Cancer-associated PP2A Aα subunits induce functional haploinsufficiency and tumorigenicity

Abstract

The introduction of SV40 small t antigen or the suppression of PP2A B56γ subunit expression contributes to the experimental transformation of human cells. To investigate the role of cancer-associated PP2A Aα subunit mutants in transformation, we introduced several PP2A Aα mutants into immortalized but nontumorigenic human cells. These PP2A Aα mutants exhibited defects in binding to other PP2A subunits and impaired phosphatase activity. Although overexpression of these mutants failed to render immortalized cells tumorigenic, partial suppression of endogenous PP2A Aα expression activated the AKT pathway and permitted cells to form tumors in immunodeficient mice. These findings suggest that cancer-associated Aα mutations contribute to cancer development by inducing functional haploinsufficiency, disturbing PP2A holoenzyme composition, and altering the enzymatic activity of PP2A. ©2005 American Association for Cancer Research.