Analysis of p53 new function for protein synthesis and identification of new anti-cancer target

• Project/Area Number: 26893181
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Biological pharmacy
• Research Institution: Kochi University
• Principal Investigator: Takushi Namba 高知大学, 教育研究部総合科学系複合領域科学部門, 特任助教 (10729859)
• Project Period (FY): 2014-08-29 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000); Fiscal Year 2015: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2014: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 小胞体 / p53 / 癌 / IRE1 / 小胞ストレス

Outline of Final Research Achievements

Altered regulation of ER stress response has been implicated in a variety of human diseases. Excessive ER function contributes to malignant phenotypes, such as chemoresistance and metastasis. Here we identified that the tumor suppressor p53 regulates ER function in response to stresses. 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. 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.

Research Products

• [Int'l Joint Research] Harvard medical school(米国)
• [Journal Article] Loss of p53 enhances the function of the endoplasmic reticulum through activation of the IRE1α/XBP1 pathway. (2015)
  • Author(s): Namba, T., Chu, K., Kodama, K., Byun, S., Yoon, KW., Hiraki, M., Mandinova, A., and Lee, S. W.
  • Journal Title: Oncotarget Volume: 24 Issue: 24 Pages: 19990-20001
  • DOI: 10.18632/oncotarget.4598
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Small-Molecule Reactivation of Mutant p53 to Wild-Type-like p53 through the p53-Hsp40 Regulatory Axis. (2015)
  • Author(s): Hiraki, M., Hwang, S. Y., Cao, S., Ramadhar, T. R., Byun, S., Yoon, K. W., Lee, K. H., Chu, K., Gurkar, A. U., Kolev, V., Zhang, J., Namba, T., Murphy, M. E., Newman, D. J., Mandinova, A., Clardy, J., and Lee, S. W.
  • Journal Title: Chemstry & Biology Volume: 22 Issue: 9 Pages: 1206-1216
  • DOI: 10.1016/j.chembiol.2015.07.016
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Regulation of endoplasmic reticulum function (2015)
  • Author(s): Namba T
  • Journal Title: Aging Volume: 7 Pages: 901-902
  • Open Access
• [Journal Article] Losing p53 loosens up ER-stress (2015)
  • Author(s): Byun, S., Namba, T., and Lee, S. W.
  • Journal Title: Aging Volume: 7 Pages: 895-896
  • Open Access / Int'l Joint Research
• [Presentation] p53の機能喪失はIRE1/XBP1経路の活性化を誘導し、癌細胞における小胞体の機能を亢進させる (2014)
  • Author(s): 難波卓司
  • Organizer: 第9回 臨床ストレス応答学会
  • Place of Presentation: 岡山大学
  • Year and Date: 2014-11-01 – 2014-11-02
• [Presentation] p53の機能喪失はIRE1/XBP1経路の活性化を誘導し、癌細胞における小胞体の機能を亢進させる (2014)
  • Author(s): 難波卓司
  • Organizer: 第87回日本生化学会大会
  • Place of Presentation: 京都
  • Year and Date: 2014-10-15 – 2014-10-18
• [Remarks] 難波研究室
  • URL: http://www.cc.kochi-u.ac.jp/~t-namba/
• [Remarks] 高知大学総合研究センターの難波卓司特任助教らの論文
  • URL: http://www.kochi-u.ac.jp/information/2016010600039/