GAS41 is required for repression of the p53 tumor suppressor pathway during normal cellular proliferation.
GAS41 is a common subunit of the TIP60 and SRCAP complexes and is essential for cell growth and viability. Here, we report that GAS41 is required for repression of the p53 tumor suppressor pathway during normal cellular proliferation. Either GAS41 small interfering RNA-mediated knockdown of GAS41 expression or specific interruptions of the carboxy-terminal coiled-coil motif of the GAS41 protein activate the p53 tumor suppressor pathway, as evidenced by p53 up-regulation, p53 serine-15 phosphorylation, and p21 transcriptional activation. Activation of the p53 pathway does not result from changes in TIP60 complex assembly or TIP60 coactivator functions for p53, since a TIP60 complex containing a coiled-coil mutant of GAS41 retains the same composition and histone acetyltransferase activity as its wild-type counterpart and since mutant GAS41 does not compromise ectopic p53-dependent transcriptional activation in a reporter gene assay. Finally, we demonstrate that GAS41 is prebound to the promoters of two p53 tumor suppressor pathway genes (p21 and p14ARF) in normal unstressed cells but is dissociated from both promoters in response to stress signals that activate p53. Our data suggest that GAS41 plays a role in repressing the p53 tumor suppressor pathway during the normal cell cycle by a TIP60-independent mechanism.
Park
Jeong Hyeon
JH
Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, NY 10021, USA.
Roeder
Robert G
RG
D000251:Adenosine Triphosphatases / Q000378:metabolism; D020816:Amino Acid Motifs; D002453:Cell Cycle; D049109:Cell Proliferation; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D051548:Histone Acetyltransferases / Q000378:metabolism; D006801:Humans; D000074443:Lysine Acetyltransferase 5; D009154:Mutation / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D021122:Protein Subunits / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D012097:Repressor Proteins / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000737:chemistry / Q000172:deficiency / Q000378:metabolism*; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000378:metabolism
D050759:Cyclin-Dependent Kinase Inhibitor p21; D021122:Protein Subunits; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D014157:Transcription Factors; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; C109446:YEATS4 protein, human; D051548:Histone Acetyltransferases; C098489:KAT5 protein, human; D000074443:Lysine Acetyltransferase 5; D000251:Adenosine Triphosphatases; C119652:SRCAP protein, human