REGULATION OF THE INDUCTION OF ORNITHINE DECARBOXYLASE IN KERATINOCYTES BY RETINOIDS

Treatment of SV40-transformed keratinocytes (Z114) with epidermal grow th factor (EGF) resulted in an increase in ornithine decarboxylase (OD C) activity and a dose-dependent increase in ODC mRNA levels. Pretreat ment of keratinocytes with all-trans-retinoic acid inhibited the EGF i nduction of ODC activity. In both quiescent and EGF-stimulated cells, all-trans-retinoic acid inhibited ODC gene transcription and lowered O DC mRNA levels, whereas glyceraldehyde phosphate dehydrogenase express ion remained unaffected. Treatment with all-trans-retinoic acid for 24 h resulted in a dose- and time-dependent decrease of up to 52 % in EG F binding to EGF receptors and a 30-75 % decrease in EGF-receptor quan tity. In addition, when cells were treated with both UV radiation and all-trans-retinoic acid, their effects were additive in causing a decr ease in EGF binding. Blocking of EGF receptors with a neutralizing ant ibody for EGF receptors inhibited the induction of ODC activity by EGF . The effects of several other retinoids, including Ro15-0778, etretin ate, Ro13-7410, etarotene, Ro40-8757, 13-cis-retinoic acid and acitret in, were also studied to determine their effects on EGF binding and OD C activity. Two of these other retinoids, 13-cis-retinoic acid and Ro1 3-7410, inhibited EF binding the most (35-46%, P < 0.001); several oth ers (etarotene, Ro40-877 and etretinate) were less effective (7-16%,), but significantly decreased EGF binding (P < 0.05), and two retinoids (Ro15-0778 and acitretin) showed no significant effect on EGF binding . In contrast, all of the retinoids tested inhibited the induction of ODC activity by EGF, although etretinate and Ro15-0778 were less effec tive. EGF signal transduction is important in ODC gene regulation, and retinoids are significant modulators of this pathway.