Regulation of ornithine decarboxylase activity by IL-2 and cyclic AMP.
IL-2 regulates the expression and activation of the principal rate-limiting enzyme of polyamine synthesis, ornithine decarboxylase (ODC). The apparent activation of ODC occurs by two independent steps. Rapid activation of enzyme occurs within the first 10 min of lymphokine treatment of cloned IL-2-dependent murine cell lines. The initial rapid rise in enzyme activity is insensitive to protein or mRNA synthesis inhibitors. The early rise in ODC activity is followed by a protracted increase in enzyme activity, apparent protein measured by [3H]difluoromethylornithine binding, and by accumulation of steady state ODC mRNA. Stable analogues of cAMP which inhibit IL-2-stimulated proliferation, suppressed only the mRNA-dependent increase in ODC activity. Phorbol esters were shown to increase steady state levels of ODC mRNA whereas cAMP analogue clearly inhibited the growth factor-induced increase in ODC mRNA. These studies show that IL-2 regulates the expression of ODC at multiple levels, including transcription and accumulation of steady state mRNA, and post-translational activation of an enzyme important for DNA synthesis. Furthermore, anti-proliferative signals such as cAMP may effect the regulation of ODC enzyme production at the level of mRNA accumulation and stability.
Farrar
W L
WL
Laboratory of Molecular Immunoregulation, National Cancer Institute, Frederick, MD 21701-1013.
Vinocour
M
M
Cleveland
J L
JL
Harel-Bellan
A
A
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D000242:Cyclic AMP / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D009955:Ornithine Decarboxylase / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000201:enzymology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects
D007376:Interleukin-2; D012333:RNA, Messenger; D015124:8-Bromo Cyclic Adenosine Monophosphate; D000242:Cyclic AMP; D009955:Ornithine Decarboxylase; D013755:Tetradecanoylphorbol Acetate