Okadaic acid mimics multiple changes in early protein phosphorylation and gene expression induced by tumor necrosis factor or interleukin-1.
Okadaic acid, a phosphatase inhibitor from a marine organism, mimics tumor necrosis factor/interleukin-1 (TNF/IL-1) in inducing changes in early cellular protein phosphorylation. A total of approximately 116 proteins exhibit significant and concordant changes in phosphorylation or dephosphorylation within 15 min in human fibroblasts activated by either okadaic acid, TNF, or IL-1. The fidelity of this mimicry by okadaic acid extends to the phosphorylation of the 27 hsp complex, stathmin, eIF-4E, myosin light chain, nucleolin, epidermal growth factor receptor, and other cdc2-kinase substrates (c-abl, RB, and p53). The okadaic acid-induced pattern of protein phosphorylation is distinct from that observed in cells treated with phorbol 12-myristate 13-acetate or with ligands like epidermal growth factor, cyclic AMP agonists, bradykinin, or interferons. Like TNF, okadaic acid also induces the transcription of immediate early response genes like c-jun and Egr-1 as well as the interleukin-6 genes. The overall early effects of okadaic acid uniquely parallel those of TNF/IL-1 and not those of other cytokines or ligands. Regulation of protein phosphatase inhibition is discussed as a mechanism for TNF/IL-1 signal transduction.
Guy
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GR
Institute of Molecular and Cell Biology, National University of Singapore.
Cao
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X
Chua
S P
SP
Tan
Y H
YH
D001345:Autoradiography; D015152:Blotting, Northern; D016203:CDC2 Protein Kinase / Q000378:metabolism*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics; D051766:Early Growth Response Protein 1; D004988:Ethers, Cyclic / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D016758:Genes, jun / Q000235:genetics; D006801:Humans; D017874:Immediate-Early Proteins; D007375:Interleukin-1 / Q000494:pharmacology*; D015850:Interleukin-6 / Q000235:genetics; D008970:Molecular Weight; D019319:Okadaic Acid; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors*; D010750:Phosphoproteins / Q000302:isolation & purification / Q000378:metabolism*; D010761:Phosphorus Radioisotopes; D010766:Phosphorylation; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D011994:Recombinant Proteins / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D016335:Zinc Fingers / Q000235:genetics
D004268:DNA-Binding Proteins; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D004988:Ethers, Cyclic; D017874:Immediate-Early Proteins; D007375:Interleukin-1; D015850:Interleukin-6; D010750:Phosphoproteins; D010761:Phosphorus Radioisotopes; D011994:Recombinant Proteins; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D019319:Okadaic Acid; D012313:RNA; D016203:CDC2 Protein Kinase; D010749:Phosphoprotein Phosphatases; D013755:Tetradecanoylphorbol Acetate