Mouse model for probing tumor suppressor activity of protein phosphatase 2A in diverse signaling pathways

Cell Cycle. 2012 Feb 1;11(3):451-9. doi: 10.4161/cc.11.3.19057. Epub 2012 Feb 1.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Benzopyrenes / toxicity
  • Disease Models, Animal
  • Fingolimod Hydrochloride
  • Gene Knock-In Techniques
  • Humans
  • Immunosuppressive Agents / pharmacology*
  • Immunosuppressive Agents / therapeutic use
  • Lung Neoplasms / chemically induced
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / genetics
  • Mice
  • Mice, Knockout
  • Point Mutation
  • Propylene Glycols / pharmacology
  • Propylene Glycols / therapeutic use
  • Protein Phosphatase 2 / chemistry
  • Protein Phosphatase 2 / genetics
  • Protein Phosphatase 2 / metabolism*
  • Signal Transduction / drug effects*
  • Sphingosine / analogs & derivatives
  • Sphingosine / pharmacology
  • Sphingosine / therapeutic use
  • Tumor Suppressor Protein p53 / metabolism
  • ras Proteins / genetics
  • ras Proteins / metabolism


  • Benzopyrenes
  • Immunosuppressive Agents
  • Propylene Glycols
  • Tumor Suppressor Protein p53
  • Protein Phosphatase 2
  • ras Proteins
  • Fingolimod Hydrochloride
  • Sphingosine