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Keratins 2 and 4/13 in reconstituted human skin are reciprocally regulated by retinoids binding to nuclear receptor RAR alpha
Dept Med Sci, Uppsala Univ, Uppsala, Sweden.
Örebro University, School of Health and Medical Sciences.
Dept Med Sci, Uppsala Univ, Uppsala, Sweden.
Dept Med Sci, Uppsala Univ, Uppsala, Sweden.
2010 (English)In: Experimental dermatology, ISSN 0906-6705, E-ISSN 1600-0625, Vol. 19, no 7, p. 674-681Article in journal (Refereed) Published
Abstract [en]

Disorders of keratinization are often treated with vitamin A derivatives (retinoids) which affect keratinocyte differentiation, including keratin (KRT) gene expression. In vivo, suprabasal keratinocytes normally express only keratin (K) 1, K2 and K10, but after topical application of all-trans retinoic acid (ATRA), the granular cells will additionally express K4 and K13, i.e. keratins normally present in oral mucosa and in cultured epidermal keratinocytes. To learn more about the retinoid regulation of keratin expression under in vivo-like conditions, we cultured keratinocytes on de-epidermized dermis in only 0.5% serum. These cells produce a normal-looking epidermis that expresses high mRNA levels of KRT1, KRT2 and KRT10, but minimal amounts of KRT4 and KRT13. Addition of ATRA to the medium for 48 h caused a dose-dependent increase in KRT4/KRT13 and a down-regulation of KRT2 mRNA. An increase in K4 protein was also found. The response was greater than the up-regulation of another retinoid-regulated gene, CRABPII. By studying 10 retinoids with different affinities for the retinoic acid receptors (RAR) and retinoid X receptors (RXR) isoforms, the reciprocal expression of KRT2 and KRT4/KRT13 could be connected with agonists for RAR alpha. Two of these agonists, CD336/Am580 and CD2081, altered the expression profile with similar potency as the pan-RAR agonists ATRA and CD367. Co-addition of a pan-RAR antagonist (CD3106/AGN193109) markedly inhibited the induction of KRT4/KRT13 expression, whereas the down-regulation of KRT2 was less affected. In conclusion, RAR alpha agonists elicit a reciprocal modulation of KRT2 and KRT4/KRT13 expression in human epidermis, but whether or not the keratin genes also possess RAR alpha-specific regulatory elements is still unclear.

Place, publisher, year, edition, pages
2010. Vol. 19, no 7, p. 674-681
Keywords [en]
cellular retinoic acid binding proteins, immunohistochemistry, keratinocytes, RT-qPCR, transcription factors, vitamin A
National Category
Medical and Health Sciences
Research subject
Biomedical Laboratory Science
Identifiers
URN: urn:nbn:se:oru:diva-12935DOI: 10.1111/j.1600-0625.2010.01079.xISI: 000278796300009OAI: oai:DiVA.org:oru-12935DiVA, id: diva2:383228
Available from: 2011-01-04 Created: 2011-01-03 Last updated: 2018-04-23Bibliographically approved

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Sirsjö, Allan

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