TY - JOUR
T1 - Ribosomal stress couples the unfolded protein response to p53-dependent cell cycle arrest
AU - Zhang, Fang
AU - Hamanaka, Robert B.
AU - Bobrovnikova-Marjon, Ekaterina
AU - Gordan, John D.
AU - Dai, Mu Shui
AU - Lu, Hua
AU - Simon, M. Celeste
AU - Diehl, J. Alan
PY - 2006/10/6
Y1 - 2006/10/6
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.M604674200
DO - 10.1074/jbc.M604674200
M3 - Article
C2 - 16893887
AN - SCOPUS:33749564033
SN - 0021-9258
VL - 281
SP - 30036
EP - 30045
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 40
ER -