Ribosomal stress couples the unfolded protein response to p53-dependent cell cycle arrest

Fang Zhang, Robert B. Hamanaka, Ekaterina Bobrovnikova-Marjon, John D. Gordan, Mu Shui Dai, Hua Lu, M. Celeste Simon, J. Alan Diehl

Research output: Contribution to journalArticle

79 Scopus citations

Abstract

Protein misfolding in the endoplasmic reticulum (ER) triggers a signaling pathway termed the unfolded protein response pathway (UPR). UPR signaling is transduced through the transmembrane ER effectors PKR-like ER kinase (PERK), inositol requiring kinase-1 (IRE-1), and activating transcription factor 6 (ATF6). PERK activation triggers phosphorylation of eIF2α leading to repression of protein synthesis, thereby relieving ER protein load and directly inhibiting cyclin D1 translation thereby contributing to cell cycle arrest. However, PERK-/- murine embryonic fibroblasts have an attenuated G1/S arrest that is not attributable to cyclin D1 loss, suggesting a cyclin D1-independent mechanism. Here we show that the UPR triggers p53 accumulation and activation. UPR induction promotes enhanced interaction between the ribosome proteins (rpL5, rpL11, and rpL23) and Hdm2 in a PERK-dependent manner. Interaction with ribosomal proteins results in inhibition of Hdm2-mediated ubiquitination and degradation of p53. Our data demonstrate that ribosomal subunit:Hdm2 association couples the unfolded protein response to p53-dependent cell cycle arrest.

Original languageEnglish (US)
Pages (from-to)30036-30045
Number of pages10
JournalJournal of Biological Chemistry
Volume281
Issue number40
DOIs
StatePublished - Oct 6 2006

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Zhang, F., Hamanaka, R. B., Bobrovnikova-Marjon, E., Gordan, J. D., Dai, M. S., Lu, H., Simon, M. C., & Diehl, J. A. (2006). Ribosomal stress couples the unfolded protein response to p53-dependent cell cycle arrest. Journal of Biological Chemistry, 281(40), 30036-30045. https://doi.org/10.1074/jbc.M604674200