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Tumor induction by a transformation-defective polyoma virus mutant blocked in signaling through Shc
1Tufts University School of Veterinary Medicine, Boston, MA, 02118, USA.
Abstract:
Transformation of cells in culture by polyoma virus requires integration of signals downstream of middle T-Shc and middle T-phosphatidylinositol 3-kinase interactions, but the same is not true for induction of tumors in the mouse. Thus, a middle T mutant defective in transformation and blocked in binding Shc is able to induce a broad spectrum of tumors after inoculation into newborn mice. The "tumor profile" induced by the mutant shows enhancement of tumors at some sites and reductions at others but otherwise resembles that induced by the wild-type virus. A nontransforming double-mutant blocked in binding phosphatidylinositol 3-kinase as well as Shc is severely affected but still induces some tumors. These results show that pathways that must cooperate to induce full transformation of cells in vitro can act independently and are to a large extent redundant in tumor induction.
Insights
Polyoma virus transformation of cells in culture needs specific signaling pathways. However, these pathways are largely redundant for tumor induction in mice, showing independent action.
Area of Science:
- Virology
- Molecular Biology
- Oncology
Background:
- Cell transformation by polyoma virus in vitro relies on signaling downstream of middle T antigen interactions with Shc and phosphatidylinositol 3-kinase.
- Tumorigenesis in vivo by polyoma virus may involve different or redundant signaling mechanisms.
Purpose of the Study:
- To investigate the role of Shc and phosphatidylinositol 3-kinase (PI3K) signaling pathways in polyoma virus-induced tumor formation in mice.
- To compare the signaling requirements for cell transformation in vitro versus tumor induction in vivo.
Main Methods:
- Utilized middle T antigen mutants of polyoma virus defective in binding Shc and/or PI3K.
- Inoculated newborn mice with wild-type and mutant polyoma viruses.
- Assessed tumor development and spectrum in inoculated mice.
Main Results:
- A middle T mutant unable to bind Shc, yet defective in cell transformation, induced a wide range of tumors in mice, similar to wild-type virus.
- A double-mutant affecting both Shc and PI3K binding was severely impaired but still capable of inducing some tumors.
- Tumor induction profiles showed site-specific enhancements and reductions compared to wild-type.
Conclusions:
- Signaling pathways essential for in vitro cell transformation are not strictly required for in vivo tumor induction by polyoma virus.
- These pathways can function independently and are largely redundant for tumor formation in a living organism.
- Polyoma virus utilizes adaptable signaling strategies for oncogenesis.