Okadaic acid induces activator protein 1 activity and immediate early gene transcription in rat pheochromocytoma cells. Mechanism of action.
The serine/threonine protein phosphatase inhibitor okadaic acid (OA) was found to enhance mRNA transcripts of c-fos and of the jun family of proto-oncogenes including c-jun, jun B and jun D in cultured pheochromocytoma PC12 cells. This expression remained elevated for more than 8 hr. An increase in the binding of the transcription factor activator protein 1 (AP1) to its DNA consensus sequence that occurred prior to early gene transcription was observed. Enhanced AP1 activity was still observed when OA was added to the cells together with the transcription inhibitor actinomycin D, or with the protein synthesis inhibitor cycloheximide, indicating that it is actually AP1 activation due to posttranslational modifications that triggers transcription of the fos and jun genes. AP1 was activated through serine/threonine phosphorylation since its activation was abolished when nuclear extracts of OA-treated cells were incubated with protein phosphatase-1 or, to a lesser extent, with protein phosphatase-2A. C-Jun and Jun D proteins are likely candidates for being phosphorylated, since they were shown to constitute the AP1 complex at the time when it was activated (2 hr after OA addition).
Haby
C
C
INSERM U338, Strasbourg, France.
Aunis
D
D
Zwiller
J
J
D000818:Animals; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D004988:Ethers, Cyclic / Q000494:pharmacology*; D017781:Genes, Immediate-Early; D016762:Genes, fos; D016758:Genes, jun; D019319:Okadaic Acid; D016716:PC12 Cells / Q000187:drug effects; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors; D054645:Protein Phosphatase 1; D054648:Protein Phosphatase 2; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis*; D051381:Rats; D014158:Transcription, Genetic / Q000187:drug effects*
D004988:Ethers, Cyclic; D016755:Proto-Oncogene Proteins c-jun; D003609:Dactinomycin; D019319:Okadaic Acid; D003513:Cycloheximide; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D054648:Protein Phosphatase 2