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J. Cell Sci. 120 (8): 1393-1404

Research Article

Mechanisms of the HRSL3 tumor suppressor function in ovarian carcinoma cells

Irina Nazarenko*, Reinhold Schäfer, and Christine Sers{ddagger}

Molecular Tumor Pathology, Institute of Pathology, University Medicine Charité Berlin, Schumannstrasse 20/21, 10117 Berlin, Germany

{ddagger} Author for correspondence (e-mail: christine.sers{at}charite.de)

Accepted for publication 29 January 2007.

Abstract: HRSL3 (also known as H-REV107-1) belongs to a class II tumor suppressor gene family and is downregulated in several human tumors including ovarian carcinomas. To unravel the mechanism of HRSL3 tumor suppressor action, we performed a yeast two-hybrid screen and identified the {alpha}-isoform of the regulatory subunit A of protein phosphatase 2A (PR65{alpha}) as a new interaction partner of HRSL3. Interaction between HRSL3 and PR65{alpha} was confirmed in vitro and by co-immunoprecipitation in mammalian cells. We demonstrate that HRSL3 binds to the endogenous PR65{alpha}, thereby partially sequestering the catalytic subunit PR36 from the PR65 protein complex, and inhibiting PP2A catalytic activity. Furthermore, binding of HRSL3 to PR65 induces apoptosis in ovarian carcinoma cells in a caspase-dependent manner. Using several mutant HRSL3 constructs, we identified the N-terminal proline-rich region within the HRSL3 protein as the domain that is relevant for both binding of PR65{alpha} and induction of programmed cell death. This suggests that the negative impact of HRSL3 onto PP2A activity is important for the HRSL3 pro-apoptotic function and indicates a role of PP2A in survival of human ovarian carcinomas. The analysis of distinct PP2A target molecules revealed PKC{zeta} as being involved in HRSL3 action. These data implicate HRSL3 as a signaling regulatory molecule, which is functionally involved in the oncogenic network mediating growth and survival of ovarian cancer cells.

Key Words: Tumor suppressor • HRSL3 • PP2A • Apoptosis

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