Gene expressions in Jurkat cells poisoned by a sulphur mustard vesicant and the induction of apoptosis.
1. The sulphur mustard vesicant 2-chloroethylethyl sulphide (CEES) induced apoptosis in Jurkat cells. 2. Akt (PKB), a pivotal protein kinase which can block apoptosis and promotes cell survival, was identified to be chiefly down-regulated in a dose-dependent manner following CEES treatment. Functional analysis showed that the attendant Akt activity was simultaneously reduced. 3. PDK1, an upstream effector of Akt, was also down-regulated following CEES exposure, but two other upstream effectors of Akt, PI3-K and PDK2, remained unchanged. 4. The phosphorylation of Akt at Ser(473) and Thr(308) was significantly decreased following CEES treatment, reflecting the suppressed kinase activity of both PDK1 and PDK2. 5. Concurrently, the anti-apoptotic genes, Bcl family, were down-regulated, in sharp contrast to the striking up-regulation of some death executioner genes, caspase 3, 6, and 8. 6. Based on these findings, a model of CEES-induced apoptosis was established. These results suggest that CEES attacked the Akt pathway, directly or indirectly, by inhibiting Akt transcription, translation, and post-translation modification. 7. Taken together, upon exposure to CEES, apoptosis was induced in Jurkat cells via the down-regulation of the survival factors that normally prevent the activation of the death executioner genes, the caspases.
Walter Reed Army Institute of Research, Silver Spring, Maryland, MD 20910-7500, USA.
Peng
P
Zhang
Patrick
P
Ng
Diana
D
Caridha
Richard A
RA
Leach
Ludmila V
LV
Asher
Mark J
MJ
Novak
William J
WJ
Smith
Steven L
SL
Zeichner
Peter K
PK
Chiang
D064413:3-Phosphoinositide-Dependent Protein Kinases; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D019254:Genes, bcl-2; D006801:Humans; D007509:Irritants / Q000633:toxicity*; D019169:Jurkat Cells; D009151:Mustard Gas / Q000633:toxicity*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt
D064413:3-Phosphoinositide-Dependent Protein Kinases; D020169:Caspases; D007509:Irritants; D009151:Mustard Gas; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; C494918:AKT1 protein, human; C578562:PDPK1 protein, human