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Mechanisms of the HRSL3 tumor suppressor function in ovarian carcinoma cells
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| Zeitschriftentitel: | Journal of Cell Science |
|---|---|
| Personen und Körperschaften: | , , |
| In: | Journal of Cell Science, 120, 2007, 8, S. 1393-1404 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
The Company of Biologists
|
| Schlagwörter: |
| author_facet |
Nazarenko, Irina Schäfer, Reinhold Sers, Christine Nazarenko, Irina Schäfer, Reinhold Sers, Christine |
|---|---|
| author |
Nazarenko, Irina Schäfer, Reinhold Sers, Christine |
| spellingShingle |
Nazarenko, Irina Schäfer, Reinhold Sers, Christine Journal of Cell Science Mechanisms of the HRSL3 tumor suppressor function in ovarian carcinoma cells Cell Biology |
| author_sort |
nazarenko, irina |
| spelling |
Nazarenko, Irina Schäfer, Reinhold Sers, Christine 1477-9137 0021-9533 The Company of Biologists Cell Biology http://dx.doi.org/10.1242/jcs.000018 <jats:p>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 α-isoform of the regulatory subunit A of protein phosphatase 2A (PR65α) as a new interaction partner of HRSL3. Interaction between HRSL3 and PR65α was confirmed in vitro and by co-immunoprecipitation in mammalian cells. We demonstrate that HRSL3 binds to the endogenous PR65α, 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 PR65α 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 PKCζ 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.</jats:p> Mechanisms of the HRSL3 tumor suppressor function in ovarian carcinoma cells Journal of Cell Science |
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| title |
Mechanisms of the HRSL3 tumor suppressor function in ovarian carcinoma cells |
| title_unstemmed |
Mechanisms of the HRSL3 tumor suppressor function in ovarian carcinoma cells |
| title_full |
Mechanisms of the HRSL3 tumor suppressor function in ovarian carcinoma cells |
| title_fullStr |
Mechanisms of the HRSL3 tumor suppressor function in ovarian carcinoma cells |
| title_full_unstemmed |
Mechanisms of the HRSL3 tumor suppressor function in ovarian carcinoma cells |
| title_short |
Mechanisms of the HRSL3 tumor suppressor function in ovarian carcinoma cells |
| title_sort |
mechanisms of the hrsl3 tumor suppressor function in ovarian carcinoma cells |
| topic |
Cell Biology |
| url |
http://dx.doi.org/10.1242/jcs.000018 |
| publishDate |
2007 |
| physical |
1393-1404 |
| description |
<jats:p>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 α-isoform of the regulatory subunit A of protein phosphatase 2A (PR65α) as a new interaction partner of HRSL3. Interaction between HRSL3 and PR65α was confirmed in vitro and by co-immunoprecipitation in mammalian cells. We demonstrate that HRSL3 binds to the endogenous PR65α, 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 PR65α 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 PKCζ 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.</jats:p> |
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| author | Nazarenko, Irina, Schäfer, Reinhold, Sers, Christine |
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| description | <jats:p>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 α-isoform of the regulatory subunit A of protein phosphatase 2A (PR65α) as a new interaction partner of HRSL3. Interaction between HRSL3 and PR65α was confirmed in vitro and by co-immunoprecipitation in mammalian cells. We demonstrate that HRSL3 binds to the endogenous PR65α, 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 PR65α 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 PKCζ 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.</jats:p> |
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| imprint | The Company of Biologists, 2007 |
| imprint_str_mv | The Company of Biologists, 2007 |
| institution | DE-D275, DE-Bn3, DE-Brt1, DE-Zwi2, DE-D161, DE-Gla1, DE-Zi4, DE-15, DE-Pl11, DE-Rs1, DE-105, DE-14, DE-Ch1, DE-L229 |
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| physical | 1393-1404 |
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| series | Journal of Cell Science |
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| spelling | Nazarenko, Irina Schäfer, Reinhold Sers, Christine 1477-9137 0021-9533 The Company of Biologists Cell Biology http://dx.doi.org/10.1242/jcs.000018 <jats:p>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 α-isoform of the regulatory subunit A of protein phosphatase 2A (PR65α) as a new interaction partner of HRSL3. Interaction between HRSL3 and PR65α was confirmed in vitro and by co-immunoprecipitation in mammalian cells. We demonstrate that HRSL3 binds to the endogenous PR65α, 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 PR65α 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 PKCζ 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.</jats:p> Mechanisms of the HRSL3 tumor suppressor function in ovarian carcinoma cells Journal of Cell Science |
| spellingShingle | Nazarenko, Irina, Schäfer, Reinhold, Sers, Christine, Journal of Cell Science, Mechanisms of the HRSL3 tumor suppressor function in ovarian carcinoma cells, Cell Biology |
| title | Mechanisms of the HRSL3 tumor suppressor function in ovarian carcinoma cells |
| title_full | Mechanisms of the HRSL3 tumor suppressor function in ovarian carcinoma cells |
| title_fullStr | Mechanisms of the HRSL3 tumor suppressor function in ovarian carcinoma cells |
| title_full_unstemmed | Mechanisms of the HRSL3 tumor suppressor function in ovarian carcinoma cells |
| title_short | Mechanisms of the HRSL3 tumor suppressor function in ovarian carcinoma cells |
| title_sort | mechanisms of the hrsl3 tumor suppressor function in ovarian carcinoma cells |
| title_unstemmed | Mechanisms of the HRSL3 tumor suppressor function in ovarian carcinoma cells |
| topic | Cell Biology |
| url | http://dx.doi.org/10.1242/jcs.000018 |