V(D)J recombination activity in lymphoid cell lines is increased by agents that elevate cAMP.
V(D)J [variable--(diversity)--joining] recombination is regulated developmentally, being restricted to cells of the early B- and T-lymphocyte lineages. In this report we show that recombination activity can also be regulated in response to chemical effectors. Compounds that increase intracellular cAMP increase V(D)J recombination of extrachromosomal substrates in pre-B-cell lines as much as 10-fold. In contrast, V(D)J recombination is reduced 5- to 8-fold in response to phorbol 12-myristate 13-acetate or to the calcium ionophore A23187. The effect of cAMP agonists on recombination appears to reflect an increase in cellular recombination activity, as indicated by the caffeine-induced rise in the level of mRNA from the recombination-activating genes RAG1 and RAG2. Our data demonstrate that intracellular second messengers modulate recombination activity in lymphoid cell lines, implying that recombination activity can be regulated by these signals in developing B and T lymphocytes.
Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892.
J P
JP
Menetski
M
M
Gellert
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology*; D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology*; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D015152:Blotting, Northern; D002110:Caffeine / Q000494:pharmacology*; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism*; D007133:Immunoglobulin Joining Region / Q000235:genetics*; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D007700:Kinetics; D051379:Mice; D010957:Plasmids; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D011995:Recombination, Genetic / Q000187:drug effects*; D013601:T-Lymphocytes / Q000276:immunology; D013806:Theophylline / Q000494:pharmacology*; D014162:Transfection
D007133:Immunoglobulin Joining Region; D007135:Immunoglobulin Variable Region; D012333:RNA, Messenger; D015124:8-Bromo Cyclic Adenosine Monophosphate; D002110:Caffeine; D013806:Theophylline; D000242:Cyclic AMP; D015056:1-Methyl-3-isobutylxanthine