Impaired TCR-mediated apoptosis and Bcl-XL expression in T cells lacking the stress kinase activator SEK1/MKK4.

The dual specificity kinase SEK1 (MKK4) is a direct activator of stress-activated protein kinases (SAPK/JNK) in response to environmental stresses or mitogenic factors. We show in Sek1(-/-)Rag(-/-) chimeric mice that a Sek1 null mutation augments the susceptibility of peripheral T cells to TCR/CD3 religation-induced apoptosis. Sek1(-/-) T cells failed to induce expression of the death suppressor Bcl-XL in response to Ag receptor activation. The Sek1 mutation did not alter the induction of apoptosis in response to etoposide, cisplatinum, Adriamycin, and gamma-irradiation. Moreover, we show that CD3epsilon activation alone leads to SEK1 activation in Sek1(+/+) T cells. These results suggest that SEK1 transduces cellular survival signals during T cell stimulation.