Anisomycin abrogates repression of protooncogene c-fos transcription in E1A + cHa-ras-transformed cells through activation of MEK/ERK kinase cascade
✍ Scribed by Alexander N. Kukushkin; Svetlana B. Svetlikova; Rustam A. Amanzholov; Valery A. Pospelov
- Publisher
- John Wiley and Sons
- Year
- 2008
- Tongue
- English
- Weight
- 207 KB
- Volume
- 103
- Category
- Article
- ISSN
- 0730-2312
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✦ Synopsis
Abstract
We have previously shown that transcription of immediate‐early c‐fos protooncogene is becoming strongly repressed in rat embryo fibroblasts transformed by oncogenes E1A and cHa‐ras, so that serum only slightly stimulated c‐fos transcription in these cells in contrast to high level of c‐fos activation in non‐transformed REF52 cells. Here we showed that stress‐inducing agent anisomycin was able to override the c‐fos repression and to induce c‐fos transcription in E1A + ras transformants. In vitro kinase assay data demonstrated that anisomycin increased phosphorylation of transactivation domain of Elk‐1 transcription factor—a key regulator of inducible c‐fos transcription. Importantly, this activation was mediated through up‐regulation of MEK/ERK but not stress‐kinase cascades JNK or p38. The activating effect of anisomycin on c‐fos transcription could be abrogated by a prior treatment with N‐acetyl‐L‐cysteine. This indicates that anisomycin potentiates generation of reactive oxygen species (ROS), which, in turn, can modulate the activity of MAP kinase‐specific phosphatases (MKPs). As anisomycin did not cause acetylation of nucleosome core histones, the present work focuses on the molecular mechanisms mediating the HDAC‐independent induction of IEG c‐fos by anisomycin in E1A + cHa‐ras‐transformed fibroblasts. J. Cell. Biochem. 103: 1005–1012, 2008. © 2007 Wiley‐Liss, Inc.