title: Loss of p53 enhances the function of the endoplasmic reticulum through activation of the IRE1α/XBP1 pathway.
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.
authors.affiliation: Science Research Center, Kochi University, Kohasu Oko-cho Nankoku-shi, Kochi, Japan.|Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
authors.forename: Takushi
authors.initials: T
authors.lastname: Namba
authors.affiliation: Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
authors.forename: Kiki
authors.initials: K
authors.lastname: Chu
authors.affiliation: Science Research Center, Kochi University, Kohasu Oko-cho Nankoku-shi, Kochi, Japan.
authors.forename: Rika
authors.initials: R
authors.lastname: Kodama
authors.affiliation: Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
authors.forename: Sanguine
authors.initials: S
authors.lastname: Byun
authors.affiliation: Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
authors.forename: Kyoung Wan
authors.initials: KW
authors.lastname: Yoon
authors.affiliation: Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Hiraki
authors.affiliation: Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Mandinova
authors.affiliation: Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
authors.forename: Sam W
authors.initials: SW
authors.lastname: Lee
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000502:physiology*; D004722:Endoribonucleases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D045325:HCT116 Cells; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000071701:Regulatory Factor X Transcription Factors; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D000071717:X-Box Binding Protein 1
chemical_list: D004268:DNA-Binding Proteins; D000071701:Regulatory Factor X Transcription Factors; C556690:STF 083010; D013449:Sulfonamides; C495901:TP53 protein, human; D013876:Thiophenes; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse; C482345:SYVN1 protein, human; D044767:Ubiquitin-Protein Ligases; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases; D046988:Proteasome Endopeptidase Complex
keywords: ER function; IRE1α/XBP1 pathway; p53 target genes; tumor suppressor p53