Calcium-dependent cyclosporin A-sensitive activation of the interleukin-2 promoter by p56lck.
T-cell antigen receptor engagement results in suboptimal activation of protein kinase C and a prolonged increase in intracellular free calcium concentration. These signals, in combination with stimulation via accessory molecules usually supplied by the antigen presenting cell, activate expression of interleukin-2 (IL-2) and initiate autocrine growth. The lymphocyte-specific tyrosine kinase p56lck is physically associated with CD4 and is brought into close proximity of the intracellular domain of the antigen receptor by CD4 recognition of the major histocompatibility complex during antigen presentation. p56lck activation enhances and may be essential for antigen receptor signaling. We report that a constitutively active form of p56lck delivers a signal which contributes to IL-2 promoter activation. The signal substituted for a calcium-mobilizing signal in a Jurkat cell model of T-cell activation. The activation was sensitive to EGTA and cyclosporin A, indicating that p56lck functions at an early stage of the calcium-mediated pathway. The transcription factor NF-AT mediated, at least in part, the p56lck activation of IL-2 expression. In addition, activated p56lck synergized with constitutively active p21Ha-ras, which can replace protein kinase C activation, resulting in activation of NF-AT in the absence of external signals.
Baldari
C T
CT
Department of Evolutionary Biology, University of Siena, Italy.
Heguy
A
A
Telford
J L
JL
D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D016572:Cyclosporine / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics* / Q000378:metabolism; D008213:Lymphocyte Activation; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D009154:Mutation; D011401:Promoter Regions, Genetic; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014162:Transfection
D007376:Interleukin-2; D016572:Cyclosporine; D011505:Protein-Tyrosine Kinases; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D002118:Calcium