Identification of p53 regulators by genome-wide functional analysis.
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 approximately 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 FLJ11339) 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.
Department of Chemistry, The Scripps Research Institute, Mail Stop SR202, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Qihong
Q
Huang
Angel
A
Raya
Paul
P
DeJesus
Sheng-Hao
SH
Chao
Kim C
KC
Quon
Jeremy S
JS
Caldwell
Sumit K
SK
Chanda
Juan C
JC
Izpisua-Belmonte
Peter G
PG
Schultz
D000818:Animals; D017209:Apoptosis; D051792:Basic Helix-Loop-Helix Proteins; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D002642:Chick Embryo; D018076:DNA, Complementary / Q000235:genetics; D005786:Gene Expression Regulation; D016158:Genes, p53; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D010641:Phenotype; D011499:Protein Processing, Post-Translational; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D000072056:Transcription Factor HES-1; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism*; D015027:Zebrafish
D051792:Basic Helix-Loop-Helix Proteins; D018076:DNA, Complementary; D018398:Homeodomain Proteins; D012097:Repressor Proteins; D000072056:Transcription Factor HES-1; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C405694:Hairy, HRT1 protein; C489734:Hes1 protein, mouse