title: Cytoplasmic CUL9/PARC ubiquitin ligase is a tumor suppressor and promotes p53-dependent apoptosis.
abstract: A wide range of cell stresses, including DNA damage, signal to p53 through posttranslational modification of p53. The cytoplasmic functions of p53 are emerging as an important constituent of role of p53 in tumor suppression. Here, we report that deletion of the Cul9 (formerly Parc) gene, which encodes an E3 ubiquitin ligase that binds to p53 and localizes in the cytoplasm, resulted in spontaneous tumor development, accelerated Eμ-Myc-induced lymphomagenesis, and rendered mice susceptible to carcinogenesis. Cul9-p53 double-mutant mice exhibited indistinguishable tumor phenotypes as p53 single-mutant mice, indicating that the function of Cul9 in tumor suppression is largely mediated by p53. Deletion of Cul9 had no significant effect on cell-cycle progression, but attenuated DNA damage-induced apoptosis. Ectopic expression of wild-type CUL9, but not a point mutant CUL9 deficient in p53 binding, promotes apoptosis. These results show CUL9 as a potential p53-activating E3 ligase in the cytoplasm.
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599-7295, USA.
authors.forename: Xin-Hai
authors.initials: XH
authors.lastname: Pei
authors.forename: Feng
authors.initials: F
authors.lastname: Bai
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Li
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Smith
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Whitewolf
authors.forename: Ran
authors.initials: R
authors.lastname: Jin
authors.forename: Yue
authors.initials: Y
authors.lastname: Xiong
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D016259:Genes, myc; D006801:Humans; D008223:Lymphoma / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D012509:Sarcoma / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism
chemical_list: D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases