STRESS-SIGNALING KINASE SEK1 PROTECTS THYMOCYTES FROM APOPTOSIS MEDIATED BY CD95 AND CD3

Distinct and evolutionarily conserved signal transduction cascades med iate survival or death in response to developmental and environmental cues, The stress-activated protein kinases, or Jun N-terminal kinases (SAPKs/JNKs)(1,2), are activated in response to a variety of cellular stresses such as changes in osmolarity and metabolism, DNA damage, hea t shock, ischaemia, or inflammatory cytokines(3-6). Sek1 (JNKK/MKK4) i s a direct activator of SAPKs/JNKs in response to environmental stress es or mitogenic factors(7-9). Here we investigate the role of Sek1 in development and apoptosis by deleting sek1 in embryonic stem (ES) cell s by homologous recombination, We provide genetic evidence that differ ent stresses utilize distinct signalling pathways for SAPK/JNK activat ion, sek1(-/-)/rag2(-/-) chimaeric mice have normal numbers of mature T cells but fewer immature CD4(+)CD8(+) thymocytes, The sek1 mutation did not affect the induction of apoptosis in response to environmental stresses in ES and T cells: instead, sek1 protected thymocytes from C D95 (Fas)- and CD3-mediated apoptosis, These data indicate that SEK1 m ediates survival signals in T-cell development.