Stress-signalling kinase Sek1 protects thymocytes from apoptosis mediated by CD95 and CD3

Hiroshi Nishina, Klaus D. Fischer, Laszlo Radvanyi, Arda Shahinian, Razqallah Hakem, Elizabeth A. Rubie, Alan Bernstein, Tak W. Mak, James R. Woodgett and Josef M. Penninger
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Hiroshi Nishina: University of Toronto
Klaus D. Fischer: Mount Sinai Hospital
Laszlo Radvanyi: University of Toronto
Arda Shahinian: University of Toronto
Razqallah Hakem: University of Toronto
Elizabeth A. Rubie: University of Toronto
Alan Bernstein: Mount Sinai Hospital
Tak W. Mak: University of Toronto
James R. Woodgett: University of Toronto
Josef M. Penninger: University of Toronto

Nature, 1997, vol. 385, issue 6614, 350-353

Abstract: Abstract Distinct and evolutionarily conserved signal transduction cascades mediate 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, heat shock, ischaemia, or inflammatory cytokines3–6. Sek1 (JNKK/MKK4) is a direct activator of SAPKs/JNKs in response to environmental stresses or mitogenic factors7–9. Here we investigate the role of Sek1 in development and apoptosis by deleting sek1 in embryonic stem (ES) cells by homologous recombination. We provide genetic evidence that different stresses utilize distinct signalling pathways for SAPK/ JNK activation, 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 CD95 (Fas)- and CD3-mediated apoptosis. These data indicate that SEK1 mediates survival signals in T-cell development.

Date: 1997
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DOI: 10.1038/385350a0

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