Diacylglycerol kinase alpha activity promotes survival of CD4+ 8+ double positive cells during thymocyte development.
The diacylglycerol kinases (DGK) form a family of isoenzymes that catalyse the conversion of diacylglycerol (DAG) to phosphatidic acid (PA), both powerful second messengers in the cell. DGKalpha is expressed in brain, peripheral T cells and thymocytes and has been shown to translocate to the nuclear matrix upon T-cell receptor (TCR) engagement. Here, we show that high level expression of DGKalpha is induced following a signal transmitted through the pre-TCR and the protein tyrosine kinase, lck. Activity of DGKalpha contributes to survival in CD4+ 8+ (DP) thymocytes as pharmacological inhibition of DGK activity results in death of this cell population both in cell suspension and thymic explants. DGKalpha promotes survival in these thymocytes through a Bcl-regulated pathway. A consequence of inhibition of DGKalpha is the specific down-regulation of Bcl-xl, whereas in transgenic mice that over-express Bcl-2, death induced by the inhibitor is partially blocked. Thus we report a novel activity of DGKalpha in survival of thymocytes immediately after entry into the DP stage in development.
Outram
Susan V
SV
Department of Biology, Imperial College of Science, Technology and Medicine, Imperial College Road, London SW7 2AZ, UK. s.outram@ic.ac.uk
Crompton
Tessa
T
Merida
Isabel
I
Varas
Alberto
A
Martinez-A
Carlos
C
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000201:enzymology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000201:enzymology; D002454:Cell Differentiation; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D019852:Diacylglycerol Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D019254:Genes, bcl-2; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D010880:Piperidines / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D011799:Quinazolines / Q000494:pharmacology; D052999:Quinazolinones; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013601:T-Lymphocytes / Q000166:cytology / Q000201:enzymology*; D051020:bcl-X Protein
C494812:Bcl2l1 protein, mouse; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D010880:Piperidines; D019253:Proto-Oncogene Proteins c-bcl-2; D011799:Quinazolines; D052999:Quinazolinones; D016693:Receptors, Antigen, T-Cell, alpha-beta; D051020:bcl-X Protein; C058544:R 59949; D019852:Diacylglycerol Kinase; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)