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Mol Cell Biol 2011 Sep;31(18):3832-44. Epub 2011 Jul

Human Cancer-Associated Mutations in A{alpha} Subunit of Protein Phosphatase 2A Increase Lung Cancer Incidence in A{alpha} Knock-in and Knockout Mice.

Ruediger, R; Ruiz, J; Walter, G.

Department of Pathology, University of California at San Diego, La Jolla, CA 92093-0612, USA.

Strong evidence has indicated that protein phosphatase 2A (PP2A) is a tumor suppressor, but a mouse model for testing the tumor suppressor activity was missing. The most abundant forms of trimeric PP2A holoenzyme consist of the scaffolding A subunit, one of several regulatory B subunits, and the catalytic C subunit. A mutations were discovered in a variety of human carcinomas. All carcinoma-associated mutant A subunits are defective in binding the B or B and C subunits. Here we describe two knock-in mice expressing cancer-associated A point mutants defective in binding B' subunits, one knockout mouse expressing truncated A defective in B and C subunit binding, and a floxed mouse for generating conditional A knockouts. We found that the cancer-associated A mutations increased the incidence of cancer by 50 to 60% in lungs of FVB mice treated with benzopyrene, demonstrating that PP2A acts as a tumor suppressor. We show that the effect of A mutation on cancer incidence is dependent on the tumor suppressor p53. The finding that the A mutation E64D, which was detected in a human lung carcinoma, increases the lung cancer incidence in mice suggests that this mutation also played a role in the development of the carcinoma in which it was discovered.

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