Physical and functional antagonism between tumor suppressor protein p53 and fortilin, an anti-apoptotic protein

Yanjie Chen, Takayuki Fujita, Di Zhang, Hung Doan, Decha Pinkaew, Zhihe Liu, Jiaxin Wu, Yuichi Koide, Andrew Chiu, Curtis Chen Jen Lin, Jui Yoa Chang, Ke He Ruan, Ken Fujise

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

Tumor suppressor protein p53, our most critical defense against tumorigenesis, can be made powerless by mechanisms such as mutations and inhibitors. Fortilin, a 172-amino acid polypeptide with potent anti-apoptotic activity, is up-regulated in many human malignancies. However, the exact mechanism by which fortilin exerts its anti-apoptotic activity remains unknown. Here we present significant insight. Fortilin binds specifically to the sequence-specific DNA binding domain of p53. The interaction of fortilin with p53 blocks p53-induced transcriptional activation of Bax. In addition, fortilin, but not a double point mutant of fortilin lacking p53 binding, inhibits p53-dependent apoptosis. Furthermore, cells with wild-type p53 and fortilin, but not cells with wild-type p53 and the double point mutant of fortilin lacking p53 binding, fail to induce Bax gene and apoptosis, leading to the formation of large tumor in athymic mice. Our results suggest that fortilin is a novel p53-interacting molecule and p53 inhibitor and that it is a logical molecular target in cancer therapy.

Original languageEnglish (US)
Pages (from-to)32575-32585
Number of pages11
JournalJournal of Biological Chemistry
Volume286
Issue number37
DOIs
StatePublished - Sep 16 2011

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Chen, Y., Fujita, T., Zhang, D., Doan, H., Pinkaew, D., Liu, Z., Wu, J., Koide, Y., Chiu, A., Lin, C. C. J., Chang, J. Y., Ruan, K. H., & Fujise, K. (2011). Physical and functional antagonism between tumor suppressor protein p53 and fortilin, an anti-apoptotic protein. Journal of Biological Chemistry, 286(37), 32575-32585. https://doi.org/10.1074/jbc.M110.217836