E2F1 MESSENGER-RNA IS DESTABILIZED IN RESPONSE TO A GROWTH INHIBITOR IN NORMAL HUMAN KERATINOCYTES BUT NOT IN A SQUAMOUS CARCINOMA CELL-LINE

Keratinocyte growth arrest is characterized by a reduction in the acti vity and expression of E2F1. Here, we examine the role posttranscripti onal processing plays in the down-regulation of E2F1 during keratinocy te growth arrest. E2F1 mRNA levels mere undetectable within 8 h of exp osure to the protein kinase C activator, 12-O-tetradecanoyl-phorbol-13 -acetate (TPA). Assays of transcript stability indicated that, in untr eated keratinocytes, the t(1/2) of E2F1 mRNA was 6.1 h and, in TPA-tre ated cells, it was 1.7 h. This destabilization was protein synthesis d ependent. In contrast, a growth inhibitor-resistant carcinoma cell lin e, SCC25, had a very stable E2F1 half-life that was only moderately re duced following TPA treatment. These data demonstrate that the initiat ion of keratinocyte growth arrest is associated with a rapid destabili zation of E2F1 mRNA. These data are consistent with the proposition th at inactivation of the posttranscriptional processing of important gro wth regulatory genes (e.g., E2F1) may contribute to neoplasia.