Pigment‐independent cAMP‐mediated epidermal thickening protects against cutaneous UV injury by keratinocyte proliferation
Open accessAbstract
The epidermis increases pigmentation and epidermal thickness in response to ultraviolet exposure to protect against UV‐associated carcinogenesis; however, the contribution of epidermal thickness has been debated. In a humanized skin mouse model that maintains interfollicular epidermal melanocytes, we found that forskolin, a small molecule that directly activates adenylyl cyclase and promotes cAMP generation, up‐regulated epidermal eumelanin accumulation in fair‐skinned melanocortin‐1‐receptor (M c1r)‐defective animals. Forskolin‐induced pigmentation was associated with a reproducible expansion of epidermal thickness irrespective of melanization or the presence of epidermal melanocytes. Rather, forskolin‐enhanced epidermal thickening was mediated through increased keratinocyte proliferation, indirectly through secreted factor(s) from cutaneous fibroblasts. We identified keratinocyte growth factor (K gf) as a forskolin‐induced fibroblast‐derived cytokine that promoted keratinocyte proliferation, as forskolin induced K gf expression both in the skin and in primary fibroblasts. Lastly, we found that even in the absence of pigmentation, forskolin‐induced epidermal thickening significantly diminished the amount of UV‐A and UV‐B that passed through whole skin and reduced the amount of UV‐B‐associated epidermal sunburn cells. These findings suggest the possibility of pharmacologic‐induced epidermal thickening as a novel UV‐protective therapeutic intervention, particularly for individuals with defects in pigmentation and adaptive melanization.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The effect of UVR on epidermal thickness described in the literature is inconsistent.
“The effect of UVR on epidermal thickness described in the literature is inconsistent (Coelho et al, 2009;Felton et al, 2020;Scott et al, 2012).”
From Effect of Repeated Low-Dose UVR Exposure on Skin Inflammation Threshold, Skin Biomarkers, and Vitamin D in Healthy Adults (2025) · cites this paper as Scott et al, 2012
The Discussion says most reports describe UV-induced epidermal thickening and that the role of melanocytes in that thickening has been unclear. It does not say that studies report inconsistent effects of UVR on epidermal thickness. I searched for conflicting or variable effects of UV exposure on thickness in our copy. (LLM, conf=0.74)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Keratinocyte–Fibroblast Interactions in Wound Healing
Werner, S., Krieg, T. M., & Smola, H. (2007) · Journal of Investigative Dermatology · doi:10.1038/sj.jid.5700786 · Cited by 1,278 · see citing works
Neuroendocrinology of the Skin1
Slominski, A., & Wortsman, J. (2000) · Endocrine Reviews · doi:10.1210/edrv.21.5.0410 · Cited by 727 · see citing works
Ultraviolet light induced injury: Immunological and inflammatory effects
Clydesdale, G. J., Dandie, G. W., & Muller, H. K. (2001) · Immunology and Cell Biology · doi:10.1046/j.1440-1711.2001.01047.x · Cited by 582 · see citing works
Alonso, L. C., & Fuchs, E. V. (2006) · Journal of Cell Science · doi:10.1242/jcs.02793 · Cited by 557 · see citing works
Neuroendocrinology of the Skin
Slominski, A. T. (2000) · Endocrine Reviews · doi:10.1210/er.21.5.457 · Cited by 503 · see citing works
Physiological factors that regulate skin pigmentation
Yamaguchi, Y., & Hearing, V. J. (2009) · BioFactors · doi:10.1002/biof.29 · Cited by 495 · see citing works
Cyclic AMP in relation to proliferation of the Epidermal cell: a new view
Green, H. (1978) · Cell · doi:10.1016/0092-8674(78)90265-9 · Cited by 481 · see citing works
Mitogenic and melanogenic stimulation of normal human melanocytes by melanotropic peptides
Abdel-Malek, Z., Swope, V. B., Suzuki, I., Akcali, C., Harriger, M. D., Boyce, S. T., Urabe, K., & Hearing, V. J. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.5.1789 · Cited by 377 · see citing works
EGF and TGF‐α in wound healing and repair
Schultz, G., Clark, W., & Rotatori, D. S. (1991) · Journal of Cellular Biochemistry · doi:10.1002/jcb.240450407 · Cited by 357 · see citing works
Topical drug rescue strategy and skin protection based on the role of Mc1r in UV-induced tanning
D'Orazio, J. A., Nobuhisa, T., Cui, R., Arya, M., Spry, M., Wakamatsu, K., Igras, V., Kunisada, T., Granter, S. R., Nishimura, E. K., et al. (2006) · Nature · doi:10.1038/nature05098 · Cited by 350 · see citing works
Self-citationKeratinocyte Growth Factor: A Unique Player in Epithelial Repair Processes
Werner, S. (1998) · Cytokine & Growth Factor Reviews · doi:10.1016/s1359-6101(98)00010-0 · Cited by 347 · see citing works
Suzuki, I., Cone, R. D., Im, S., Nordlund, J. J., & ABDEL‐MALEK, Z. A. (1996) · Endocrinology · doi:10.1210/endo.137.5.8612494 · Cited by 332 · see citing works
Slominski, A. T., & Paus, R. (1993) · Journal of Investigative Dermatology · doi:10.1016/0022-202x(93)90507-e · Cited by 290 · see citing works
Keratinocyte-Melanocyte Interactions During Melanosome Transfer
Seiberg, M. (2001) · Pigment Cell Research · doi:10.1034/j.1600-0749.2001.140402.x · Cited by 290 · see citing works
Ito, S., Nakanishi, Y., Valenzuela, R. K., Brilliant, M. H., Kolbe, L., & Wakamatsu, K. (2011) · Pigment Cell & Melanoma Research · doi:10.1111/j.1755-148x.2011.00864.x · Cited by 242 · see citing works
Self-citationKunisada, T., Yoshida, H., Yamazaki, H., Miyamoto, A., Hemmi, H., Nishimura, E. K., Shultz, L. D., Nishikawa, S., & Hayashi, S. (1998) · Development · doi:10.1242/dev.125.15.2915 · Cited by 240 · see citing works
Labeling Nuclear DNA Using DAPIPreprint
Chazotte, B. (2011) · Cold Spring Harbor Protocols · doi:10.1101/pdb.prot5556 · Cited by 222 · see citing works
Kunisada, T., Lu, S.-Z., Yoshida, H., Nishikawa, S., Nishikawa, S., Mizoguchi, M., Hayashi, S., Tyrrell, L., Williams, D. A., Wang, X., et al. (1998) · The Journal of Experimental Medicine · doi:10.1084/jem.187.10.1565 · Cited by 208 · see citing works
Brauchle, M. A., Angermeyer, K., Hübner, G., & Werner, S. (1994) · PubMed · Cited by 203 · see citing works
Selective elimination of fibroblasts from cultures of normal human melanocytes
Halaban, R., & Alfano, F. D. (1984) · In Vitro Cellular & Developmental Biology - Plant · doi:10.1007/bf02619590 · Cited by 186 · see citing works
Stimulation of Growth of Keratinocytes by Basic Fibroblast Growth Factor
O’Keefe, E. J., Chiu, M. L., & Payne, R. E. (1988) · Journal of Investigative Dermatology · doi:10.1111/1523-1747.ep12560956 · Cited by 171 · see citing works
Modulation of keratinocyte growth factor and its receptor in reepithelializing human skin.
Marchese, C., Chedid, M., Dirsch, O., Csaky, K. G., di Pompeo, F. S., Latini, C., LaRochelle, W. J., Torrisi, M. R., & Aaronson, S. A. (1995) · The Journal of Experimental Medicine · doi:10.1084/jem.182.5.1369 · Cited by 163 · see citing works
Im, S., Moro, O., Peng, F., Medrano, E. E., Cornelius, J., Babcock, G. F., Nordlund, J. J., & ABDEL‐MALEK, Z. A. (1998) · PubMed · Cited by 141 · see citing works
Stepping up melanocytes to the challenge of UV exposure
Abdel-Malek, Z. A., Kadekaro, A. L., & Swope, V. B. (2010) · Pigment Cell & Melanoma Research · doi:10.1111/j.1755-148x.2010.00679.x · Cited by 134 · see citing works
Regulation of keratinocyte function by growth factors
Hashimoto, K. (2000) · Journal of Dermatological Science · doi:10.1016/s0923-1811(00)00141-9 · Cited by 132 · see citing works
Methods for Synchronizing Cells at Specific Stages of the Cell Cycle
Jackman, J., & O'Connor, P. M. (1998) · Current Protocols in Cell Biology · doi:10.1002/0471143030.cb0803s00 · Cited by 131 · see citing works
Beer, H., Florence, C., Dammeier, J., McGuire, L., Werner, S., & Duan, D. R. (1997) · Oncogene · doi:10.1038/sj.onc.1201383 · Cited by 122 · see citing works
Skin as an endocrine organ: implications for its function
Slominski, A., Wortsman, J., Paus, R., Elias, P. M., Tobin, D. J., & Feingold, K. R. (2008) · Drug Discovery Today Disease Mechanisms · doi:10.1016/j.ddmec.2008.04.004 · Cited by 116 · see citing works
The Melanocortin 1 Receptor and the UV Response of Human Melanocytes—A Shift in Paradigm<sup>†</sup>
Abdel‐Malek, Z. A., Knittel, J., Kadekaro, A. L., Swope, V. B., & Starner, R. (2008) · Photochemistry and Photobiology · doi:10.1111/j.1751-1097.2008.00294.x · Cited by 111 · see citing works
Altered expression of keratinocyte growth factor and its receptor in psoriasis.
Finch, P. W., Murphy, F., Cardinale, I. R., & Krueger, J. G. (1997) · Europe PMC (PubMed Central) · Cited by 105 · see citing works
The major pathways of keratinocyte differentiation as defined by keratin expression: an overview.
Galvin, S., Loomis, C. A., Manabe, M., et al. (1989) · PubMed · Cited by 102 · see citing works
Cardinali, G., Bolasco, G., Aspite, N., Lucania, G., Lotti, L. V., Torrisi, M. R., & Picardo, M. (2007) · Journal of Investigative Dermatology · doi:10.1038/sj.jid.5701063 · Cited by 91 · see citing works
Comparing Quantitative Measures of Erythema, Pigmentation and Skin Response using Reflectometry
Wagner, J. K., Jovel, C., Norton, H., Parra, E. J., & Shriver, M. D. (2002) · Pigment Cell Research · doi:10.1034/j.1600-0749.2002.02042.x · Cited by 91 · see citing works
Control of melanocyte differentiation by a MITF–PDE4D3 homeostatic circuitPreprint
Khaled, M., Levy, C., & Fisher, D. E. (2010) · Genes & Development · doi:10.1101/gad.1937710 · Cited by 88 · see citing works
Chakraborty, A. K., Funasaka, Y., Slominski, A. T., Bolognia, J. L., Sodi, S., Ichihashi, M., & Pawelek, J. M. (1999) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1999.tb08668.x · Cited by 88 · see citing works
Braun, S., Krampert, M., Bodó, E., Kümin, A., Born-Berclaz, C., Paus, R., & Werner, S. (2006) · Journal of Cell Science · doi:10.1242/jcs.03259 · Cited by 82 · see citing works
Normal murine melanocytes in culture
Tamura, A., Halaban, R., Moellmann, G. E., Cowan, J. M., Lerner, M. R., & Lerner, A. B. (1987) · In Vitro Cellular & Developmental Biology - Plant · doi:10.1007/bf02628423 · Cited by 79 · see citing works
Characterization of sunburn cells after exposure to ultraviolet light
Bayerl, C., Taake, S., Moll, I., & Jung, E. G. (1995) · Photodermatology Photoimmunology & Photomedicine · doi:10.1111/j.1600-0781.1995.tb00157.x · Cited by 78 · see citing works
The effects of ultraviolet exposure on skin melanin pigmentation.
Ortonne, J. P. (1990) · PubMed · Cited by 76 · see citing works
Bino, S. D., Vioux, C., Rossio-Pasquier, P., Jomard, A., Démarchez, M., Asselineau, D., & Bernerd, F. (2004) · British Journal of Dermatology · doi:10.1111/j.0007-0963.2004.05886.x · Cited by 75 · see citing works
Kinetics of G1 transit following brief starvation for serum factors.
Campisi, J., Morreo, G., & Pardee, A. B. (1984) · Experimental Cell Research · doi:10.1016/0014-4827(84)90647-5 · Cited by 71 · see citing works
Keratinocyte growth factor down-regulates intracellular ROS production induced by UVB
Kovacs, D., Raffa, S., Flori, E., Aspite, N., Briganti, S., Cardinali, G., Torrisi, M. R., & Picardo, M. (2009) · Journal of Dermatological Science · doi:10.1016/j.jdermsci.2009.01.005 · Cited by 61 · see citing works
Passeron, T., Namiki, T., Passeron, H. J., Le Pape, E., & Hearing, V. J. (2009) · Journal of Investigative Dermatology · doi:10.1038/jid.2008.182 · Cited by 60 · see citing works
Takahashi, H., Honma, M., Miyauchi, Y., Nakamura, S., Ishida‐Yamamoto, A., & Iizuka, H. (2004) · Archives of Dermatological Research · doi:10.1007/s00403-004-0478-z · Cited by 54 · see citing works
Wang, X., Bi, Z., Chu, W., & Wan, Y. (2005) · International Journal of Molecular Medicine · doi:10.3892/ijmm.16.6.1117 · Cited by 54 · see citing works
van Erp, P. E. J., de Mare, S., Rijzewijk, J. J., et al. (1989) · The Histochemical Journal · doi:10.1007/bf01798497 · Cited by 50 · see citing works
Spry, M. L., Vanover, J. C., Scott, T. L., Abona‐Ama, O., Wakamatsu, K., Ito, S., & D'Orazio, J. A. (2008) · Pigment Cell & Melanoma Research · doi:10.1111/j.1755-148x.2008.00536.x · Cited by 38 · see citing works
Self-citationDibutyryl Cyclic AMP Modulates Keratinocyte Migration Without Alteration on Integrin Expression
Iwasaki, T., Chen, J. D., Kim, J. P., et al. (1994) · Journal of Investigative Dermatology · doi:10.1111/1523-1747.ep12383031 · Cited by 36 · see citing works
Kang, Y., Choi, E.-J., Choi, Y., & Hwang, J. (2011) · Experimental Dermatology · doi:10.1111/j.1600-0625.2010.01236.x · Cited by 34 · see citing works
Primary Mouse Keratinocyte Culture
Pirrone, A., Hager, B., & Fleckman, P. H. (2004) · Humana Press eBooks · doi:10.1385/1-59259-830-7:003 · Cited by 29 · see citing works
The effect of serum starvation on DNA, RNA and protein synthesis during interphase in L-cells
Zetterberg, A., & Sköld, O. (1969) · Experimental Cell Research · doi:10.1016/0014-4827(69)90374-7 · Cited by 23 · see citing works
Phosphodiesterase 7A inhibitor ASB16165 impairs proliferation of keratinocytes in vitro and in vivo
Goto, M., Kadoshima-Yamaoka, K., Murakawa, M., et al. (2010) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2010.01.024 · Cited by 22 · see citing works
Vanover, J. C., Spry, M. L., Hamilton, L., Wakamatsu, K., Ito, S., & D'Orazio, J. A. (2009) · Pigment Cell & Melanoma Research · doi:10.1111/j.1755-148x.2009.00617.x · Cited by 19 · see citing works
Self-citationAugmentation of keratinocyte differentiation by the epidermal mitogen, 8-bromo-cAMP
Tong, P. S. L., & Marcelo, C. L. (1983) · Experimental Cell Research · doi:10.1016/0014-4827(83)90393-2 · Cited by 13 · see citing works
Combined Fontana-Masson/Perls' staining.
Zappi, E. A., & Lombardo, W. (1984) · PubMed · Cited by 12 · see citing works
Implications of UV-induced inflammation and immunomodulation.
Cooper, K. D., Baron, E. D., & Matsui, M. S. (2003) · PubMed · Cited by 11 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
D'Orazio, J., Jarrett, S., Amaro-Ortiz, A., & Scott, T. (2013) · International Journal of Molecular Sciences · doi:10.3390/ijms140612222 · Cited by 1,984 · see citing works
Self-citationUltraviolet Radiation, Aging and the Skin: Prevention of Damage by Topical cAMP Manipulation
Amaro-Ortiz, A., Yan, B., & D'Orazio, J. (2014) · Molecules · doi:10.3390/molecules19056202 · Cited by 360 · see citing works
Self-citationDessauer, C. W., Watts, V. J., Ostrom, R. S., Conti, M., Dove, S., & Seifert, R. (2017) · Pharmacological Reviews · doi:10.1124/pr.116.013078 · Cited by 201 · see citing works
de Boer, F., Kezic, S., van der Lelie, G., Motazedi, E., Rustemeyer, T., van Dijk, A., Almasian, M., Jakasa, I., & van der Molen, H. F. (2025) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2025.01.024 · Cited by 4 · see citing works
- Authors
- Scott, T. L., Christian, P. A., Kesler, M. V., Donohue, K. M., Shelton, B., Wakamatsu, K., Ito, S., & D'Orazio, J.
- Affiliations
- University of Kentucky (US)
- Fujita Health University (JP)
- Corresponding author
- D'Orazio, John
- Venue
- Experimental Dermatology
- Publisher
- Wiley
- Published
- 2012-09-21
- Volume
- 21
- Issue
- 10
- Pages
- 771-777
- ISSN
- 0906-6705 (ISSN-L)
- 1600-0625
- PMC
- PMC3481176
- OpenAlex
- W2142827380
- Cited by
- 61
- References
- 56
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 8 · 2023: 4 · 2022: 4 · 2021: 6 · 2020: 6 · 2019: 1 · 2018: 4 · 2017: 1 · 2016: 2 · 2015: 3 · 2014: 7 · 2013: 2
- FWCI
- 1.82
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Experimental Dermatology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer (R01 CA131075-02)
- Wendy Will Case Cancer Research Fund
- Markey Cancer Foundation
- Children's Miracle Network
- Jennifer and David Dickens Melanoma Research Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › melanin and skin pigmentation
- Health Sciences › Medicine › Dermatology › Skin Protection and Aging
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- epidermal thickening, cAMP signaling, forskolin, adenylate cyclase, keratinocyte proliferation, keratinocyte growth factor, UV protection, ultraviolet radiation, MC1R, eumelanin, sunburn cells
- MeSH terms
- Cyclic AMP, Animals, Disease Models, Animal, Epidermis, Colforsin, Humans, Melanocytes, Mice, Inbred C57BL, Mice, Transgenic, Pigments, Biological, Skin, Skin Pigmentation, Ultraviolet Rays, Keratinocytes, Apoptosis, Cell Proliferation, Mice, Keratin-14
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
