RT Journal Article
SR Electronic
T1 Human Cancer-Associated Mutations in Aα Subunit of Protein Phosphatase 2A Increase Lung Cancer Incidence in Aα Knock-in and Knockout Mice
JF Molecular and Cellular Biology
JO Mol. Cell. Biol.
FD American Society for Microbiology
SP MCB.05744-11
DO 10.1128/MCB.05744-11
A1 Ruediger, Ralf
A1 Ruiz, Jennifer
A1 Walter, Gernot
YR 2011
UL http://mcb.asm.org/content/early/2011/07/26/MCB.05744-11.abstract
AB Strong evidence indicates 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 Aα subunit, one of several regulatory B subunits, and the catalytic Cα subunit. Aα mutations were discovered in a variety of human carcinomas. All carcinoma-associated mutant Aα subunits are defective in binding B or B and C subunits. Here we describe two knock-in mice expressing cancer-associated Aα point mutants defective in binding B' subunits, one knockout mouse expressing truncated Aα defective in B and C subunit binding, and a floxed mouse for generating conditional Aα knockouts. We found that the cancer-associated Aα mutations increase the incidence of cancer by 50-60% in lung of FVB mice treated with benzopyrene, demonstrating that PP2A acts as tumor suppressor. We show that the effect of Aα mutation on cancer incidence is dependent on the tumor suppressor p53. The finding that Aα 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.