DOWN-REGULATION OF TROPOMYOSIN-2 EXPRESSION IN C-JUN-TRANSFORMED RAT FIBROBLASTS INVOLVES INDUCTION OF A MEK1-DEPENDENT AUTOCRINE LOOP

Overexpression of the c-Jun transcription factor in rodent fibroblasts may result in cell transformation or in apoptosis, The mechanisms whe reby c-Jun induces transformation are unknown. We show here that the e xpression of high-molecular weight tropomyosin-2 (TM-2) is down-regula ted in c-jun-transformed FR3T3 rat fibroblasts, However, down-regulati on did not seem to be a direct effect of c-Jun on TM-2 gene expression . Thus, TM down-regulation in c-jun-transformed cells was alleviated b y inhibitors of Has (BZA-5B) or MEK1 (PD98059). Furthermore, medium co nditioned by c-jun-transformed cells induced TM-2 down-regulation in u ntransformed cells by a mechanism requiring MEK1. Consistent with a ce ntral role for the MEK/ERK, but not SEK/JNK, pathway for TM down-regul ation, constitutively active mutants of Raf induced TM downregulation, whereas constitutively active Rac did not. We also show that anchorag e-independent growth of c-jun-transformed cells requires MEK1. These f indings suggest that indirect induction of the MEK/ERK pathway is cent ral to c-Jun-induced transformation of rat fibroblasts.