p21ras mediates control of IL-2 gene promoter function in T cell activation.
It has been shown previously in T cells that stimulation of protein kinase C or the T cell antigen receptor leads to a rapid and persistent activation of p21ras as measured by a dramatic increase in the amount of bound GTP. These stimuli are also known to induce the expression of the T lymphocyte growth factor, interleukin-2 (IL-2), an essential growth factor for the immune system. Receptor induced activation of p21ras has been demonstrated in several cell types but involvement of protein kinase C as an upstream activator of p21ras appears to be unique to T cells. In this study we show that p21ras acts as a component of the protein kinase C and T cell antigen receptor downstream signalling pathway controlling IL-2 gene expression. In the murine T cell line EL4, constitutively active p21ras greatly potentiates the phorbol ester and T cell receptor agonist induced production of IL-2 as measured both by biological assay for the cytokine and by the use of a reporter construct. Active p21ras also partially replaces the requirement for protein kinase C activation in synergizing with a calcium ionophore to induce production of IL-2. Furthermore, using a dominant negative mutant of ras, Ha-rasN17, we show that endogenous ras function is essential for induction of IL-2 expression in response to protein kinase C or T cell receptor stimulation. Activation of ras proteins is thus a necessary but not sufficient event in the induction of IL-2 synthesis. Ras proteins are therefore pivotal signalling molecules in T cell activation.
Rayter
S I
SI
Signal Transduction Laboratories, Imperial Cancer Research Fund, Lincoln's Inn Fields, London, UK.
Woodrow
M
M
Lucas
S C
SC
Cantrell
D A
DA
Downward
J
J
D000818:Animals; D002118:Calcium / Q000378:metabolism; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics; D004789:Enzyme Activation; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics*; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D010957:Plasmids; D011401:Promoter Regions, Genetic; D011493:Protein Kinase C / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*; D014407:Tumor Cells, Cultured
D007376:Interleukin-2; D015500:Chloramphenicol O-Acetyltransferase; D011493:Protein Kinase C; D016283:Proto-Oncogene Proteins p21(ras); D002118:Calcium