Wide Functional Analysis

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 101; no. 10; pp. 3456 - 3461
• Main Authors: Huang, Qihong, Raya, Angel, DeJesus, Paul, Chao, Sheng-Hao, Quon, Kim C., Caldwell, Jeremy S., Chanda, Sumit K., Izpisua-Belmonte, Juan C., Schultz, Peter G.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 09.03.2004; National Acad Sciences
• Subjects: Animals; Apoptosis; Basic Helix-Loop-Helix Transcription Factors; Biological Sciences; Cell Line; Cell Transformation, Neoplastic; Cellular biology; Chick Embryo; Complementary DNA; Danio rerio; DNA, Complementary - genetics; Embryos; FLJ11339 gene; Freshwater; Gene expression; Gene Expression Regulation; Genes; Genes, p53; Genotype & phenotype; HCT116 cells; HES1 gene; HEY1 gene; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; M17S2 gene; Mice; NR2F2 gene; Osr1 gene; Phenotype; Phenotypes; Plasmids; Protein Processing, Post-Translational; Proteins; ras gene; Regulator genes; Repressor Proteins - genetics; Repressor Proteins - metabolism; SFRS10 gene; TFAP4 gene; Transcription Factor HES-1; Transcription Factors - genetics; Transcription Factors - metabolism; Transcription, Genetic; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumors; Zebrafish
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0308562100

The p53 tumor-suppressor protein is a critical mediator of cellular growth arrest and the induction of apoptosis. To identify proteins involved in the modulation of p53 transcriptional activity, a gain-of-function cellular screen was carried out with an arrayed matrix of ≈20,000 cDNAs. Nine genes previously unknown to be involved in regulating p53 activity were identified. Overexpression of seven of these genes (Hey1, Hes1, TFAP4, Osr1, NR2F2, SFRS10, and FLI11339) resulted in up-regulation of p53 activity; overexpression of two genes (M17S2 and cathepsin B) resulted in down-regulation of p53 activity in mammalian cells. HES1, HEY1, and TFAP4, which are members of the basic helix-loop-helix transcription family, and OSR1 were shown to activate p53 through repression of HDM2 transcription. Ectopic expression of these basic helix-loop-helix transcription factors in both zebrafish and avian developmental systems activated p53 and induced apoptosis in vivo, resulting in a phenotype similar to that of p53 overexpression. Furthermore, ras- and myc-mediated transformation of mouse embryonic fibroblasts was abrogated by expression of HEY1 in a p53-dependent manner. These results suggest that these transcription factors are members of an evolutionarily conserved network that governs p53 function.