Role of Pirh2 in mediating the regulation of p53 and c-Myc

Anne Hakem, Miyuki Bohgaki, Bénédicte Lemmers, Elisabeth Tai, Leonardo Salmena, Elzbieta Matysiak-Zablocki, Yong Sam Jung, Jana Karaskova, Lilia Kaustov, Shili Duan, Jason Madore, Paul Boutros, Yi Sheng, Marta Chesi, P. Leif Bergsagel, Bayardo Perez-Ordonez, Anne Marie Mes-Masson, Linda Penn, Jeremy Squire, Xinbin ChenIgor Jurisica, Cheryl Arrowsmith, Otto Sanchez, Samuel Benchimol, Razqallah Hakem

Research output: Contribution to journalArticle

41 Scopus citations

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.

Original languageEnglish (US)
Article numbere1002360
JournalPLoS Genetics
Volume7
Issue number11
DOIs
StatePublished - Nov 2011

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

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    Hakem, A., Bohgaki, M., Lemmers, B., Tai, E., Salmena, L., Matysiak-Zablocki, E., Jung, Y. S., Karaskova, J., Kaustov, L., Duan, S., Madore, J., Boutros, P., Sheng, Y., Chesi, M., Bergsagel, P. L., Perez-Ordonez, B., Mes-Masson, A. M., Penn, L., Squire, J., ... Hakem, R. (2011). Role of Pirh2 in mediating the regulation of p53 and c-Myc. PLoS Genetics, 7(11), [e1002360]. https://doi.org/10.1371/journal.pgen.1002360