The tetramerization domain of p53 is required for efficient BAK oligomerization.
In addition to a well-defined transcriptional activity that is necessary for efficient apoptosis induction, the p53 tumor suppressor also has a direct apoptogenic role at the mitochondria. This direct role in cell death is mediated at least in part by interaction of p53 with BCL2 family members, including the pro-apoptotic protein BAK. Whereas it is currently accepted that the mitochondrial function of p53 contributes to its tumor suppressive role, the regulation of p53 function at this organelle is poorly understood. In this manuscript we examine the role of p53 oligomerization in the regulation of its pro-apoptotic function at the mitochondria, specifically in regard to its ability to induce BAK oligomerization. We find that deletion or mutation of p53's oligomerization domain markedly impairs the ability of this protein to oligomerize BAK. Along these lines, cross-linking studies indicate that the majority of p53 localized to mitochondria is in dimeric or higher-order oligomeric form. In support of the importance of the p53-BAK interaction in the localization of p53 to mitochondria, we find that mouse embryo fibroblasts from the BAK null mouse have greatly reduced mitochondrial p53 compared to wild type fibroblasts. These data indicate that pro-apoptotic BAK, unlike other BCL2 family members, may serve as a major receptor for p53 on the mitochondria.
Pietsch
E Christine
EC
Program in Cell and Developmental Biology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
Leu
J I-Ju
JI
Frank
Amanda
A
Dumont
Patrick
P
George
Donna L
DL
Murphy
Maureen E
ME
D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D004622:Embryo, Mammalian / Q000166:cytology / Q000382:microbiology; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D008928:Mitochondria / Q000737:chemistry / Q000378:metabolism*; D009154:Mutation; D017434:Protein Structure, Tertiary; D017384:Sequence Deletion; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics / Q000378:metabolism*
D016159:Tumor Suppressor Protein p53; D050998:bcl-2 Homologous Antagonist-Killer Protein