Ribosomal stress couples the unfolded protein response to p53-dependent cell cycle arrest.
Protein misfolding in the endoplasmic reticulum (ER) triggers a signaling pathway termed the unfolded protein response path-way (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 eIF2alpha 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 G(1)/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.
Zhang
Fang
F
Leonard and Madlyn Abramson Family Cancer Research Institute and Howard Hughes Medical Institute, University of Pennsylvania Cancer Center, Philadelphia, Pennsylvania 19104, USA.
Hamanaka
Robert B
RB
Bobrovnikova-Marjon
Ekaterina
E
Gordan
John D
JD
Dai
Mu-Shui
MS
Lu
Hua
H
Simon
M Celeste
MC
Diehl
J Alan
JA
D002453:Cell Cycle / Q000502:physiology*; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D045325:HCT116 Cells; D006801:Humans; D017510:Protein Folding; D012270:Ribosomes / Q000737:chemistry* / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D013312:Stress, Physiological / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000172:deficiency / Q000502:physiology*
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016159:Tumor Suppressor Protein p53