| Induction of transforming growth factor-alpha expression in human keratinocytes by phorbol esters. | |
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MedLine Citation:
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PMID: 2925687 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Exposure of cultured human epidermal keratinocytes to the protein kinase C (Ca2+- and phospholipid-dependent protein kinase)-activating phorbol esters 12-O-tetradecanoylphorbol-13-acetate (TPA) or 4-beta-phorbol-12,13-didecanoate markedly enhanced accumulation of transforming growth factor-alpha (TGF-alpha) mRNA and secretion of TGF-alpha protein. The nonactivating phorbol ester, 4-alpha-phorbol 12,13-didecanoate, had no effect. In the absence of exogenous growth factors, confluent cultures of keratinocytes express low or undetectable levels of TGF-alpha mRNA and protein. While TPA and epidermal growth factor treatment of keratinocyte cultures deprived of growth factors both induced TGF-alpha mRNA expression, maximum induction by TPA is 5-fold greater than epidermal growth factor. Furthermore, the addition of epidermal growth factor did not enhance TPA-mediated induction of TGF-alpha mRNA expression. Under these experimental conditions, TPA increased levels of secreted TGF-alpha protein by 20-fold at 24 h. Concentration dependence and kinetic studies of TGF-alpha expression showed that TPA (greater than or equal to 1 ng/ml) induced accumulation of TGF-alpha mRNA with an optimum concentration of 10 ng/ml. TGF-alpha mRNA expression increased within 1 h following TPA treatment (10 ng/ml) and peaked at 5 h. At 24 h, TPA-treated cultures still expressed elevated levels of TGF-alpha mRNA (1.7-fold). Protein secretion into the medium was enhanced 2-fold (5 h) to 3-fold (24 h) by TPA treatment of keratinocyte cultures containing growth factors. Prolonged pretreatment (24 h) of keratinocyte cultures with TPA caused marked desensitization of TGF-alpha mRNA expression to repeated stimulation by phorbol ester. The synthetic diacylglycerol, 1,2-sn-dioctanoylglycerol, enhanced levels of TGF-alpha transcription and secretion of TGF-alpha protein. The rate of TGF-alpha mRNA accumulation peaked and declined earlier for 1,2-sn-dioctanoylglycerol compared to TPA. 1,2-sn-Dioctanoylglycerol (50 micrograms/ml) increased production and secretion of TGF-alpha protein, but less than TPA treatment. An inhibitor of protein kinase C, 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine, also inhibited 1,2-sn-dioctanoylglycerol-mediated accumulation of TGF-alpha mRNA. Cycloheximide failed to inhibit TGF-alpha mRNA expression induced by TPA and, when added alone to keratinocyte cultures, significantly enhanced TGF-alpha mRNA accumulation. Actinomycin D abrogated transcriptional activation of TGF-alpha mRNA by TPA. These studies suggest that activation of protein kinase C by active phorbol esters or diacylglycerols is responsible, at least in part, for TGF-alpha gene expression.(ABSTRACT TRUNCATED AT 400 WORDS) |
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Authors:
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M R Pittelkow; P B Lindquist; R T Abraham; R Graves-Deal; R Derynck; R J Coffey |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 264 ISSN: 0021-9258 ISO Abbreviation: J. Biol. Chem. Publication Date: 1989 Mar |
Date Detail:
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Created Date: 1989-04-25 Completed Date: 1989-04-25 Revised Date: 2007-11-15 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 5164-71 Citation Subset: IM |
Affiliation:
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Department of Dermatology, Mayo Clinic/Foundation, Rochester, Minnesota 55905. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Adult Cells, Cultured Colony-Forming Units Assay Dose-Response Relationship, Drug Epidermis / metabolism*, physiology Humans Infant, Newborn Kinetics Mitogens Phorbol Esters / pharmacology* Protein Kinase C / antagonists & inhibitors, metabolism Transcription, Genetic / drug effects Transforming Growth Factors / biosynthesis*, physiology |
| Grant Support | |
ID/Acronym/Agency:
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CA46413/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Mitogens; 0/Phorbol Esters; 76057-06-2/Transforming Growth Factors; EC 2.7.11.13/Protein Kinase C |
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