title: p53Ψ is a transcriptionally inactive p53 isoform able to reprogram cells toward a metastatic-like state.
abstract: Although much is known about the underlying mechanisms of p53 activity and regulation, the factors that influence the diversity and duration of p53 responses are not well understood. Here we describe a unique mode of p53 regulation involving alternative splicing of the TP53 gene. We found that the use of an alternative 3' splice site in intron 6 generates a unique p53 isoform, dubbed p53Ψ. At the molecular level, p53Ψ is unable to bind to DNA and does not transactivate canonical p53 target genes. However, like certain p53 gain-of-function mutants, p53Ψ attenuates the expression of E-cadherin, induces expression of markers of the epithelial-mesenchymal transition, and enhances the motility and invasive capacity of cells through a unique mechanism involving the regulation of cyclophilin D activity, a component of the mitochondrial inner pore permeability. Hence, we propose that p53Ψ encodes a separation-of-function isoform that, although lacking canonical p53 tumor suppressor/transcriptional activities, is able to induce a prometastatic program in a transcriptionally independent manner.
authors: Cold Spring Harbor Laboratory Cancer Center, Cold Spring Harbor, NY 11724;
authors: Serif
authors: S
authors: Senturk
authors: Cold Spring Harbor Laboratory Cancer Center, Cold Spring Harbor, NY 11724;
authors: Zhan
authors: Z
authors: Yao
authors: Cold Spring Harbor Laboratory Cancer Center, Cold Spring Harbor, NY 11724;
authors: Matthew
authors: M
authors: Camiolo
authors: Department of Cardiothoracic Surgery, Weill Cornell Medical Center, New York, NY 10065;
authors: Brendon
authors: B
authors: Stiles
authors: Memorial Sloan-Kettering Cancer Center, New York, NY 10065;
authors: Trushar
authors: T
authors: Rathod
authors: Bioengineering Department, University of Pennsylvania, Philadelphia, PA 19104; and.
authors: Alice M
authors: AM
authors: Walsh
authors: Department of Pathology, Stony Brook University, Stony Brook, NY 11794.
authors: Alice
authors: A
authors: Nemajerova
authors: Bioengineering Department, University of Pennsylvania, Philadelphia, PA 19104; and.
authors: Matthew J
authors: MJ
authors: Lazzara
authors: Department of Cardiothoracic Surgery, Weill Cornell Medical Center, New York, NY 10065;
authors: Nasser K
authors: NK
authors: Altorki
authors: Cold Spring Harbor Laboratory Cancer Center, Cold Spring Harbor, NY 11724;
authors: Adrian
authors: A
authors: Krainer
authors: Department of Pathology, Stony Brook University, Stony Brook, NY 11794.
authors: Ute M
authors: UM
authors: Moll
authors: Memorial Sloan-Kettering Cancer Center, New York, NY 10065;
authors: Scott W
authors: SW
authors: Lowe
authors: Memorial Sloan-Kettering Cancer Center, New York, NY 10065;
authors: Luca
authors: L
authors: Cartegni
authors: Cold Spring Harbor Laboratory Cancer Center, Cold Spring Harbor, NY 11724; sordella@cshl.edu.
authors: Raffaella
authors: R
authors: Sordella
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D051927:CD24 Antigen / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D016158:Genes, p53; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D007438:Introns; D055370:Lung Injury / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D009154:Mutation; D009362:Neoplasm Metastasis / Q000235:genetics*; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D022821:RNA Splice Sites; D017382:Reactive Oxygen Species / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D051927:CD24 Antigen; C497889:CD24 protein, human; C497483:CD44 protein, human; D015820:Cadherins; D000081406:Peptidyl-Prolyl Isomerase F; D018960:Hyaluronan Receptors; C000631446:PPIF protein, mouse; D020033:Protein Isoforms; D022821:RNA Splice Sites; D017382:Reactive Oxygen Species; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D021983:Cyclophilins
keywords: cancer; reactive oxygen species