Dataset Information

RXR? ablation in epidermal keratinocytes enhances UVR-induced DNA damage, apoptosis, and proliferation of keratinocytes and melanocytes.

ABSTRACT: We show here that keratinocytic nuclear receptor retinoid X receptor-? (RXR?) regulates mouse keratinocyte and melanocyte homeostasis following acute UVR. Keratinocytic RXR? has a protective role in UVR-induced keratinocyte and melanocyte proliferation/differentiation, oxidative stress-mediated DNA damage, and cellular apoptosis. We discovered that keratinocytic RXR?, in a cell-autonomous manner, regulates mitogenic growth responses in skin epidermis through secretion of heparin-binding EGF-like growth factor, GM-CSF, IL-1?, 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, ?-melanocyte stimulating hormone, stem cell factor, and fibroblast growth factor-2 in skin of mice lacking RXR? in epidermal keratinocytes (RXR?(ep-/-) mice), which in a non-cell-autonomous manner modulated melanocyte proliferation and activation after UVR. RXR?(ep-/-) 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.

SUBMITTER: Wang Z

PROVIDER: S-EPMC3073005 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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RXRα ablation in epidermal keratinocytes enhances UVR-induced DNA damage, apoptosis, and proliferation of keratinocytes and melanocytes.

Wang Zhixing Z Coleman Daniel J DJ Bajaj Gaurav G Liang Xiaobo X Ganguli-Indra Gitali G Indra Arup K AK

The Journal of investigative dermatology 20101014 1

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 ...[more]

PMID: 20944655

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Project description:Vitiligo is an acquired skin depigmentation disease in which excessive reactive oxygen species (ROS) play a critical pathogenic role in melanocyte destruction. The complex crosstalk between melanocytes and keratinocytes in vitiligo suggests that treatments aimed at protecting both the cells might be meaningful. In this study, we investigated the effect of 4-octyl itaconate (4-OI), an itaconate derivative, on ultraviolet B- (UVB-) induced apoptosis in HaCaT and PIG1 cells and the underlying mechanisms. HaCaT and PIG1 cells were pretreated with 4-OI (50 or 100 μM) for 24 h and then exposed to 300 mJ/cm2 UVB (emission range 290-320 nm, emission peak 310 nm). ROS levels and cell apoptosis were investigated using fluorescence microscopy and flow cytometry 24 h after irradiation. In addition, nuclear translocation and the expression of pathway-related proteins and mRNAs were detected using confocal microscopy, western blotting, and qRT-PCR, respectively. Our results demonstrated that UVB induced apoptosis in HaCaT and PIG1 cells, whereas inhibition of ROS production could reverse this effect. Furthermore, 4-OI attenuated UVB-induced apoptosis in HaCaT and PIG1 cells in a concentration-dependent manner by reducing the ROS levels. Moreover, 4-OI induced nuclear translocation and activation of nuclear factor erythroid 2-related factor 2 (Nrf2), and Nrf2 silencing reversed the inhibitory effect of 4-OI on the UVB-induced increase in ROS production and apoptosis in HaCaT and PIG1 cells. In addition, in vivo experiments using the Institute of Cancer Research mouse model showed that 4-OI via tail vein injection (10 mg/kg/day for six consecutive days) could reduce skin damage induced by UVB (400 mJ/cm2/day for five consecutive days). In conclusion, 4-OI can protect melanocytes and keratinocytes from UVB-induced apoptosis by Nrf2 activation-dependent ROS inhibition and can potentially treat skin disorders associated with oxidative stress, such as vitiligo.

Dataset Information

RXR? ablation in epidermal keratinocytes enhances UVR-induced DNA damage, apoptosis, and proliferation of keratinocytes and melanocytes.

Publications

RXRα ablation in epidermal keratinocytes enhances UVR-induced DNA damage, apoptosis, and proliferation of keratinocytes and melanocytes.

Similar Datasets

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