title: The prolyl-isomerase Pin1 activates the mitochondrial death program of p53.
abstract: In response to intense stress, the tumor protein p53 (p53) tumor suppressor rapidly mounts a direct mitochondrial death program that precedes transcription-mediated apoptosis. By eliminating severely damaged cells, this pathway contributes to tumor suppression as well as to cancer cell killing induced by both genotoxic drugs and non-genotoxic p53-reactivating molecules. Here we have explored the role had in this pathway by the prolyl-isomerase Pin1 (peptidylprolyl cis/trans isomerase, NIMA-interacting 1), a crucial transducer of p53's phosphorylation into conformational changes unleashing its pro-apoptotic activity. We show that Pin1 promotes stress-induced localization of p53 to mitochondria both in vitro and in vivo. In particular, we demonstrate that upon stress-induced phosphorylation of p53 on Ser46 by homeodomain interacting protein kinase 2, Pin1 stimulates its mitochondrial trafficking signal, that is, monoubiquitination. This pathway is induced also by the p53-activating molecule RITA, and we demonstrate the strong requirement of Pin1 for the induction of mitochondrial apoptosis by this compound. These findings have significant implications for treatment of p53-expressing tumors and for prospective use of p53-activating compounds in clinics.
authors.affiliation: Laboratorio Nazionale CIB, Area Science Park, Padriciano 99, 34149 Trieste, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Sorrentino
authors.forename: M
authors.initials: M
authors.lastname: Mioni
authors.forename: C
authors.initials: C
authors.lastname: Giorgi
authors.forename: N
authors.initials: N
authors.lastname: Ruggeri
authors.forename: P
authors.initials: P
authors.lastname: Pinton
authors.forename: U
authors.initials: U
authors.lastname: Moll
authors.forename: F
authors.initials: F
authors.lastname: Mantovani
authors.forename: G
authors.initials: G
authors.lastname: Del Sal
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D005663:Furans / Q000494:pharmacology; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D019696:Peptidylprolyl Isomerase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D005663:Furans; C118989:NSC 652287; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; C115114:HIPK2 protein, human; D017346:Protein Serine-Threonine Kinases; D019696:Peptidylprolyl Isomerase