Mutant p53 protects cells from 12-O-tetradecanoylphorbol-13-acetate-induced death by attenuating activating transcription factor 3 induction.
Mutations in p53 are ubiquitous in human tumors. Some p53 mutations not only result in loss of wild-type (WT) activity but also grant additional functions, termed "gain of function." In this study, we explore how the status of p53 affects the immediate response gene activating transcription factor 3 (ATF3) in the 12-O-tetradecanoylphorbol-13-acetate (TPA)-protein kinase C (PKC) pathway. We show that high doses of TPA induce ATF3 in a WT p53-independent manner correlating with PKCs depletion and cell death. We show that cells harboring mutant p53 have attenuated ATF3 induction and are less sensitive to TPA-induced death compared with their p53-null counterparts. Mutagenesis analysis of the ATF3 promoter identified the regulatory motifs cyclic AMP-responsive element binding protein/ATF and MEF2 as being responsible for the TPA-induced activation of ATF3. Moreover, we show that mutant p53 attenuates ATF3 expression by two complementary mechanisms. It interacts with the ATF3 promoter and influences its activity via the MEF2 site, and additionally, it attenuates transcriptional expression of the ATF3 activator MEF2D. These data provide important insights into the molecular mechanisms that underlie mutant p53 gain of function.
Buganim
Yosef
Y
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
Kalo
Eyal
E
Brosh
Ran
R
Besserglick
Hila
H
Nachmany
Ido
I
Rais
Yoach
Y
Stambolsky
Perry
P
Tang
Xiaohu
X
Milyavsky
Michael
M
Shats
Igor
I
Kalis
Marina
M
Goldfinger
Naomi
N
Rotter
Varda
V
D051700:Activating Transcription Factor 3 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D006801:Humans; D026161:MADS Domain Proteins / Q000235:genetics / Q000378:metabolism; D064326:MEF2 Transcription Factors; D008969:Molecular Sequence Data; D009154:Mutation; D018006:Myogenic Regulatory Factors / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D013755:Tetradecanoylphorbol Acetate / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
C490449:ATF3 protein, human; D051700:Activating Transcription Factor 3; C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D026161:MADS Domain Proteins; D064326:MEF2 Transcription Factors; C578043:MEF2D protein, human; D018006:Myogenic Regulatory Factors; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D013755:Tetradecanoylphorbol Acetate