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Updated: Jul 16, 2026
Heterotypic Three-dimensional In Vitro Modeling of Stromal-Epithelial Interactions During Ovarian Cancer Initiation and Progression
Published on: August 28, 2012
Mechanisms of the HRSL3 tumor suppressor function in ovarian carcinoma cells
Irina Nazarenko1, Reinhold Schäfer, Christine Sers
1Molecular Tumor Pathology, Institute of Pathology, University Medicine Charité Berlin, Schumannstrasse 20/21, 10117 Berlin, Germany.
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 (PR65alpha) as a new interaction partner of HRSL3. Interaction between HRSL3 and PR65alpha was confirmed in vitro and by co-immunoprecipitation in mammalian cells. We demonstrate that HRSL3 binds to the endogenous PR65alpha, 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 PR65alpha 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 PKCzeta 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.
Insights
HRSL3, a tumor suppressor, interacts with protein phosphatase 2A (PP2A) subunit PR65alpha, inhibiting its activity and inducing apoptosis in ovarian cancer cells. This highlights PP2A
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Signaling
Background:
- HRSL3 is a tumor suppressor gene downregulated in ovarian carcinomas.
- Understanding HRSL3's mechanism is crucial for cancer therapy.
Purpose of the Study:
- To elucidate the mechanism of HRSL3 tumor suppressor activity.
- To identify HRSL3 interaction partners and their functional consequences.
Main Methods:
- Yeast two-hybrid screen to identify interacting proteins.
- In vitro and co-immunoprecipitation assays to confirm interactions.
- Analysis of HRSL3 mutants and PP2A target molecules.
Main Results:
- HRSL3 interacts with PR65alpha, a regulatory subunit of PP2A.
- HRSL3 binding inhibits PP2A catalytic activity by sequestering PR36.
- HRSL3 induces caspase-dependent apoptosis in ovarian cancer cells.
- The N-terminal proline-rich region of HRSL3 is critical for PR65alpha binding and apoptosis induction.
- PKCzeta is implicated as a downstream target in HRSL3 action.
Conclusions:
- HRSL3 acts as a signaling regulator by inhibiting PP2A activity.
- PP2A plays a role in the survival of ovarian carcinomas.
- HRSL3's pro-apoptotic function is linked to PP2A inhibition.
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