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Association of the viral oncoprotein STP-C488 with cellular ras
1New England Primate Research Center, Harvard Medical School, Southborough, Massachusetts 01772-9102, USA.
Abstract:
The STP-C488 oncogene of herpesvirus saimiri has transforming activity independent of the rest of the viral genome. We now demonstrate that STP-C488 associates with cellular ras in transformed cells. Mutations that disrupted this association with ras disrupted the transforming ability of the STP-C488 oncogene. Binding assays showed that STP-C488 was capable of competing with raf-1 for binding to ras. Expression of STP-C488 activated the ras signaling pathway as evidenced by a two- to fourfold increase in the ratio of ras-GTP to ras-GDP and by the constitutive activation of mitogen-activated protein kinase. Consistent with an activation of signaling through ras, STP-C488 expression induced ras-dependent neurite outgrowth in PC12 cells. STP-C488 is the first virus-encoded protein shown to achieve oncogenic transformation via association with cellular ras.
Insights
Herpesvirus saimiri
Area of Science:
- Oncogenic transformation
- Molecular biology
- Virology
Background:
- The STP-C488 oncogene from herpesvirus saimiri exhibits transforming activity.
- Its mechanism of action, independent of the viral genome, was previously unclear.
Purpose of the Study:
- To investigate the molecular mechanism by which the STP-C488 oncogene transforms cells.
- To determine if STP-C488 interacts with cellular signaling pathways, specifically the ras pathway.
Main Methods:
- Co-immunoprecipitation and binding assays to assess STP-C488 and ras interaction.
- Analysis of ras-GTP/GDP ratios and mitogen-activated protein kinase (MAPK) activation.
- Neurite outgrowth assays in PC12 cells to evaluate ras-dependent signaling.
Main Results:
- STP-C488 directly associates with cellular ras in transformed cells.
- Disruption of the STP-C488-ras interaction abolished the oncogene's transforming ability.
- STP-C488 competes with raf-1 for binding to ras, activating the ras signaling pathway.
- Increased ras-GTP levels and constitutive MAPK activation were observed.
- STP-C488 induced ras-dependent neurite outgrowth in PC12 cells.
Conclusions:
- STP-C488 oncogene transforms cells by directly associating with and activating cellular ras.
- This interaction leads to the activation of downstream signaling pathways, including MAPK.
- STP-C488 represents the first identified viral oncoprotein that achieves oncogenic transformation through interaction with the cellular ras pathway.