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 Blood, 8 January 2009, Vol. 113, No. 2, pp. 422-428.
Prepublished online as a Blood First Edition Paper on October 9, 2008; DOI 10.1182/blood-2008-06-165134.

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MYELOID NEOPLASIA

Protein phosphatase 2A inactivates Bcl2's antiapoptotic function by dephosphorylation and up-regulation of Bcl2-p53 binding

Xingming Deng1, Fengqin Gao1, and W. Stratford May1

1 Department of Medicine, Division of Hematology/Oncology, University of Florida Shands Cancer Center, Gainesville

Bcl2 is associated with chemoresistance and poor prognosis in patients with various hematologic malignancies. DNA damage-induced p53/Bcl2 interaction at the outer mitochondrial membrane results in a Bcl2 conformational change with loss of its antiapoptotic activity in interleukin-3–dependent myeloid H7 cells. Here we find that specific disruption of protein phosphatase 2A (PP2A) activity by either expression of small t antigen or depletion of PP2A/C by RNA interference enhances Bcl2 phosphorylation and suppresses cisplatin-stimulated p53/Bcl2 binding in association with prolonged cell survival. By contrast, treatment of cells with C2-ceramide (a potent PP2A activator) or expression of the PP2A catalytic subunit (PP2A/C) inhibits Bcl2 phosphorylation, leading to increased p53/Bcl2 binding and apoptotic cell death. Mechanistically, PP2A-mediated dephosphorylation of Bcl2 in vitro promotes its direct interaction with p53 as well as a conformational change in Bcl2. PP2A directly interacts with the BH4 domain of Bcl2 as a docking site to potentially "bridge" PP2A to Bcl2's flexible loop domain containing the target serine 70 phosphorylation site. Thus, PP2A may provide a dual inhibitory effect on Bcl2's survival function by both dephosphorylating Bcl2 and enhancing p53-Bcl2 binding. Activating PP2A to dephosphorylate Bcl2 and/or increase Bcl2/p53 binding may represent an efficient and novel approach for treatment of hematologic malignancies.


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