Mdm2 Regulates p53 mRNA Translation through Inhibitory Interactions with Ribosomal Protein L26

Yaara Ofir-Rosenfeld; Kristy Boggs; Dan Michael; Michael B. Kastan; Moshe Oren

doi:10.1016/j.molcel.2008.08.031

Mdm2 Regulates p53 mRNA Translation through Inhibitory Interactions with Ribosomal Protein L26

Yaara Ofir-Rosenfeld, Kristy Boggs, Dan Michael, Michael B. Kastan, Moshe Oren^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

196 Citations (Scopus)

Abstract

Mdm2 regulates the p53 tumor suppressor by promoting its proteasome-mediated degradation. Mdm2 and p53 engage in an autoregulatory feedback loop that maintains low p53 activity in nonstressed cells. We now report that Mdm2 regulates p53 levels also by targeting ribosomal protein L26. L26 binds p53 mRNA and augments its translation. Mdm2 binds L26 and drives its polyubiquitylation and proteasomal degradation. In addition, the binding of Mdm2 to L26 attenuates the association of L26 with p53 mRNA and represses L26-mediated augmentation of p53 protein synthesis. Under nonstressed conditions, both mechanisms help maintain low cellular p53 levels by constitutively tuning down p53 translation. In response to genotoxic stress, the inhibitory effect of Mdm2 on L26 is attenuated, enabling a rapid increase in p53 synthesis. The Mdm2-L26 interaction thus represents an additional important component of the autoregulatory feedback loop that dictates cellular p53 levels and activity.

Original language	English
Pages (from-to)	180-189
Number of pages	10
Journal	Molecular Cell
Volume	32
Issue number	2
DOIs	https://doi.org/10.1016/j.molcel.2008.08.031
Publication status	Published - 24 Oct 2008

Bibliographical note

National Cancer Institute; Dr. Miriam and Sheldon Adelson Medical Research Foundation; Prostate Cancer Foundation (Israel) Center of Excellence; Yad Abraham Center for Cancer Diagnosis and Therapy [R37ES05777, 2P30CA021765]; American Lebanese Syrian Associated Charities (ALSAC)We thank J. Wakim for help with the GST pull-down experiments; Y. Aylor for fruitful discussions: and B. Vogelstein, A. Levine, Y. Shiloh, and D. Bohmann for the gift of plasmids. Supported in part by grant R37 CA40099 from the National Cancer Institute, the Dr. Miriam and Sheldon Adelson Medical Research Foundation, a Prostate Cancer Foundation (Israel) Center of Excellence, and the Yad Abraham Center for Cancer Diagnosis and Therapy to M.O. grants R37ES05777 and 2P30CA021765 to M.B.K.; and the American Lebanese Syrian Associated Charities (ALSAC) of the St. Jude Children's Research Hospital.

All Science Journal Classification (ASJC) codes

Molecular Biology
Cell Biology

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10.1016/j.molcel.2008.08.031

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title = "Mdm2 Regulates p53 mRNA Translation through Inhibitory Interactions with Ribosomal Protein L26",

abstract = "Mdm2 regulates the p53 tumor suppressor by promoting its proteasome-mediated degradation. Mdm2 and p53 engage in an autoregulatory feedback loop that maintains low p53 activity in nonstressed cells. We now report that Mdm2 regulates p53 levels also by targeting ribosomal protein L26. L26 binds p53 mRNA and augments its translation. Mdm2 binds L26 and drives its polyubiquitylation and proteasomal degradation. In addition, the binding of Mdm2 to L26 attenuates the association of L26 with p53 mRNA and represses L26-mediated augmentation of p53 protein synthesis. Under nonstressed conditions, both mechanisms help maintain low cellular p53 levels by constitutively tuning down p53 translation. In response to genotoxic stress, the inhibitory effect of Mdm2 on L26 is attenuated, enabling a rapid increase in p53 synthesis. The Mdm2-L26 interaction thus represents an additional important component of the autoregulatory feedback loop that dictates cellular p53 levels and activity.",

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Mdm2 Regulates p53 mRNA Translation through Inhibitory Interactions with Ribosomal Protein L26

Abstract

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