Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

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


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Evolution of Retinoid and Steroid Signaling: Vertebrate Diversification from an Amphioxus Perspective.
R. Albalat, F. Brunet, V. Laudet, and M. Schubert (2011)
Genome Biol Evol 3, 985-1005
   Abstract »    Full Text »    PDF »
The DNA binding factor Hmg20b is a repressor of erythroid differentiation.
F. Esteghamat, T. B. van Dijk, H. Braun, S. Dekker, R. van der Linden, J. Hou, P. Fanis, J. Demmers, W. van IJcken, Z. Ozgur, et al. (2011)
Haematologica 96, 1252-1260
   Abstract »    Full Text »    PDF »
Atypical Protein Kinase C {zeta} Exhibits a Proapoptotic Function in Ovarian Cancer.
I. Nazarenko, M. Jenny, J. Keil, C. Gieseler, K. Weisshaupt, J. Sehouli, S. Legewie, L. Herbst, W. Weichert, S. Darb-Esfahani, et al. (2010)
Mol. Cancer Res. 8, 919-934
   Abstract »    Full Text »    PDF »
The tumor suppressor gene H-Rev107 functions as a novel Ca2+-independent cytosolic phospholipase A1/2 of the thiol hydrolase type.
T. Uyama, J. Morishita, X.-H. Jin, Y. Okamoto, K. Tsuboi, and N. Ueda (2009)
J. Lipid Res. 50, 685-693
   Abstract »    Full Text »    PDF »
Identification and Functional Characterization of Adipose-specific Phospholipase A2 (AdPLA).
R. E. Duncan, E. Sarkadi-Nagy, K. Jaworski, M. Ahmadian, and H. S. Sul (2008)
J. Biol. Chem. 283, 25428-25436
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882