Anisomycin abrogates repression of protooncogene c-fos transcription in E1A + cHa-ras-transformed cells through activation of MEK/ERK kinase cascade.
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.
Kukushkin
Alexander N
AN
Institute of Cytology, Russian Academy of Sciences, Saint-Petersburg 194064, Russia. kan@mail.cytspb.rssi.ru
Svetlikova
Svetlana B
SB
Amanzholov
Rustam A
RA
Pospelov
Valery A
VA
D017500:Adenovirus E1A Proteins / Q000096:biosynthesis*; D000818:Animals; D000841:Anisomycin / Q000494:pharmacology*; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing / Q000187:drug effects / Q000502:physiology; D016762:Genes, fos / Q000187:drug effects*; D011905:Genes, ras / Q000187:drug effects; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000235:genetics*; D020928:Mitogen-Activated Protein Kinases; D010766:Phosphorylation; D016760:Proto-Oncogene Proteins c-fos / Q000097:blood*; D051381:Rats; D015533:Transcriptional Activation / Q000187:drug effects; D050807:ets-Domain Protein Elk-1 / Q000187:drug effects
D017500:Adenovirus E1A Proteins; D017874:Immediate-Early Proteins; D016760:Proto-Oncogene Proteins c-fos; D050807:ets-Domain Protein Elk-1; D000841:Anisomycin; D020928:Mitogen-Activated Protein Kinases