title: Physical and functional antagonism between tumor suppressor protein p53 and fortilin, an anti-apoptotic protein.
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.
authors.affiliation: Division of Cardiology, Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas 77555, USA.
authors.forename: Yanjie
authors.initials: Y
authors.lastname: Chen
authors.forename: Takayuki
authors.initials: T
authors.lastname: Fujita
authors.forename: Di
authors.initials: D
authors.lastname: Zhang
authors.forename: Hung
authors.initials: H
authors.lastname: Doan
authors.forename: Decha
authors.initials: D
authors.lastname: Pinkaew
authors.forename: Zhihe
authors.initials: Z
authors.lastname: Liu
authors.forename: Jiaxin
authors.initials: J
authors.lastname: Wu
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Koide
authors.forename: Andrew
authors.initials: A
authors.lastname: Chiu
authors.forename: Curtis Chen-Jen
authors.initials: CC
authors.lastname: Lin
authors.forename: Jui-Yoa
authors.initials: JY
authors.lastname: Chang
authors.forename: Ke-He
authors.initials: KH
authors.lastname: Ruan
authors.forename: Ken
authors.initials: K
authors.lastname: Fujise
mesh_terms: D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D017354:Point Mutation; D011485:Protein Binding; D014183:Transplantation, Heterologous; D000090324:Tumor Protein, Translationally-Controlled 1; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis / Q000235:genetics
chemical_list: C494826:BAX protein, human; D014408:Biomarkers, Tumor; D051034:Inhibitor of Apoptosis Proteins; C495901:TP53 protein, human; D000090324:Tumor Protein, Translationally-Controlled 1; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein