title: Regulation of p53 tetramerization and nuclear export by ARC.
abstract: 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.
authors: Departments of Medicine and Cell Biology, Cardiovascular Research Center, and Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors: Roger S-Y
authors: RS
authors: Foo
authors: Young-Jae
authors: YJ
authors: Nam
authors: Marc Jason
authors: MJ
authors: Ostreicher
authors: Mark D
authors: MD
authors: Metzl
authors: Russell S
authors: RS
authors: Whelan
authors: Chang-Fu
authors: CF
authors: Peng
authors: Anthony W
authors: AW
authors: Ashton
authors: Weimin
authors: W
authors: Fu
authors: Kartik
authors: K
authors: Mani
authors: Suet-Feung
authors: SF
authors: Chin
authors: Elena
authors: E
authors: Provenzano
authors: Ian
authors: I
authors: Ellis
authors: Nichola
authors: N
authors: Figg
authors: Sarah
authors: S
authors: Pinder
authors: Martin R
authors: MR
authors: Bennett
authors: Carlos
authors: C
authors: Caldas
authors: Richard N
authors: RN
authors: Kitsis
mesh_terms: 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
chemical_list: 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