Regulation of p53 tetramerization and nuclear export by ARC.
Inactivation of the transcription factor p53 is central to carcinogenesis. Yet only approximately one-half of cancers have p53 loss-of-function mutations. Here, we demonstrate a mechanism for p53 inactivation by apoptosis repressor with caspase recruitment domain (ARC), a protein induced in multiple cancer cells. The direct binding in the nucleus of ARC to the p53 tetramerization domain inhibits p53 tetramerization. This exposes a nuclear export signal in p53, triggering Crm1-dependent relocation of p53 to the cytoplasm. Knockdown of endogenous ARC in breast cancer cells results in spontaneous tetramerization of endogenous p53, accumulation of p53 in the nucleus, and activation of endogenous p53 target genes. In primary human breast cancers with nuclear ARC, p53 is almost always WT. Conversely, nearly all breast cancers with mutant p53 lack nuclear ARC. We conclude that nuclear ARC is induced in cancer cells and negatively regulates p53.
Foo
Roger S-Y
RS
Departments of Medicine and Cell Biology, Cardiovascular Research Center, and Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Nam
Young-Jae
YJ
Ostreicher
Marc Jason
MJ
Metzl
Mark D
MD
Whelan
Russell S
RS
Peng
Chang-Fu
CF
Ashton
Anthony W
AW
Fu
Weimin
W
Mani
Kartik
K
Chin
Suet-Feung
SF
Provenzano
Elena
E
Ellis
Ian
I
Figg
Nichola
N
Pinder
Sarah
S
Bennett
Martin R
MR
Caldas
Carlos
C
Kitsis
Richard N
RN
D021581:Active Transport, Cell Nucleus; D001943:Breast Neoplasms / Q000196:embryology*; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D003598:Cytoskeletal Proteins / Q000378:metabolism / Q000502:physiology*; D019281:Dimerization; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D028884:Karyopherins / Q000378:metabolism; D008954:Models, Biological; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000378:metabolism / Q000502:physiology*; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000502:physiology*; D000097606:Exportin 1 Protein
D020169:Caspases; D003598:Cytoskeletal Proteins; D028884:Karyopherins; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear; D016159:Tumor Suppressor Protein p53; D000097606:Exportin 1 Protein; C495901:TP53 protein, human; C092069:activity regulated cytoskeletal-associated protein