Ultraviolet irradiation of human skin causes functional vitamin A deficiency, preventable by all-trans retinoic acid pre-treatment

  • An Erratum to this article was published on 01 July 1999


We report here that ultraviolet irradiation substantially reduced the mRNA and protein of the two major nuclear retinoid receptors, RAR-γ and RXR-α, in human skin in vivo. Pre-treatment with retinoic acid mitigated this loss of nuclear retinoid receptors. Ultraviolet irradiation caused a near-total loss of retinoic acid induction of two RAR/RXR target genes, cellular retinoic acid binding protein-II and RA 4-hydroxylase, but did not affect 1,25-dihydroxyvitamin D3 induction of the vitamin D receptor/RXR-regulated gene vitamin D 24-hydroxylase. In effect, ultraviolet irradiation causes a functional vitamin A deficiency that may have deleterious effects on skin function, contributing to skin photo-aging and carcinogenesis.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Ultraviolet irradiation reduces nuclear retinoid receptor proteins and mRNAs in adult human skin in vivo.
Figure 2: Repeated exposure to UV irradiation causes sustained reduction in RXR-α, but not RAR-γ, in human skin in vivo.
Figure 3: Pre-treatment with topical RA reduces loss of RAR-γ and RXR-α in UV-irradiated adult human skin in vivo.
Figure 4: UV irradiation abolishes responsiveness to all-trans retinoic acid (RA), but not to 1,25-dihydroxyvitamin D3 in human skin in vivo.


  1. 1

    De Luca, L.M. Retinoids and their receptors in differentiation, embryogenesis and neoplasia. FASEB J. 5, 2924–2933 (1991).

    CAS  Article  Google Scholar 

  2. 2

    Futoryan, T. & Gilchrest, B.A. Retinoids and the skin. Nutr. Rev. 52, 299–310 ( 1994).

    CAS  Article  Google Scholar 

  3. 3

    Pfahl, M. Nuclear receptor/AP-1 interaction. Endocr. Rev. 14, 651–658 (1993).

    CAS  PubMed  Google Scholar 

  4. 4

    Mangelsdorf, D.J. & Evans, R.M. The RXR heterodimers and orphan receptors. Cell 83, 841– 850 (1995).

    CAS  Article  Google Scholar 

  5. 5

    Chambon, P. A decade of molecular biology of retinoic acid receptors. FASEB J. 10, 940–954 ( 1996).

    CAS  Article  Google Scholar 

  6. 6

    Imakado, S. et al. Targeting expression of a dominant-negative retinoic acid receptor mutant in the epidermis of transgenic mice results in loss of barrier function. Genes Dev. 9, 317– 329 (1995).

    CAS  Article  Google Scholar 

  7. 7

    Saitou, M. et al. Inhibition of skin development by targeted expression of a dominant-negative retinoic acid receptor. Nature 374, 159–162 (1995).

    CAS  Article  Google Scholar 

  8. 8

    Feng, X. et al. Suprabasal expression of a dominant-negative RXR alpha mutant in transgenic mouse epidermis impairs regulation of gene transcription and basal keratinocyte proliferation by RAR-selective retinoids. Genes Dev. 11, 59–71 ( 1997).

    CAS  Article  Google Scholar 

  9. 9

    Kastner, P., Mark, M. & Chambon, P. Nonsteroid nuclear receptors: what are genetic studies telling us about their role in real life? Cell 83, 859–869 (1995).

    CAS  Article  Google Scholar 

  10. 10

    Kumar, R., Shoemaker, A.R. & Verma, A.K. Retinoic acid nuclear receptors and tumor promotion: decreased expression of retinoic acid nuclear receptors by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate. Carcinogenesis (London) 15, 701–705 (1994).

    CAS  Article  Google Scholar 

  11. 11

    Darwiche, N. et al. Loss of retinoic acid receptors in mouse skin and skin tumors is associated with activation of the ras(Ha) oncogene and high risk for premalignant progression. Cancer Res. 56, 4942– 4949 (1996).

    CAS  PubMed  Google Scholar 

  12. 12

    Lotan, R. et al. Suppression of retinoic acid receptor-beta in premalignant oral lesions and its up-regulation by isotretinoin. N. Engl. J. Med. 332, 1405–1410 ( 1995).

    CAS  Article  Google Scholar 

  13. 13

    Darwiche, N. et al. Mouse skin tumor progression results in differential expression of retinoic acid and retinoid X receptors. Cancer Res. 55, 2774–2782 (1995).

    CAS  PubMed  Google Scholar 

  14. 14

    Lotan, R. Retinoids in cancer chemoprevention. FASEB J. 10, 1031–1039 (1996).

    CAS  Article  Google Scholar 

  15. 15

    De Luca, L.M. et al. Vitamin A in epithelial differentiation and skin carcinogenesis. Nutr. Rev. 52, 45–52 (1994).

    Article  Google Scholar 

  16. 16

    Fitzgerald, P., Teng, M., Chandraratna, R.A.S., Heyman, R.A. & Allegretto, E.A. Retinoic acid receptor α expression correlates with retinoid-induced growth inhibition of human breast cancer cells regardless of estrogen receptor status. Cancer Res. 57, 2642–2650 ( 1997).

    CAS  PubMed  Google Scholar 

  17. 17

    Marks, R. An overview of skin cancers: incidence and causation. Cancer 75, 607–612 (1995).

    CAS  Article  Google Scholar 

  18. 18

    Shea, C.R. & Parrish, J.A. in Physiology, Biochemistry, and Molecular Biology of the Skin Vol. II (ed. Goldsmith, L.A.) 910 –927 (Oxford University Press, New York, 1991).

    Google Scholar 

  19. 19

    Campbell, C., Quinn, A.G., Angus, B., Farr, P.M. & Rees, J.L. Wavelength specific patterns of p53 induction in human skin following exposure to UV radiation. Cancer Res. 53, 2697–2699 (1993).

    CAS  PubMed  Google Scholar 

  20. 20

    Fornace, A.J. Mammalian genes induced by radiation; activation of genes associated with growth control. Annu. Rev. Genet. 26, 507 –526 (1992).

    CAS  Article  Google Scholar 

  21. 21

    Holick, M. Environmental factors that influence the cutaneous production of vitamin D. Am. J. Clin. Nutr. 61, 638S– 645S (1995).

    CAS  Article  Google Scholar 

  22. 22

    Fisher, G.J. et al. Molecular basis of sun-induced premature skin ageing and retinoid antagonism. Nature 379, 335– 339 (1996).

    CAS  Article  Google Scholar 

  23. 23

    Fisher, G.J. et al. Pathophysiology of premature skin aging induced by ultraviolet light. N. Engl. J. Med. 337, 1419– 1428 (1997).

    CAS  Article  Google Scholar 

  24. 24

    Fisher, G.J. et al. Retinoic acid inhibits induction of c-Jun protein by ultraviolet radiation that occurs subsequent to activation of mitogen- activated protein kinase pathways in human skin in vivo. J. Clin. Invest. 101, 1432–1440 ( 1998).

    CAS  Article  Google Scholar 

  25. 25

    Fisher, G.J. et al. Immunological identification and functional quantitation of retinoic acid and retinoid X receptor proteins in human skin. J. Biol. Chem. 269, 20629–20635 (1994).

    CAS  PubMed  Google Scholar 

  26. 26

    Ohyama, Y. et al. Identification of a vitamin D-responsive element in the 5'-flanking region of the rat 25-hydroxyvitamin D3 24-hydroxylase gene. J. Biol. Chem. 269, 10545–10550 (1994).

    CAS  PubMed  Google Scholar 

  27. 27

    Kang, S., Li, X.Y., Duell, E.A. & Voorhees, J.J. The retinoid X receptor agonist 9-cis retinoic acid and the 24-hydroxylase inhibitor ketoconazole increase activity of 1,25-dihydroxyvitamin D3 in human skin in vivo. J. Invest. Dermatol. 108, 513–518 (1997).

    CAS  Article  Google Scholar 

  28. 28

    Li, X.Y., Xiao, J.H., Feng, X., Li, Q. & Voorhees, J.J. Retinoid X receptor-specific ligands synergistically upregulate 1,25-dihydroxyvitamin D3-dependent transcription in epidermal keratinocytes in vitro and in vivo. J. Invest. Dermtol. 108, 506–512 (1997).

    CAS  Article  Google Scholar 

  29. 29

    Berlett, B.S. & Stadtman, E.R. Protein oxidation in aging, disease, and oxidative stress. J. Biol. Chem. 272, 20313–20316 (1997).

    CAS  Article  Google Scholar 

  30. 30

    Grune, T., Reinheckel, T. & Davies, K.J.A. Degradation of oxidized proteins in mammalian cells. FASEB J. 11, 526–534 (1997).

    CAS  Article  Google Scholar 

  31. 31

    Duell, E.A., Kang, S. & Voorhees, J.J. Retinoic acid isomers applied to human skin in vivo each induce a 4-hydroxylase that inactivates only trans retinoic acid. J. Invest. Dermatol. 106, 316– 320 (1996).

    CAS  Article  Google Scholar 

  32. 32

    Arbour, N.C., Prahl, J.M. & DeLuca, H.F. Stabilization of the vitamin D receptor in rat osteosarcoma cells through the action of 1,25-dihydroxyvitamin D3. Mol. Endocrinol. 7, 1307–1312 (1993).

    CAS  PubMed  Google Scholar 

  33. 33

    Xiao, J.H., Durand, B., Chambon, P. & Voorhees, J.J. Endogenous retinoic acid receptor (RAR)-retinoid X receptor (RXR) heterodimers are the major functional forms regulating retinoid-responsive elements in adult human keratinocytes. J. Biol. Chem. 270, 3001– 3011 (1995).

    CAS  Article  Google Scholar 

  34. 34

    Fisher, G.J. & Voorhees, J.J. Molecular mechanisms of retinoid actions in skin. FASEB J. 10, 1002– 1013 (1996).

    CAS  Article  Google Scholar 

  35. 35

    Nagpal, S., Athanikar, J. & Chandraratna, R.A. Separation of transactivation and AP1 antagonism functions of retinoic acid receptor-s alpha. J. Biol. Chem. 270 , 923–927 (1995).

    CAS  Article  Google Scholar 

  36. 36

    van der Leun, J.C. UV radiation from sunlight: summary, conclusions and recommendations. J. Photochem. Photobiol. 35, 237–244 (1996).

    CAS  Article  Google Scholar 

  37. 37

    Angel, P. et al. Phorbol ester-inductible genes contain a common cis element recognized by a TPA-modulated trans-acting factor. Cell 49, 729–739 (1987).

    CAS  Article  Google Scholar 

  38. 38

    Fisher, G.J. & Voorhees, J.J. Molecular mechanisms of photoaging and its prevention by retinoic acid: Ultraviolet irradiation induces MAP kinase signal transduction cascades that induce AP-1-regulated matrix metalloproteinases that degrade human skin in vivo. J. Invest. Dermatol. Symp. Proc. 3, 61–68 ( 1998).

    CAS  Article  Google Scholar 

  39. 39

    Saez, E. et al. c-fos is required for malignant progression of skin tumors. Cell 82, 721–732 (1995).

    CAS  Article  Google Scholar 

  40. 40

    Astrom, A. et al. Molecular cloning of two human cellular retinoic acid-binding proteins (CRABP). Retinoic acid-induced expression of CRAPB-II but not CRABP-I in adult skin in vivo and in skin fibroblasts in vitro. J. Biol. Chem. 266, 17662–17666 (1991).

    CAS  PubMed  Google Scholar 

  41. 41

    White, J.A. et al. cDNA cloning of human retinoic acid-metabolizing enzyme (hP450RAI) identifies a novel family of cytochromes P450 (CYP26). J. Biol. Chem. 272, 18538–18541 ( 1997).

    CAS  Article  Google Scholar 

  42. 42

    Chen, K.S., Prahl, J.M. & DeLuca, H.F. Isolation and expression of human 1,25-dihydroxyvitamin D3 24-hydroxylase cDNA. Proc. Natl. Acad. Sci. USA 90, 4543–4547 (1993).

    CAS  Article  Google Scholar 

  43. 43

    Fisher, G.J. et al. All-trans retinoic acid induces cellular retinol-binding protein in human skin in vivo. J. Invest. Dermatol. 105, 80–86 (1995).

    CAS  Article  Google Scholar 

  44. 44

    Bradford, M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem. 72, 248–254 ( 1976).

    CAS  Article  Google Scholar 

Download references


The authors thank C. Petersen and S. Rehbine for tissue procurement, J. Granger for technical assistance, L. VanGoor for graphics preparation, T. Hamilton for statistical analyses and A. Chapple for editorial assistance. We thank P. Chambon for RAR and RXR cDNA plasmids, M. Petkovich for human RA 4-hydroxylase cDNA, M. Haussler for human vitamin D 24-hydroxylase cDNA, and M.R. Uskokovic and P. Bollag at Hoffmann La Roche (Nutley, New Jersey) for 1,25-dihydroxyvitamin D 3 . This study was supported in part by the Babcock Endowment for Dermatological Research, the Dermatology Foundation (SK), and a grant from the Johnson & Johnson Corporation.

Author information



Corresponding author

Correspondence to Gary J. Fisher.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Wang, Z., Boudjelal, M., Kang, S. et al. Ultraviolet irradiation of human skin causes functional vitamin A deficiency, preventable by all-trans retinoic acid pre-treatment. Nat Med 5, 418–422 (1999). https://doi.org/10.1038/7417

Download citation

Further reading


Sign up for the Nature Briefing newsletter for a daily update on COVID-19 science.
Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing