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


CONCLUSIONS
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.
Kiefer
F
F
Research Institute of Molecular Pathology, Vienna, Austria.
Anhauser
I
I
Soriano
P
P
Aguzzi
A
A
Courtneidge
S A
SA
Wagner
E F
EF
D000818:Animals; D000831:Animals, Newborn; D000952:Antigens, Polyomavirus Transforming / Q000096:biosynthesis*; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic; D016391:Genes, src; D006390:Hemangioendothelioma / Q000235:genetics / Q000473:pathology; D006391:Hemangioma / Q000235:genetics / Q000473:pathology; D017403:In Situ Hybridization; D051379:Mice; D008817:Mice, Mutant Strains; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000952:Antigens, Polyomavirus Transforming; D011505:Protein-Tyrosine Kinases