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Loss of p53 enhances the function of the endoplasmic reticulum through activation of the IRE1α/XBP1 pathway
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Takushi Namba1,2,*, Kiki Chu2,*, Rika Kodama1, Sanguine Byun2, Kyoung Wan Yoon2, Masatsugu Hiraki2 Anna Mandinova2 and Sam W. Lee2
1 Science Research Center, Kochi University, Kohasu Oko-cho Nankoku-shi, Kochi, Japan
2 Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA
* These authors have contributed equally to this work
Sam W. Lee, email:
Takushi Namba, email:
Keywords: tumor suppressor p53, p53 target genes, ER function, IRE1α/XBP1 pathway
Received: April 27, 2015 Accepted: June 18, 2015 Published: June 23, 2015
Altered regulation of ER stress response has been implicated in a variety of human diseases, such as cancer and metabolic diseases. Excessive ER function contributes to malignant phenotypes, such as chemoresistance and metastasis. Here we report that the tumor suppressor p53 regulates ER function in response to stress. We found that loss of p53 function activates the IRE1α/XBP1 pathway to enhance protein folding and secretion through upregulation of IRE1α and subsequent activation of its target XBP1. We also show that wild-type p53 interacts with synoviolin (SYVN1)/HRD1/DER3, a transmembrane E3 ubiquitin ligase localized to ER during ER stress and removes unfolded proteins by reversing transport to the cytosol from the ER, and its interaction stimulates IRE1α degradation. Moreover, IRE1α inhibitor suppressed protein secretion, induced cell death in p53-deficient cells, and strongly suppressed the formation of tumors by p53-deficient human tumor cells in vivo compared with those that expressed wild-type p53. Therefore, our data imply that the IRE1α/XBP1 pathway serves as a target for therapy of chemoresistant tumors that express mutant p53.
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