TY - JOUR
T1 - Role of Pirh2 in mediating the regulation of p53 and c-Myc
AU - Hakem, Anne
AU - Bohgaki, Miyuki
AU - Lemmers, Bénédicte
AU - Tai, Elisabeth
AU - Salmena, Leonardo
AU - Matysiak-Zablocki, Elzbieta
AU - Jung, Yong Sam
AU - Karaskova, Jana
AU - Kaustov, Lilia
AU - Duan, Shili
AU - Madore, Jason
AU - Boutros, Paul
AU - Sheng, Yi
AU - Chesi, Marta
AU - Bergsagel, P. Leif
AU - Perez-Ordonez, Bayardo
AU - Mes-Masson, Anne Marie
AU - Penn, Linda
AU - Squire, Jeremy
AU - Chen, Xinbin
AU - Jurisica, Igor
AU - Arrowsmith, Cheryl
AU - Sanchez, Otto
AU - Benchimol, Samuel
AU - Hakem, Razqallah
PY - 2011/11
Y1 - 2011/11
N2 - 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.
AB - 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.
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U2 - 10.1371/journal.pgen.1002360
DO - 10.1371/journal.pgen.1002360
M3 - Article
C2 - 22125490
AN - SCOPUS:81755160906
SN - 1553-7390
VL - 7
JO - PLoS genetics
JF - PLoS genetics
IS - 11
M1 - e1002360
ER -