Loss of p53 enhances the function of the endoplasmic reticulum through activation of the IRE1α/XBP1 pathway

Journal Reference

Oncotarget. 2015;6(24):19990-20001.

Namba T1,2, Chu K2, Kodama R1, Byun S2, Yoon KW2, Hiraki M2, Mandinova A2, Lee SW2.

[expand title=”Show Affiliations”]
  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.
[/expand]

Abstract

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.

Go To Oncotarget

Figure legend. U2OS cells expressing calreticulin-RFP were transduced with the pDsRed-ER vector to visualize the amount of endoplasmic reticulum using confocal microscopy.

 

Loss of p53 enhances function endoplasmic reticulum through activation of the IRE1. Global Medical Discovery