TY - JOUR
T1 - An ARF-Independent c-MYC-activated tumor suppression pathway mediated by ribosomal protein-Mdm2 interaction
AU - Macias, Everardo
AU - Jin, Aiwen
AU - Deisenroth, Chad
AU - Bhat, Krishna
AU - Mao, Hua
AU - Lindström, Mikael S.
AU - Zhang, Yanping
N1 - Funding Information:
We thank K. Itahana, Y. Itahana, and K. Gooding for their helpful advice and technical assistance. Y.Z. is a recipient of a Career Award in Biomedical Science from the Burroughs Wellcome Fund, Howard Temin Award from the National Cancer Institute, and Scholar Award from the Leukemia and Lymphoma Society. This study was supported by grants from the National Institutes of Health and the American Cancer Society to Y.Z.
PY - 2010/9
Y1 - 2010/9
N2 - In vitro studies have shown that inhibition of ribosomal biogenesis can activate p53 through ribosomal protein (RP)-mediated suppression of Mdm2 E3 ligase activity. To study the physiological significance of the RP-Mdm2 interaction, we generated mice carrying a cancer-associated cysteine-to-phenylalanine substitution in the zinc finger of Mdm2 that disrupted its binding to RPL5 and RPL11. Mice harboring this mutation, retain normal p53 response to DNA damage, but lack of p53 response to perturbations in ribosome biogenesis. Loss of RP-Mdm2 interaction significantly accelerates Eμ-Myc-induced lymphomagenesis. Furthermore, ribosomal perturbation-induced p53 response does not require tumor suppressor p19ARF. Collectively, our findings establish RP-Mdm2 interaction as a genuine p53 stress-signaling pathway activated by aberrant ribosome biogenesis and essential for safeguarding against oncogenic c-MYC-induced tumorigenesis.
AB - In vitro studies have shown that inhibition of ribosomal biogenesis can activate p53 through ribosomal protein (RP)-mediated suppression of Mdm2 E3 ligase activity. To study the physiological significance of the RP-Mdm2 interaction, we generated mice carrying a cancer-associated cysteine-to-phenylalanine substitution in the zinc finger of Mdm2 that disrupted its binding to RPL5 and RPL11. Mice harboring this mutation, retain normal p53 response to DNA damage, but lack of p53 response to perturbations in ribosome biogenesis. Loss of RP-Mdm2 interaction significantly accelerates Eμ-Myc-induced lymphomagenesis. Furthermore, ribosomal perturbation-induced p53 response does not require tumor suppressor p19ARF. Collectively, our findings establish RP-Mdm2 interaction as a genuine p53 stress-signaling pathway activated by aberrant ribosome biogenesis and essential for safeguarding against oncogenic c-MYC-induced tumorigenesis.
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U2 - 10.1016/j.ccr.2010.08.007
DO - 10.1016/j.ccr.2010.08.007
M3 - Article
C2 - 20832751
AN - SCOPUS:77956518791
SN - 1535-6108
VL - 18
SP - 231
EP - 243
JO - Cancer cell
JF - Cancer cell
IS - 3
ER -