Retinoic acid receptors as regulators of human epidermal keratinocyte differentiation.

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Vollberg TM Sr, Nervi C, George MD, Fujimoto W, Krust A, Jetten AM

Retinoic acid receptors as regulators of human epidermal keratinocyte differentiation.

Mol Endocrinol. 1992 May;6(5):667-76.

PubMed ID

1318502 [ View in PubMed

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Abstract

To examine the role of nuclear retinoic acid (RA) receptors (RARs) in the regulation of squamous differentiation in normal human epidermal keratinocytes (NHEK), we analyzed binding activity, mRNA expression, and transcriptional activity of the endogenously expressed RARs. Specific RA-binding activity eluted from size-exclusion HPLC with an apparent mol wt of 50 kilodaltons and was predominantly (greater than 95%) associated with the NHEK nuclear cell fraction. This RAR-binding activity represented in part the expression of RAR alpha and RAR gamma genes, whose transcripts were expressed in similar abundance in undifferentiated NHEK. Differentiation resulted in lower mRNA expression of RAR alpha relative to the mRNA expression of RAR gamma. Treatment of NHEK cells with 10(-6) M RA did not induce expression of RAR beta mRNA. Similarly, three squamous cell carcinoma cell lines derived from human skin and oral cavity expressed RAR alpha and RAR gamma transcripts, but not RAR beta transcripts. Transfection of NHEK with chloramphenicol acetyltransferase (CAT) reporter plasmids indicated that the endogenously expressed RARs could activate transcription through the RAR beta response element in a concentration-dependent manner with doses of 10(-9) M RA and higher. CAT expression was not activated through TRE, a palindromic thyroid hormone response element with purported RA responsiveness. The competitive binding of benzoic acid derivatives of RA to RAR correlated with the ability of each analog to suppress mRNA expression of the squamous cell markers, involucrin, type I transglutaminase, and SQ37, and to activate transcription of the RAR beta response element-CAT reporter. These results demonstrate that the control of NHEK differentiation by RA is consistent with the interaction of the retinoid with RAR and the regulation of transcription by that ligand-receptor complex.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Tretinoin	Retinoic acid receptor alpha	Protein	Humans	Yes	Agonist	Details

Pharmaco-transcriptomics

Drug	Drug Groups	Gene	Gene ID	Change	Interaction	Chromosome
Tretinoin	Approved Investigational Nutraceutical	IVL	3713	downregulated	Tretinoin analog results in decreased expression of IVL mRNA	1q21.3
Tretinoin	Approved Investigational Nutraceutical	SPRR1B	6699	downregulated	Tretinoin analog results in decreased expression of SPRR1B mRNA	1q21.3
Tretinoin	Approved Investigational Nutraceutical	TGM1	7051	downregulated	Tretinoin analog results in decreased expression of TGM1 mRNA	14q12