Endoplasmic reticulum stress accelerates p53 degradation by the cooperative actions of Hdm2 and glycogen synthase kinase 3beta.
Inactivation of the tumor suppressor p53 by degradation is a mechanism utilized by cells to adapt to endoplasmic reticulum (ER) stress. However, the mechanisms of p53 destabilization by ER stress are not known. We demonstrate here that the E3 ubiquitin-ligase Hdm2 is essential for the nucleocytoplasmic transport and proteasome-dependent degradation of p53 in ER-stressed cells. We also demonstrate that p53 phosphorylation at S315 and S376 is required for its nuclear export and degradation by Hdm2 without interfering with the ubiquitylation process. Furthermore, we show that p53 destabilization in unstressed cells utilizes the cooperative action of Hdm2 and glycogen synthase kinase 3beta, a process that is enhanced in cells exposed to ER stress. In contrast to other stress pathways that stabilize p53, our findings further substantiate a negative role of ER stress in p53 activation with important implications for the function of the tumor suppressor in cells with a dysfunctional ER.
Pluquet
Olivier
O
Lady Davis Institute for Medical Research, McGill University, Sir Mortimer B. Davis-Jewish General Hospital, 3755 Cote-Ste-Catherine Street, Montreal, Quebec H3T 1E2, Canada.
Qu
Li-Ke
LK
Baltzis
Dionissios
D
Koromilas
Antonis E
AE
D000818:Animals; D002460:Cell Line; D003513:Cycloheximide / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D051379:Mice; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000502:physiology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D021381:Protein Transport; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D019284:Thapsigargin / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D014415:Tunicamycin / Q000494:pharmacology; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
D005231:Fatty Acids, Unsaturated; D007976:Leupeptins; D011500:Protein Synthesis Inhibitors; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; D014415:Tunicamycin; D012694:Serine; D019284:Thapsigargin; D004317:Doxorubicin; D003513:Cycloheximide; D044767:Ubiquitin-Protein Ligases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; C038753:leptomycin B