Mutant p53 gain of function: repression of CD95(Fas/APO-1) gene expression by tumor-associated p53 mutants.
Tumor-associated mutant forms of p53 can exert an antiapoptotic gain of function activity, which probably confers a selective advantage upon tumor cells harboring such mutations. We report that mutant p53 suppresses the expression of the CD95 (Fas/APO-1) gene, encoding a death receptor implicated in a variety of apoptotic responses. Moderate (40-50%) downregulation of CD95 mRNA and surface protein expression by mutant p53 correlates with partial protection against CD95-dependent cell death. Excess mutant p53 represses the transcriptional activity of the CD95 promoter, with the extent of repression varying among different tumor-associated p53 mutants. Furthermore, mutant p53 protein binds the CD95 promoter in vitro, in a region distinct from the one implicated in tight interactions of the CD95 gene with wild-type p53. Hence, the CD95 promoter is likely to be a direct target for downregulation by mutant p53. This activity of mutant p53 may contribute to its gain of function effects in oncogenesis.
Zalcenstein
Amir
A
Department of Molecular Cell Biology, Weizmann Institute of Science, PO Box 26, Rehovot, 76100, Israel.
Stambolsky
Perry
P
Weisz
Lilach
L
Müller
Martina
M
Wallach
David
D
Goncharov
Tanya M
TM
Krammer
Peter H
PH
Rotter
Varda
V
Oren
Moshe
M
D017209:Apoptosis; D015536:Down-Regulation; D006801:Humans; D009154:Mutation; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis; D012097:Repressor Proteins / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*; D019014:fas Receptor / Q000032:analysis / Q000235:genetics*
D012333:RNA, Messenger; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; D019014:fas Receptor