Acetylation of the DNA binding domain regulates transcription-independent apoptosis by p53.
The tumor suppressor p53 induces apoptosis by altering the transcription of pro-apoptotic targets in the nucleus and by a direct, nontranscriptional role at the mitochondria. Although the post-translational modifications regulating nuclear apoptotic functions of p53 have been thoroughly characterized, little is known of how transcription-independent functions are controlled. We and others identified acetylation of the p53 DNA binding domain at lysine 120 as a critical event in apoptosis induction. Although initial studies showed that Lys-120 acetylation plays a role in p53 function in the nucleus, we report here a role for Lys-120 acetylation in transcription-independent apoptosis. We demonstrate that the Lys-120-acetylated isoform of p53 is enriched at mitochondria. The acetylation of Lys-120 does not appear to regulate the ability of p53 to interact with the pro-apoptotic proteins BCL-XL and BAK. However, displacement of the inhibitory MCL-1 protein from BAK is compromised when Lys-120 acetylation is blocked. Functional studies show that mutation of Lys-120 to a nonacetylated residue, as occurs in human cancer, inhibits transcription-independent apoptosis, and enforced acetylation of Lys-120 enhances transcription-independent apoptosis. These data support a model whereby Lys-120 acetylation contributes to both the transcription-dependent and -independent apoptotic pathways induced by p53.
Sykes
Stephen M
SM
Biomedical Graduate Studies, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Stanek
Timothy J
TJ
Frank
Amanda
A
Murphy
Maureen E
ME
McMahon
Steven B
SB
D000107:Acetylation; D017209:Apoptosis; D001665:Binding Sites; D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000737:chemistry / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D017354:Point Mutation; D020033:Protein Isoforms / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
D064549:Myeloid Cell Leukemia Sequence 1 Protein; D020033:Protein Isoforms; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051020:bcl-X Protein; D004247:DNA; D008239:Lysine