Overexpression of Ras, Raf and L-myc but not Bcl-2 family proteins is linked with resistance to TCR-mediated apoptosis and tumorigenesis in thymic lymphomas from TCR transgenic mice.

Mice with transgenic TCR anti H-Y/Db develop spontaneous thymic tumors with a high frequency (up to 50%). Oncogenicity of TCR transgenes could depend on the deregulated expression of oncoproteins engaged in transduction pathways leading to proliferation or apoptosis. In agreement with this possibility we have found that cells of thymic lymphomas from TCR transgenic mice were largely resistant to TCR-dependent Ca++-mediated apoptosis but not to TCR-independent, p53-mediated (etoposide) apoptosis. Here we show raised expression of Bcl-2 protein in some but not in all thymic lymphoma cell lines. It suggests that the antiapoptotic function of Bcl-2 is not necessary for the process of tumorigenesis and the resistance of these lymphomas to Ca++-mediated apoptosis. On the other hand we show that all thymic lymphomas overexpressed Ras/Raf and L-myc proteins. Stimulation of the Ras/Raf pathway was reported to be required to maintain cell viability by preventing programmed cell death in thymic tumors derived from lck transgenic mice. Similarly, in TCR transgenic lymphomas overexpression of Ras, Raf and L-myc but not Bcl-2 family proteins may be responsible for the resistance of these lymphomas to TCR-mediated apoptosis but not affect p53-mediated apoptosis.