TY - JOUR
T1 - RXRα ablation in epidermal keratinocytes enhances UVR-induced DNA damage, apoptosis, and proliferation of keratinocytes and melanocytes
AU - Wang, Zhixing
AU - Coleman, Daniel J.
AU - Bajaj, Gaurav
AU - Liang, Xiaobo
AU - Ganguli-Indra, Gitali
AU - Indra, Arup K.
N1 - Funding Information:
We thank Pierre Chambon and Daniel Metzger for helpful advice and critically reviewing the article and Cliff Pereira for statistical analysis. We also thank Talicia Savage, Erin Bredeweg, and Steven Ma for help in sample processing. These studies were supported by grant ES016629-01A1 to AI from the National Institute of Environmental and Health Sciences (NIEHS) at the National Institutes of Health, an OHSU Medical Research Foundation grant to AI, and an NIEHS Center grant (ES00210) to the Oregon State University Environmental Health Sciences Center. In addition, we thank Mark Zabriskie, and Gary DeLander of the OSU College of Pharmacy for continuous support and encouragement.
PY - 2011/1
Y1 - 2011/1
N2 - We show here that keratinocytic nuclear receptor retinoid X receptor-α (RXRα) regulates mouse keratinocyte and melanocyte homeostasis following acute UVR. Keratinocytic RXRα has a protective role in UVR-induced keratinocyte and melanocyte proliferation/differentiation, oxidative stress-mediated DNA damage, and cellular apoptosis. We discovered that keratinocytic RXRα, in a cell-autonomous manner, regulates mitogenic growth responses in skin epidermis through secretion of heparin-binding EGF-like growth factor, GM-CSF, IL-1α, and cyclooxygenase-2 and activation of mitogen-activated protein kinase pathways. We identified altered expression of several keratinocyte-derived mitogenic paracrine growth factors such as endothelin 1, hepatocyte growth factor, α-melanocyte stimulating hormone, stem cell factor, and fibroblast growth factor-2 in skin of mice lacking RXRα in epidermal keratinocytes (RXRαep-/- mice), which in a non-cell-autonomous manner modulated melanocyte proliferation and activation after UVR. RXRαep-/- mice represent a unique animal model in which UVR induces melanocyte proliferation/activation in both epidermis and dermis. Considered together, the results of our study suggest that RXR antagonists, together with inhibitors of cell proliferation, can be effective in preventing solar UVR-induced photocarcinogenesis.
AB - We show here that keratinocytic nuclear receptor retinoid X receptor-α (RXRα) regulates mouse keratinocyte and melanocyte homeostasis following acute UVR. Keratinocytic RXRα has a protective role in UVR-induced keratinocyte and melanocyte proliferation/differentiation, oxidative stress-mediated DNA damage, and cellular apoptosis. We discovered that keratinocytic RXRα, in a cell-autonomous manner, regulates mitogenic growth responses in skin epidermis through secretion of heparin-binding EGF-like growth factor, GM-CSF, IL-1α, and cyclooxygenase-2 and activation of mitogen-activated protein kinase pathways. We identified altered expression of several keratinocyte-derived mitogenic paracrine growth factors such as endothelin 1, hepatocyte growth factor, α-melanocyte stimulating hormone, stem cell factor, and fibroblast growth factor-2 in skin of mice lacking RXRα in epidermal keratinocytes (RXRαep-/- mice), which in a non-cell-autonomous manner modulated melanocyte proliferation and activation after UVR. RXRαep-/- mice represent a unique animal model in which UVR induces melanocyte proliferation/activation in both epidermis and dermis. Considered together, the results of our study suggest that RXR antagonists, together with inhibitors of cell proliferation, can be effective in preventing solar UVR-induced photocarcinogenesis.
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U2 - 10.1038/jid.2010.290
DO - 10.1038/jid.2010.290
M3 - Article
C2 - 20944655
AN - SCOPUS:78650279241
SN - 0022-202X
VL - 131
SP - 177
EP - 187
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
IS - 1
ER -