Stress-signalling kinase Sek1 protects thymocytes from apoptosis mediated by CD95 and CD3.
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), are activated in response to a variety of cellular stresses such as changes in osmolarity and metabolism, DNA damage, heat shock, ischaemia, or inflammatory cytokines. Sek1 (JNKK/MKK4) is a direct activator of SAPKs/JNKs in response to environmental stresses or mitogenic factors. 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.
Nishina
H
H
The Amgen Institute, Ontario Cancer Institute, Toronto, Canada.
Fischer
K D
KD
Radvanyi
L
L
Shahinian
A
A
Hakem
R
R
Rubie
E A
EA
Bernstein
A
A
Mak
T W
TW
Woodgett
J R
JR
Penninger
J M
JM
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D017252:CD3 Complex / Q000502:physiology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D002678:Chimera; D004268:DNA-Binding Proteins; D004789:Enzyme Activation; D017353:Gene Deletion; D018390:Gene Targeting; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D011494:Protein Kinases / Q000235:genetics / Q000502:physiology*; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells; D013601:T-Lymphocytes / Q000166:cytology; D013950:Thymus Gland / Q000166:cytology*; D019014:fas Receptor / Q000502:physiology*
D017252:CD3 Complex; D004268:DNA-Binding Proteins; D011506:Proteins; C499308:Rag2 protein, mouse; C064655:V(D)J recombination activating protein 2; D019014:fas Receptor; D011494:Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; C482559:MAP2K4 protein, human; C482562:Map2k4 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases