STAT3 PLAYS AN IMPORTANT ROLE IN ONCOGENIC ROS-LIKE AND INSULIN-LIKE-GROWTH-FACTOR-I RECEPTOR-INDUCED ANCHORAGE-INDEPENDENT GROWTH

The role of signal transducers and activators of transcription (STATs) in receptor protein-tyrosine kinase (PTH)-induced cell growth and tra nsformation was investigated using an inducible epidermal growth facto r receptor-Res chimeric receptor called ER2 and a constitutively activ ated insulin-like growth factor I receptor called NM1, both of which a re able to induce anchorage-independent growth of NM 3T3 cells. ER2 an d NM1 receptor PTKs are able to cause Stat3 activation. Coexpressing t he dominant negative Stat3 mutant with ER2 or NM1 in transiently or st able transfected cells resulted in a dramatic inhibition of colonies i nduced by these receptor PTKs and a moderate inhibition of their mitog enicity in monolayer. Therefore, Stat3 is not only important for initi ation of transformation, as demonstrated by inhibition of the epiderma l growth factor-inducible colony formation of the ER2 cells by the mut ant, but it is also required for the maintenance of transformation, as evidenced by reversion of the NM1 transformed cells, The DNA binding and transcriptional activities of the endogenous Stat3 were greatly in hibited in the ER2 and NM1 cells co-expressing the Stat3 mutants. We c onclude that activated function of Stat3 is required for the establish ment and maintenance of Ros and insulin-like growth factor I receptor PTK-induced cell transformation.