5515

PPP2CA

PP2Ac|PP2CA|PP2Calpha|RP-C;protein phosphatase 2, catalytic subunit, alpha isozyme;PPP2CA;protein phosphatase 2, catalytic subunit, alpha isozyme

PP2A-alpha|protein phosphatase 2 (formerly 2A), catalytic subunit, alpha isoform|protein phosphatase 2A catalytic subunit, alpha isoform|replication protein C|serine/threonine protein phosphatase 2A, catalytic subunit, alpha isoform|serine/threonine-prote

5q31.1

protein-coding

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 Aalpha subunit, one of several regulatory B subunits, and the catalytic Calpha subunit. Aalpha mutations were discovered in a variety of human carcinomas. All carcinoma-associated mutant Aalpha subunits are defective in binding the B or B and C subunits. Here we describe two knock-in mice expressing cancer-associated Aalpha point mutants defective in binding B subunits, one knockout mouse expressing truncated Aalpha defective in B and C subunit binding, and a floxed mouse for generating conditional Aalpha knockouts. We found that the cancer-associated Aalpha 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 Aalpha mutation on cancer incidence is dependent on the tumor suppressor p53. The finding that the Aalpha 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.