title: Role of Pirh2 in mediating the regulation of p53 and c-Myc.
abstract: Ubiquitylation is fundamental for the regulation of the stability and function of p53 and c-Myc. The E3 ligase Pirh2 has been reported to polyubiquitylate p53 and to mediate its proteasomal degradation. Here, using Pirh2 deficient mice, we report that Pirh2 is important for the in vivo regulation of p53 stability in response to DNA damage. We also demonstrate that c-Myc is a novel interacting protein for Pirh2 and that Pirh2 mediates its polyubiquitylation and proteolysis. Pirh2 mutant mice display elevated levels of c-Myc and are predisposed for plasma cell hyperplasia and tumorigenesis. Consistent with the role p53 plays in suppressing c-Myc-induced oncogenesis, its deficiency exacerbates tumorigenesis of Pirh2(-/-) mice. We also report that low expression of human PIRH2 in lung, ovarian, and breast cancers correlates with decreased patients' survival. Collectively, our data reveal the in vivo roles of Pirh2 in the regulation of p53 and c-Myc stability and support its role as a tumor suppressor.
authors: Ontario Cancer Institute, University Health Network and Department of Medical Biophysics, University of Toronto, Toronto, Canada. ahakem@uhnres.utoronto.ca
authors: Anne
authors: A
authors: Hakem
authors: Miyuki
authors: M
authors: Bohgaki
authors: Bénédicte
authors: B
authors: Lemmers
authors: Elisabeth
authors: E
authors: Tai
authors: Leonardo
authors: L
authors: Salmena
authors: Elzbieta
authors: E
authors: Matysiak-Zablocki
authors: Yong-Sam
authors: YS
authors: Jung
authors: Jana
authors: J
authors: Karaskova
authors: Lilia
authors: L
authors: Kaustov
authors: Shili
authors: S
authors: Duan
authors: Jason
authors: J
authors: Madore
authors: Paul
authors: P
authors: Boutros
authors: Yi
authors: Y
authors: Sheng
authors: Marta
authors: M
authors: Chesi
authors: P Leif
authors: PL
authors: Bergsagel
authors: Bayardo
authors: B
authors: Perez-Ordonez
authors: Anne-Marie
authors: AM
authors: Mes-Masson
authors: Linda
authors: L
authors: Penn
authors: Jeremy
authors: J
authors: Squire
authors: Xinbin
authors: X
authors: Chen
authors: Igor
authors: I
authors: Jurisica
authors: Cheryl
authors: C
authors: Arrowsmith
authors: Otto
authors: O
authors: Sanchez
authors: Samuel
authors: S
authors: Benchimol
authors: Razqallah
authors: R
authors: Hakem
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D057809:HEK293 Cells; D006801:Humans; D053208:Kaplan-Meier Estimate; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D011836:Radiation Tolerance; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000235:genetics
chemical_list: C489427:MYC protein, human; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C485369:RCHY1 protein, human; C568505:Rchy1 protein, mouse; D044767:Ubiquitin-Protein Ligases