AZATYROSINE INHIBITS THE ACTIVATION OF C-RAF-1, C-JUN AND AP1 BUT NOTTHE ACTIVATION OF RAS DURING SIGNAL-TRANSDUCTION TRIGGERED BY ONCOGENIC C-ERBB-2

Azatyrosine [L-beta-(5-hydroxy-2-pyridyl)alanine] is known to convert ras- or raf- transformed NIH3T3 cells to a normal phenotype. We report herein that azatyrosine also inhibits the growth of c-erbB-2-transfor med cells and induces normal morphology. We attempted to identify the signal-transduction process triggered by oncogenic c-ErbB-2 that was i nhibited by azatyrosine. Azatyrosine neither affected the phosphorylat ion of the introduced oncogenic c-ErbB-2 nor did it suppress activatio n of Ras induced by introduction of c-ErbB-2. Thus, azatyrosine did no t inhibit the signal transduction from oncogenic c-ErbB-2 to Ras. Howe ver, azatyrosine inhibited increases in phosphorylation of c-Raf-1 and c-Jun induced by oncogenic c-ErbB-2. Furthermore, azatyrosine inhibit ed activation of the 12-O-tetradecanoylphorbol-13-acetate (TPA) respon se element in response to stimulation by oncogenic c-ErbB-2. These res ults suggest that azatyrosine acts downstream of Ras in signal transdu ction from oncogenic c-ErbB-2 to nuclear factors.