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.
Nishina
H
H
Amgen Institute, Department of Medical Biophysics, University of Toronto, Ontario, Canada.
Radvanyi
L
L
Raju
K
K
Sasaki
T
T
Kozieradzki
I
I
Penninger
J M
JM
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000276:immunology* / Q000528:radiation effects; D017252:CD3 Complex / Q000502:physiology; D002678:Chimera; D004317:Doxorubicin / Q000633:toxicity; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D005047:Etoposide / Q000633:toxicity; D005720:Gamma Rays / Q000009:adverse effects; D018869:Heat-Shock Response / Q000235:genetics / Q000276:immunology; D048670:MAP Kinase Kinase 4; D051379:Mice; D018345:Mice, Knockout; D020929:Mitogen-Activated Protein Kinase Kinases; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics*; D011505:Protein-Tyrosine Kinases / Q000172:deficiency* / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000235:genetics; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D016176:T-Lymphocyte Subsets / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism; D014466:Ultraviolet Rays / Q000009:adverse effects; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D051020:bcl-X Protein
C494812:Bcl2l1 protein, mouse; D017252:CD3 Complex; D019253:Proto-Oncogene Proteins c-bcl-2; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D051020:bcl-X Protein; D005047:Etoposide; D004317:Doxorubicin; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D048670:MAP Kinase Kinase 4; C482562:Map2k4 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases