title: TP53exon-6 truncating mutations produce separation of function isoforms with pro-tumorigenic functions.
abstract: TP53truncating mutations are common in human tumors and are thought to give rise to p53-null alleles. Here, we show thatTP53exon-6 truncating mutations occur at higher than expected frequencies and produce proteins that lack canonical p53 tumor suppressor activities but promote cancer cell proliferation, survival, and metastasis. Functionally and molecularly, these p53 mutants resemble the naturally occurring alternative p53 splice variant, p53-psi. Accordingly, these mutants can localize to the mitochondria where they promote tumor phenotypes by binding and activating the mitochondria inner pore permeability regulator, Cyclophilin D (CypD). Together, our studies reveal thatTP53exon-6 truncating mutations, contrary to current beliefs, act beyond p53 loss to promote tumorigenesis, and could inform the development of strategies to target cancers driven by these prevalent mutations.
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, United States.|Graduate Program in Genetics, Stony Brook University, Stony Brook, United States.
authors.forename: Nitin H
authors.initials: NH
authors.lastname: Shirole
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, United States.|Graduate Program in Molecular and Cellular Biology, Stony Brook University, Stony Brook, United States.
authors.forename: Debjani
authors.initials: D
authors.lastname: Pal
authors.affiliation: Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, United States.
authors.forename: Edward R
authors.initials: ER
authors.lastname: Kastenhuber
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, United States.
authors.forename: Serif
authors.initials: S
authors.lastname: Senturk
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, United States.
authors.forename: Joseph
authors.initials: J
authors.lastname: Boroda
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, United States.
authors.forename: Paola
authors.initials: P
authors.lastname: Pisterzi
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, United States.
authors.forename: Madison
authors.initials: M
authors.lastname: Miller
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, United States.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Munoz
authors.affiliation: Department of Medicinal Chemistry, University of Ljubljana, Ljubljana, Slovenia.
authors.forename: Marko
authors.initials: M
authors.lastname: Anderluh
authors.affiliation: Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, United States.
authors.forename: Marc
authors.initials: M
authors.lastname: Ladanyi
authors.affiliation: Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, United States.
authors.forename: Scott W
authors.initials: SW
authors.lastname: Lowe
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, United States.|Graduate Program in Genetics, Stony Brook University, Stony Brook, United States.|Graduate Program in Molecular and Cellular Biology, Stony Brook University, Stony Brook, United States.
authors.forename: Raffaella
authors.identifier: 0000-0001-9745-1227
authors.initials: R
authors.lastname: Sordella
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D021983:Cyclophilins / Q000378:metabolism; D004195:Disease Models, Animal; D064593:Heterografts; D006801:Humans; D008819:Mice, Nude; D051336:Mitochondrial Membranes / Q000502:physiology; D009154:Mutation; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000473:pathology*; D010539:Permeability; D020033:Protein Isoforms; D017384:Sequence Deletion; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D000097322:Peptidyl-Prolyl Isomerase D
chemical_list: D021983:Cyclophilins; D020033:Protein Isoforms; D016159:Tumor Suppressor Protein p53; C495901:TP53 protein, human; C114456:PPID protein, human; D000097322:Peptidyl-Prolyl Isomerase D
keywords: CypD; TP53 truncations; cancer; cancer biology; cell biology; human; metastasis; mitochondria; mouse; tumor suppressor