An ARF-independent c-MYC-activated tumor suppression pathway mediated by ribosomal protein-Mdm2 Interaction.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Macias, E; Jin, A; Deisenroth, C; Bhat, K; Mao, H; Lindström, MS; Zhang, Y

Published Date

  • September 14, 2010

Published In

Volume / Issue

  • 18 / 3

Start / End Page

  • 231 - 243

PubMed ID

  • 20832751

Pubmed Central ID

  • 20832751

Electronic International Standard Serial Number (EISSN)

  • 1878-3686

Digital Object Identifier (DOI)

  • 10.1016/j.ccr.2010.08.007

Language

  • eng

Conference Location

  • United States