title: Mouse model for probing tumor suppressor activity of protein phosphatase 2A in diverse signaling pathways.
abstract: Evidence that protein phosphatase 2A (PP2A) is a tumor suppressor in humans came from the discovery of mutations in the genes encoding the Aα and Aβ subunits of the PP2A trimeric holoenzymes, Aα-B-C and Aβ-B-C. One point mutation, Aα-E64D, was found in a human lung carcinoma. It renders Aα specifically defective in binding regulatory B' subunits. Recently, we reported a knock-in mouse expressing Aα-E64D and an Aα knockout mouse. The mutant mice showed a 50-60% increase in the incidence of lung cancer induced by benzopyrene. Importantly, PP2A's tumor suppressor activity depended on p53. These data provide the first direct evidence that PP2A is a tumor suppressor in mice. In addition, they suggest that PP2A is a tumor suppressor in humans. Here, we report that PP2A functions as a tumor suppressor in mice that develop lung cancer triggered by oncogenic K-ras. We discuss whether PP2A may function as a tumor suppressor in diverse tissues, with emphasis on endometrial and ovarian carcinomas, in which Aα mutations were detected at a high frequency. We propose suitable mouse models for examining whether PP2A functions as tumor suppressor in major growth-stimulatory signaling pathways, and we discuss the prospect of using the PP2A activator FTY720 as a drug against malignancies that are driven by these pathways.
authors.affiliation: Department of Pathology, University of California, San Diego, La Jolla, CA, USA. gwalter@ucsd.edu
authors.forename: Gernot
authors.initials: G
authors.lastname: Walter
authors.forename: Ralf
authors.initials: R
authors.lastname: Ruediger
mesh_terms: D000818:Animals; D001580:Benzopyrenes / Q000633:toxicity; D004195:Disease Models, Animal; D000068876:Fingolimod Hydrochloride; D055879:Gene Knock-In Techniques; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D008175:Lung Neoplasms / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D017354:Point Mutation; D011409:Propylene Glycols / Q000494:pharmacology / Q000627:therapeutic use; D054648:Protein Phosphatase 2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D001580:Benzopyrenes; D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D016159:Tumor Suppressor Protein p53; D054648:Protein Phosphatase 2; D018631:ras Proteins; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine