Differential role for ADP-ribosylation in gene expression during the activation of T lymphocytes by various stimuli.
Simple competitive inhibitors of the nuclear enzyme ADP-ribosyltransferase, such as 3-methoxybenzamide (3MB), are known to block mitogen-induced activation of lymphocytes by inhibiting an early event. We now report that 3MB affects neither the generation of inositol phosphates nor the increase in cytoplasmic calcium in human T lymphocytes stimulated with phytohaemagglutinin (PHA), indicating that it acts on later or parallel events. The proliferative response to the phorbol ester 12-o-tetradecanoylphorbol-13-acetate (TPA) was much less sensitive to 3MB than was the response to PHA. Similarly, the TPA-induced increases in the expression of the c-myc proto-oncogene and of the Tac polypeptide of the interleukin-2 receptor were not affected by 3MB, whereas the same responses to either PHA or the calcium ionophore A23187 were inhibited by 3MB. The data suggest that 3MB affects the calcium-mediated signal for T-lymphocyte activation, acting after the increase in cytoplasmic calcium, and possibly also affects other signal transduction pathways distinct from the hydrolysis of polyphosphoinositides. There are some similarities between the actions of 3MB and cyclosporin.
King
S L
SL
Department of Immunology, St George's Hospital Medical School, London, U.K.
McNerney
R
R
Whitley
G S
GS
Johnstone
A P
AP
D000246:Adenosine Diphosphate Ribose / Q000502:physiology*; D001549:Benzamides / Q000494:pharmacology; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D000090063:Proto-Oncogene Mas; D011519:Proto-Oncogenes / Q000187:drug effects; D015375:Receptors, Interleukin-2 / Q000187:drug effects / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*
D001549:Benzamides; C000715470:MAS1 protein, human; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D000090063:Proto-Oncogene Mas; D015375:Receptors, Interleukin-2; D000246:Adenosine Diphosphate Ribose; C025159:3-methoxybenzamide