p44/42 mitogen-activated protein kinase is involved in the expression of ornithine decarboxylase in leukaemia L1210 cells

The involvement of p44/42 mitogen-activated protein kinase (MAPK) in the in duction of ornithine decarboxylase (ODC) was investigated by using PD98059, a specific MAPK-kinase (MEK1/2) inhibitor, and other signal-transduction i nhibitors. In D,L-alpha-difluoromethylornithine (DFMO)-resistant L1210 cell s stimulated to grow from quiescence, treatment with PD98059 inhibited p44/ 42 MAPK phosphorylation and the induction of ODC activity and protein. A ma rked reduction of the accumulation of mature ODC mRNA and its intron-contai ning precursor was observed, whereas ODC turnover was hardly affected. PD98 059 also reduced the content of antizyme, but not that of antizyme mRNA. U0 126, a novel and more potent inhibitor of MEK1/2, provoked a dose-dependent inhibition of ODC induction at lower concentrations with respect to PD9805 9. Other effective inhibitors of ODC induction proved to be genistein, manu mycin A, herbimycin A, LY294002, wortmannin and KT5823, suggesting the invo lvement of other key proteins of signal-transduction pathways, i.e. Ras, Sr c, phosphatidylinositol 3-kinase and cGMP-dependent protein kinase, which m ay have a positive impact on MAPK. Cells kept in a DFMO-free medium, and th us containing high levels of putrescine and spermidine, showed enhanced MAP K phosphorylation and lower sensitivity to PD98059, compared with cells mai ntained in the presence of DFMO. In conclusion, these results indicate that the activation of p44/42 MAPK may favour the expression of ODC, and that p olyamines, in turn, may affect the phosphorylation state of MAPK.