Transcriptional activation of immediate-early genes c-fos, c-jun, and Egr-1 in response to anisomycin treatment of cells transformed by the E1A and cHa-ras oncogenes

Abstract

The antibiotic anisomycin, a well-known stress factor, has been found to induce the transcription of immediate-early gene c-fos, which is under negative control in cells transformed by oncogenes E1A and cHa-ras. The c-fos gene activation is short-term: it reaches its maximum 1 h after anisomycin treatment, and then the transcription level decreases, which is characteristic of immediate-early genes. The transcription levels of two other immediate-early genes, c-jun and Egr-1, are already relatively high in the absence of anisomycin; however, anisomycin treatment further increases them. In E1A+ras transformants, anisomycin induces the mitogen-activated protein (MAP) kinase of extracellular signal-regulated kinase (MEK/ERK) pathway and the jun N-terminal kinase (JNK) MAP kinase pathway of signal transduction, whereas p38 kinase pathway is not activated. Specific inhibitors of different MAP kinase cascades have been used to demonstrate that the anisomycin-induced transcription of the c-fos gene is mainly regulated via the MEK/ERK pathway, whereas the high c-jun transcription level is maintained by JNK activity. The anisomycin treatment of E1A+ras transformants, even at high concentrations of the antibiotic, does not ultimately lead to the accumulation of acetylated forms of core histones, including histone H3; therefore, the anisomycin-induced transcriptional activation of immediate-early genes is not related to chromatin decondensation in the region of the promoters of these genes.