Characterization of the Role of the PP2A-AB Gene, a Putative Tumor Suppressor, in Cell Growth and Tumorigenesis



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The PP2A-Aβ gene (PPP2R1B) encodes the β isoform of the A subunit of serine/threonine protein phosphatase 2A. Mutations in PP2A-Aβ have been identified in a wide variety of human cancers. The important role of protein phosphatase 2A in down regulating cell growth suggests these mutations may contribute to cancer susceptibility and tumorigenesis by compromising the function of PP2A-Aβ and that PP2A-Aβ may act as a tumor suppressor. Screening of cancer patient DNAs revealed an association between a germline alteration of the PP2A-Aβ and breast carcinoma and identified alterations of PP2A-Aβ in lung carcinoma and ALL patient genomic DNAs. The biochemical consequences of these PP2A-Aβ mutations on PP2A function were investigated by in vitro and in vivo coimmunoprecipitations between the PP2A-Aβ subunit and the B and C subunits of PP2A. These studies showed mutations in PP2A-Aβ confer a loss of function by reducing its ability to bind the B and C subunits, destabilizing the PP2A-Aβ containing PP2A complex. The affect of the PP2A-Aβ gene on cell growth was analyzed by transfecting the PP2A-Aβ gene into cancer cell line deficient for wild type PP2A-Aβ and deriving stable cell lines. The PP2A-Aβ gene appeared to confer a relative disadvantage to transfected cells, resulting in a lower fraction of derived stable lines compared to controls. These cell lines were tested for proliferation and colony formation in soft agar. No significant difference was observed in the growth rate of PP2A-Aβ cell lines compared to controls. One of the PP2A-Aβ stable cell lines demonstrated dramatic suppression of colony formation in soft agar, but this was not confirmed in any additional PP2A-Aβ stable cell lines, leaving this finding inconclusive. The stable cell lines were also analyzed by Western blotting for changes in the Wnt signaling cascade. Cell lines expressing exogenous PP2A-Aβ are found to have lower levels of β-catenin compared to control cell lines. This suggests that the PP2A-Aβ gene is involved in regulating the Wnt signaling pathway, which is shown to be involved in cell growth control and is similarly affected by known tumor suppressor genes.

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