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The role of keratinocyte‐derived α‐melanocyte‐stimulating hormone and endothelin 1 signaling in a murine melanoma‐susceptible model
Author(s) -
Kyryachenko Sergiy,
Schumann Canan,
Indra Arup
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.523.11
Subject(s) - keratinocyte , retinoid x receptor , melanocyte , autocrine signalling , melanoma , melanocyte stimulating hormone , cancer research , nuclear receptor , microbiology and biotechnology , biology , signal transduction , receptor , retinoid , endocrinology , hormone , medicine , cell culture , transcription factor , biochemistry , retinoic acid , genetics , gene
Nuclear receptor RXRα is a member of steroid hormone retinoid‐X‐receptor family. Mice with epidermal deletion of RXRα (RXRαep−/−) develop melanoma‐like tumors upon chemical carcinogen treatment. This suggests that distinct non‐cell autonomous molecular events mediated by RXRα in keratinocytes may regulate melanoma progression. Melanocyte homeostasis in skin is largely influenced by signals from neighboring keratinocytes, autocrine signals, and environmental factors, such as ultraviolet radiation (UVR). UVR affects melanocytes directly by damaging the DNA and indirectly by stimulating the synthesis of keratinocyte‐derived factors, such as endothelin 1 (EDN1) and α‐melanocyte stimulating hormone (α‐MSH). Pharmacological inhibition of EDN1 signaling enhances UV‐induced DNA damage in melanocytes, but it does not affect the proliferation of keratinocytes, melanocytes, and dermal cells in control (RXRαL2/L2) and RXRαep−/− mice. In contrast, inhibition of α‐MSH signaling reduces UV‐induced DNA damage in all skin cell types. Moreover, it also leads to minimal increase in proliferation of dermal cells, but not of keratinocytes and melanocytes in the skin of RXRαL2/L2 and RXRαep−/− mice. This research will help to evaluate strategies for preventing and/or curing UV‐induced melanoma by using a combination of antagonists and/or agonists of keratinocyte‐derived factors. Grant Funding Source : NIEHS grant R01ES016629 (to AI)