Cancer-associated PP2A Aalpha subunits induce functional haploinsufficiency and tumorigenicity.
The introduction of SV40 small t antigen or the suppression of PP2A B56gamma subunit expression contributes to the experimental transformation of human cells. To investigate the role of cancer-associated PP2A Aalpha subunit mutants in transformation, we introduced several PP2A Aalpha mutants into immortalized but nontumorigenic human cells. These PP2A Aalpha 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 Aalpha expression activated the AKT pathway and permitted cells to form tumors in immunodeficient mice. These findings suggest that cancer-associated Aalpha mutations contribute to cancer development by inducing functional haploinsufficiency, disturbing PP2A holoenzyme composition, and altering the enzymatic activity of PP2A.
Chen
Wen
W
Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
Arroyo
Jason D
JD
Timmons
Jamie C
JC
Possemato
Richard
R
Hahn
William C
WC
D000595:Amino Acid Sequence; D001483:Base Sequence; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D004789:Enzyme Activation; D006238:Haploidy; D006801:Humans; D016297:Mutagenesis, Site-Directed; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D021122:Protein Subunits; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
D021122:Protein Subunits; D051057:Proto-Oncogene Proteins c-akt; D010749:Phosphoprotein Phosphatases