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M302715200v1
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Papers In Press, published online ahead of print August 12, 2003
J. Biol. Chem, 10.1074/jbc.M302715200
Submitted on March 17, 2003
Revised on August 12, 2003
Accepted on August 12, 2003

Protein phosphatase 2A associates with Rb2/p130 and mediates retinoic acid induced growth suppression of ovariancarcinoma cells

Scott C. Vuocolo, Enhksetseg Purev, Dongmei Zhang, Jiri Bartek, Klaus Hansen, Dianne Robert Soprano, and Kenneth J. Soprano

Microbiology and Immunology, Temple University School of Medicine, Philadelphia, PA 19001

Corresponding Author: scottvuocolo{at}hotmail.com

Levels of Rb2/p130 protein are increased 5-10 fold following all-trans retinoic acid (ATRA) treatment of the retinoid sensitive ovarian adenocarcinoma cell line CAOV3, but not the retinoid resistant SKOV3 adenocarcinoma cell line. We found that this increase in Rb2/p130 protein in ATRA treated CAOV3 cells was the result of an increased protein stability. Moreover, Rb2/p130 exhibited a decreased ubiquitination following ATRA treatment. Since phosphorylation frequently mediates ubiquitination of proteins, we examined the serine/threonine phosphatase activity in our CAOV3 cells following ATRA treatment. A significant increase in ser/thr phosphatase activity was found, and correlated to a rise in the level of serine/threonine phosphatase PP2A catalytic subunit alpha. In addition, co-immunoprecipitation and GST-pulldown studies demonstrate that PP2A and Rb2/p130 associate. We have made use of a battery of Rb2/p130 mutants to determine the sites de-phosphorylated in response to ATRA treatment of CAOV3 cells. Obligate CDK4 phosphorylation sites seemed most important to the stability of the protein, and are among the candidate sites that are de-phosphorylated by PP2A following ATRA treatment. Finally, using both siRNA specific to the catalytic subunit of PP2A, as well as a variant of the SKOV3 cell line which overexpresses PP2A, we have shown that modulation of PP2A protein level correlates to the ability of ATRA to inhibit growth of ovarian carcinoma cells. Our data suggest that ATRA mediates growth inhibition by stabilizing Rb2/p130 via a mechanism that involves induction of PP2A, an enzyme which can potentially dephosphorylate Rb2/p130 thereby protecting it from degradation by the proteasome.


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