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J. Biol. Chem., Vol. 278, Issue 43, 41881-41889, October 24, 2003

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Protein Phosphatase 2A Associates with Rb2/p130 and Mediates Retinoic Acid-induced Growth Suppression of Ovarian Carcinoma Cells^*

Scott Vuocolo, Enkhtsetseg Purev, Dongmei Zhang, Jiri Bartek¶, Klaus Hansen¶, Dianne Robert Soprano||**, and Kenneth J. Soprano**

From the Microbiology and Immunology and ^||Biochemistry and the ^**Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140 and the ^¶Institute of Cancer Biology, Danish Cancer Society, Copenhagen 2100, Denmark

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 adenocarcinoma cell line SKOV3. We found that this increase in Rb2/p130 protein levels in ATRA-treated CAOV3 cells was the result of an increased protein stability. Moreover, Rb2/p130 exhibited a decreased ubiquitination following ATRA treatment. Because 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, which correlated with a rise in the level of protein phosphatase 2A (PP2A) catalytic subunit-. In addition, co-immunoprecipitation and glutathione S-transferase pull-down studies demonstrated that PP2A and Rb2/p130 associate. We have made use of a battery of Rb2/p130 mutants to determine the sites dephosphorylated 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 dephosphorylated by PP2A following ATRA treatment. Finally, using both small interfering RNA specific to the catalytic subunit of PP2A and a variant of the SKOV3 cell line that overexpresses PP2A, we have shown that modulation of PP2A protein levels correlates with 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 that can potentially dephosphorylate Rb2/p130, thereby protecting it from degradation by the proteasome.

Received for publication, March 17, 2003 , and in revised form, August 4, 2003.

^* This work was supported in part by National Institutes of Health Grants DE 13139 and CA 64945 (to K. J. S.) and National Institutes of Health Training Grant 5T32AI0710 (to the Department of Microbiology and Immunology, Temple University School of Medicine and S. V.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Microbiology and Immunology, Temple University School of Medicine, 3400 North Broad St., Philadelphia, PA 19140. Tel.: 215-707-7774; E-mail: sopranok{at}temple.edu.

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