1. ¹Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, PA, USA
2. ²Department of Biochemistry, Temple University School of Medicine, Philadelphia, PA, USA

Correspondence: Dr KJ Soprano, Department of Microbiology and Immunology, Temple University School of Medicine, 3400 North Broad Street, Philadelphia, PA 19140, USA. E-mail: sopranok@temple.edu

Abstract

Despite a number of attempts to improve treatment of ovarian cancer, it remains the most common cause of death from gynecological cancers. Thus, it is very important to identify more effective drugs for treatment and prevention of ovarian cancer. All-trans-retinoic acid (ATRA) has been shown to arrest the growth of ovarian carcinoma cells in G0/G1 and to significantly elevate levels of Rb2/p130 protein, a member of the retinoblastoma family of tumor suppressors. As ATRA treatment leads to a significant increase in the amount of Rb2/p130 protein but not mRNA, the elevated levels of Rb2/p130 protein is likely the result of increased stability. In studies to elucidate the mechanism by which ATRA alters Rb2/p130 stability in ovarian cancer cells, it was determined that PP2A, a serine/threonine phosphatase, binds and dephosphorylates Rb2/p130. Dephosphorylated Rb2/p130 exhibits decreased ubiquitination and thus is not degraded by the proteasome. The sites at which PP2A catalytic subunit (PP2Ac) interacts with Rb2/p130 have been localized to the NLS in the C-terminus of Rb2/p130. These sites are also involved in the interaction of Rb/p130 with importin and importin , members of the nuclear transport machinery. It is known that importin recognizes a NLS on a target protein and importin binds the nuclear pore complex. Moreover, it has been shown that the binding of importin to NLS significantly decreases with phosphorylation of NLS. In ATRA-treated ovarian carcinoma cells, PP2A binds to Rb2/p130 and dephosphorylates the NLS of Rb2/p130 leading to the interaction of importin with Rb2/p130. Importin then binds to the importin -Rb2/p130 complex, leading to the translocation of the Rb2/p130 to the nucleus where it acts to arrest ovarian cancer cells in G1 and suppress proliferation.