Abstract:
: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.
journal_name
Mol Cell Bioljournal_title
Molecular and cellular biologyauthors
Pluquet O,Qu LK,Baltzis D,Koromilas AEdoi
10.1128/MCB.25.21.9392-9405.2005subject
Has Abstractpub_date
2005-11-01 00:00:00pages
9392-405issue
21eissn
0270-7306issn
1098-5549pii
25/21/9392journal_volume
25pub_type
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