ANALYSIS OF THE ROLE OF MKK-4 SEK-1 IN T-CELL DEVELOPMENT AND APOPTOSIS/

The stress-activated protein kinases (SAPK) are a group of dual-specif icity kinases with potential roles in the control of apoptosis and pro liferation. In most cells they are regulated through phosphorylation b y MKK-4. We have investigated the role of MKK-4 in T cell development and function by generating transgenic animals expressing catalytically inactive MKK-4 (dMKK-4) in the thymus. Our results show that overexpr ession of dMKK-4 does not interfere with normal T cell development. Fu rthermore, expression of dMKK-4 inhibits Fas- but not phorbol ester pl us ionomycin-induced activation of SAPK, suggesting that a SAPK kinase different from MKK-4 is responsible for the regulation of SAPK activa tion after stimulation of T cells with phorbol ester plus ionomycin. W e then analyzed the effect of dMKK-4 on Fas-induced apoptosis of thymo cytes. Our results show that activation of SAPK is not a necessary eve nt in Fas-induced apoptosis of thymocytes.