Overexpression of the oncoprotein prothymosin alpha triggers a p53 response that involves p53 acetylation.
Activation of the tumor suppressor protein p53 is a critical cellular response to various stress stimuli and to inappropriate activity of growth-promoting proteins, such as Myc, Ras, E2F, and beta-catenin. Protein stability and transcriptional activity of p53 are modulated by protein-protein interactions and post-translational modifications, including acetylation. Here, we show that inappropriate activity of prothymosin alpha (PTMA), an oncoprotein overexpressed in human cancers, triggers a p53 response. Overexpression of PTMA enhanced p53 transcriptional activity in reporter gene assays for p53 target gene promoters hdm2, p21, and cyclin G. Overexpressed PTMA resulted in increased mRNA and protein levels for endogenous p53 target genes, hdm2 and p21, and in growth suppression. In contrast, reduction of endogenous PTMA through RNA interference decreased p53 transcriptional activity. Histone acetyltransferases (HATs) act as p53 coactivators and acetylate p53. PTMA, known to interact with HATs, led to increased levels of acetylated p53. PTMA did not increase the transcriptional activity of an acetylation-deficient p53 mutant, suggesting that p53 acetylation is an indispensable part of the p53 response to PTMA. Chromatin immunoprecipitation assays showed that excess PTMA associates with the p21 promoter and results in increased levels of acetylated p53 at the p21 promoter. Our findings indicate that overexpressed PTMA elicits a p53 response that involves p53 acetylation.
Kobayashi
Takahiko
T
Hokkaido University Medical Hospital, Primary Care Medicine, Sapporo, Japan. 1961koba@med.hokudai.ac.jp
Wang
Ting
T
Maezawa
Masaji
M
Kobayashi
Masanobu
M
Ohnishi
Shunsuke
S
Hatanaka
Kazuteru
K
Hige
Shuhei
S
Shimizu
Yuichi
Y
Kato
Mototsugu
M
Asaka
Masahiro
M
Tanaka
Junji
J
Imamura
Masahiro
M
Hasegawa
Kiminori
K
Tanaka
Yoshiyuki
Y
Brachmann
Rainer K
RK
D000107:Acetylation; D045744:Cell Line, Tumor; D056746:Cyclin G; D056766:Cyclin G1; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis / Q000235:genetics; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics; D045325:HCT116 Cells; D006801:Humans; D011498:Protein Precursors / Q000096:biosynthesis* / Q000235:genetics; D051736:Proto-Oncogene Proteins c-mdm2 / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013947:Thymosin / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000235:genetics; D015533:Transcriptional Activation; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
C534702:CCNG1 protein, human; C493956:CDKN1A protein, human; D056746:Cyclin G; D056766:Cyclin G1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D011498:Protein Precursors; D012333:RNA, Messenger; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C040782:prothymosin alpha; D013947:Thymosin; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2