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Molecular Biology, Pathobiology and Genetics |
Subunits Induce Functional Haploinsufficiency and Tumorigenicity
1 Department of Medical Oncology, Dana-Farber Cancer Institute and Departments of Medicine, Brigham and Women's Hospital and 2 Department of Pathology, Harvard Medical School, Boston, Massachusetts; 3 Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts; and 4 Department of Toxicology, School of Public Health, Zhongshan University, Guangzhou, P.R. China
Requests for reprints: William C. Hahn, Dana-Farber Cancer Institute, 44 Binney Street, Dana 710C, Boston, MA 02115. Phone: 617-632-2641; Fax: 617-632-2375; E-mail: william_hahn{at}dfci.harvard.edu.
The introduction of SV40 small t antigen or the suppression of PP2A B56
subunit expression contributes to the experimental transformation of human cells. To investigate the role of cancer-associated PP2A A
subunit mutants in transformation, we introduced several PP2A A mutants into immortalized but nontumorigenic human cells. These PP2A A 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 A expression activated the AKT pathway and permitted cells to form tumors in immunodeficient mice. These findings suggest that cancer-associated A mutations contribute to cancer development by inducing functional haploinsufficiency, disturbing PP2A holoenzyme composition, and altering the enzymatic activity of PP2A.
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