Signaling pathways leading to the induction of ornithine decarboxylase: Opposite effects of p44/42 mitogen-activated protein kinase (MAPK) and p38 MAPK inhibitors

Treatment of serum-starved, human ECV304 cells with histamine or ATP elicit ed a transient induction of ornithine decarboxylase (ODC), a key enzyme in polyamine synthesis, to an extent similar to that provoked by phorbol myris tate acetate or serum re-addition. All these agents also provoked an increa se in active phosphorylated p44/42 mitogen-activated protein kinase (MAPK) and p38 MAPK. The involvement of p44/42 MAPK and p38 MAPK in the induction of ODC was investigated by using selective inhibitors. U0126 and PD98059, t wo specific p44/42 MAPK kinase inhibitors, prevented the induction of ODC e licited by any stimulus employed, whereas SB203580 and SB202190, which are widely used as p38 MAPK inhibitors, enhanced ODC induction in a way that ap peared dependent on p44/42 MAPK activation. By using inhibitors of other ke y signaling proteins that may lead to activation of p44/42 MAPK, we provide evidence that protein kinase C, but not phosphoinositide 3-kinase, is invo lved in histamine-stimulated ODC induction. These results show that the p44 /42 MAPK pathway, but not p38 MAPK, is essential for ODC induction stimulat ed either by agonists of G-protein-coupled receptors, phorbol esters, or se rum, and suggest that the inhibition of ODC induction may be an important e vent in the antiproliferative response to p44/42 MAPK pathway inhibitors. ( C) 2000 Elsevier Science Inc. All rights reserved.