Endothelial cell transformation by polyomavirus middle T antigen in mice lacking Src-related kinases

Friedemann Kiefer, Ingrid Anhauser, Philippe Soriano, Adriano Aguzzi, Sara Courtneidge, Erwin F. Wagner

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Abstract

Background: Expression of polyomavirus middle T antigen (PymT) rapidly induces endothelial tumors (hemangiomas) in mice, with an apparent single rate-limiting step. Because activation of Src-like kinases is thought to be an important component of PymT-induced transformation, we have analyzed the functional requirement for individual kinases in this process. This type of analysis has only recently become possible, with the generation of 'gene knock-out' mice lacking each of the kinase genes src, fyn and yes. Results Hemangiomas develop efficiently in newborn mice lacking either src, fyn or yes after inoculation with a PymT-transducing retrovirus. In src-  and fyn-deficient mice, the kinetics of induction and the histological properties of the tumors were indistinguishable from those in wild-type mice. In contrast, a reduced number of tumors arose in yes-deficient mice, with a significantly longer latency period. Transformed endothelial cell lines derived from the induced hemangiomas, however, did not differ in their morphological and tumorigenic properties from cell lines established previously from wild-type mice. Biochemical analysis of complexes between PymT and the Src-related kinases in these cell lines suggests that the Yes kinase is responsible for a significant amount of the PymT-associated kinase activity in transformed endothelial cells. Conclusion We have demonstrated that inactivation of a single tyrosine kinase of the Src family in endothelial cells does not abrogate PymT-induced hemangioma formation. As the remaining kinases do not compensate for the absence of a family member by elevated kinase activity, the loss - which affects the transformation process to varying degrees - can be studied in this model system. Our studies suggest that the PymT-Yes kinase complex plays a major role in the tumor-initiating action of PymT.

Original languageEnglish (US)
Pages (from-to)100-109
Number of pages10
JournalCurrent Biology
Volume4
Issue number2
DOIs
Publication statusPublished - Feb 1 1994
Externally publishedYes

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ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)

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