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TCDD suppression of tissue transglutaminase stimulation by retinoids in malignant human keratinocytes
1Department of Environmental Toxicology, University of California, Davis 95616-8588, USA.
Abstract:
The human keratinocyte line SCC-4 is a model system in which to explore the mechanism by which 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) interferes with the action of hormones in the steroid receptor superfamily. In present work, retinoid induction of tissue transglutaminase mRNA was suppressed 60-70% by 10 nM TCDD in the human squamous carcinoma cell line SCC-4. This effect occurred without enhanced degradation of the mRNA and thus appeared to result from altered transcription. The actions of all-trans-retinoic acid and the synthetic retinoid TTNPB ((E)4-[2-(5,6,7,8-tetrahydro-5,5,8, 8-tetramethyl-2-naphthylenyl)-1propenyl] benzoic acid), which resists metabolic degradation, were suppressed to the same extent without obvious changes in their EC(50)s. In addition, TCDD suppression of reporter transcription, driven by a retinoic acid response element, was not evident in transient or stable transfections of SCC-4 cells. Sodium butyrate (3 mM) alone induced tissue transglutaminase and augmented retinoid induction. In the presence of butyrate, TCDD acted as an inducer and did not reduce retinoid stimulation. Retinoic acid induction of tissue transglutaminase displayed a lag phase of >24 h, indicating that the induction has an indirect component. Rather than depleting active retinoid in the culture medium or generally inactivating retinoid receptor function, TCDD may suppress retinoid action in this case by interfering with the late phase of induction.
Insights
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) suppresses retinoid-induced tissue transglutaminase mRNA in SCC-4 cells, likely by altering transcription. This TCDD effect may involve interference with the late induction phase, not receptor function.
Area of Science:
- Endocrinology
- Molecular Biology
- Cell Biology
Background:
- The human keratinocyte SCC-4 cell line serves as a model to study dioxin interference with steroid hormone receptors.
- 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is known to interact with the aryl hydrocarbon receptor, influencing various cellular processes.
Purpose of the Study:
- To investigate the mechanism by which TCDD interferes with retinoid signaling in SCC-4 cells.
- To determine if TCDD affects retinoid induction of tissue transglutaminase (TG) mRNA levels.
Main Methods:
- SCC-4 cells were treated with TCDD and retinoids (all-trans-retinoic acid, TTNPB).
- Tissue transglutaminase mRNA levels and degradation were assessed.
- Reporter gene assays using retinoic acid response elements were performed.
- The effect of sodium butyrate on retinoid induction and TCDD interference was examined.
Main Results:
- TCDD (10 nM) suppressed retinoid induction of tissue transglutaminase mRNA by 60-70% in SCC-4 cells.
- Suppression occurred without increased mRNA degradation, suggesting transcriptional regulation.
- TCDD did not alter the EC50 of retinoids or affect reporter gene transcription.
- Sodium butyrate enhanced retinoid induction, and TCDD acted as an inducer in its presence.
- Retinoid induction showed a lag phase, indicating an indirect component.
Conclusions:
- TCDD interferes with retinoid action in SCC-4 cells, primarily at the transcriptional level.
- The mechanism appears to involve suppression of the late phase of retinoid induction, rather than general receptor inactivation or retinoid depletion.
- Sodium butyrate modifies TCDD's effect, suggesting complex interactions within the signaling pathways.