Supranuclear Melanin Caps Reduce Ultraviolet Induced DNA Photoproducts in Human Epidermis

Kobayashi, Nobuhiko; Nakagawa, Akemi; Muramatsu, Tsutomu; Yamashina, Yukio; Shirai, Toshihiko; Hashimoto, Mitsumasa; Ishigaki, Yasuhito; Ohnishi, Takeo; Mori, Toshio

doi:10.1046/j.1523-1747.1998.00178.x

Cited by 215 publications

(181 citation statements)

References 29 publications

(35 reference statements)

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“…In the cells, melanosomes collect over the nucleus to protect the cellular DNA from radiation damage 40,41 . The mechanism behind this protection by melanin relies upon chemical reactions involved in photoprotection which cause efficient internal conversion of harmful UV into a harmless level of heat energy rather than harmful reactive species such as free radicals.…”

Section: Melanocytes and Melaninmentioning

confidence: 99%

“…It is packaged into vesicles called melanosomes in the melanocytes and transported out of the cells along microtubules in their dentritic arms (see Chapter 1, Figure 1.2) 39 . Melanosomes collect over the nucleus of keratinocytes in the skin where melanin then provides protection against harmful UV radiation by converting the radiation into harmless heat energy 41 .…”

Section: Introductionmentioning

confidence: 99%

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Role of the pro-survival molecule Bfl-1 in melanoma

Hind

Carter

Harris

et al. 2015

The International Journal of Biochemistry & Cell Biology

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Melanoma, the cancer derived from the melanocytes of the skin, is becoming an ever more common cancer in the ageing population of the developed world and displays an intrinsic resistance to current therapies. This chemo resistance makes metastatic melanoma an extremely difficult cancer to treat leading to a 5 year survival rate of just 20%. As such, it is important to unearth new potential drug targets to increase the prospects for melanoma patients.Bfl-1 is a pro-survival protein of the Bcl-2 family of apoptosis regulating proteins. It has been found to be over-expressed in a small subset of chemo resistant tumours, including melanoma. Accordingly, I characterised the molecule in melanoma cells and determined its role in protecting these cells from chemotherapy-induced apoptosis. I elucidated the expression profile and half-lives of the protein and mRNA across a panel of melanoma cell-lines and healthy melanocytes. I also confirmed, using pathway specific inhibitors, that Bfl-1 was transcriptionally regulated by the NFB pathway and concluded through pulsechase experiments that Bfl-1 protein was degraded, at least in part, by the proteasome. Subcellular fractionation and indirect immunofluorescence techniques elucidated that Bfl-1 was located mostly at the mitochondria in both resting and apoptotic cells, with a diffuse level present throughout the cytoplasm. As well as characterising the protein in both melanoma cells and healthy primary melanocytes, I determined its role in the resistance of these cells to apoptosis. Over-expressed Bfl-1 was found to protect melanoma cells from apoptosis caused by a range of chemotherapeutic agents in A375 melanoma cells, which naturally expressed very low levels of Bfl-1. Further, knock down of Bfl-1 using siRNA technology in melanoma cells revealed the dependence of these cells on Bfl-1 for their resistance to certain chemotherapeutic agents currently used in melanoma treatment, including the MEK inhibitor PD901. All together, this research contributes to our understanding of Bfl-1 and highlights it as a potentially important therapeutic target in metastatic melanoma.

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Section: Melanocytes and Melaninmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Role of the pro-survival molecule Bfl-1 in melanoma

Hind

Carter

Harris

et al. 2015

The International Journal of Biochemistry & Cell Biology

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“…1D). UVRactivated current increased in a dose-dependent manner, required a minimum dose of 140 mJ/cm 2 , and reached saturating amplitude at 340 mJ/cm 2 (Fig. 1E), which was blocked in the presence of ruthenium red (RR, 10 μM), a broad TRP channel inhibitor ( Fig.…”

mentioning

confidence: 99%

“…Solar ultraviolet radiation (UVR), a prevalent risk factor for skin cancer, evokes a unique response in human skin that leads to increased pigmentation (1). UVR-induced pigmentation is a protective response mediated by melanin synthesis in human epidermal melanocytes (HEMs) to shield DNA from UVR-induced damage (2). While the mechanism by which short-wavelength UVR (UVB) results in increased pigmentation has been characterized (1), very little is known about phototransduction of long-wavelength UVR (UVA) in human skin.…”

mentioning

confidence: 99%

UV light phototransduction activates transient receptor potential A1 ion channels in human melanocytes

Bellono

Kammel

Zimmerman

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

123

139

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Human skin is constantly exposed to solar ultraviolet radiation (UVR), the most prevalent environmental carcinogen. Humans have the unique ability among mammals to respond to UVR by increasing their skin pigmentation, a protective process driven by melanin synthesis in epidermal melanocytes. The molecular mechanisms used by melanocytes to detect and respond to longwavelength UVR (UVA) are not well understood. We recently identified a UVA phototransduction pathway in melanocytes that is mediated by G protein-coupled receptors and leads to rapid calcium mobilization. Here we report that in human epidermal melanocytes physiological doses of UVR activate a retinal-dependent current mediated by transient receptor potential A1 (TRPA1) ion channels. The TRPA1 photocurrent is UVA-specific and requires G protein and phospholipase C signaling, thus contributing to UVAinduced calcium responses to mediate downstream cellular effects and providing evidence for TRPA1 function in mammalian phototransduction. Remarkably, TRPA1 activation is required for the UVR-induced and retinal-dependent early increase in cellular melanin. Our results show that TRPA1 is essential for a unique extraocular phototransduction pathway in human melanocytes that is activated by physiological doses of UVR and results in early melanin synthesis.

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“…Melanin synthesis, a multistep process involving tyrosinase as a key enzyme (Sanchez-Ferrer et al, 1995), takes place in specialized organelles called melanosomes (Hearing, 1999). Through dendrite-like processes, melanin is transferred to the keratinocytes (Yamamoto and Bhawan, 1994) in which it forms supranuclear caps that reduce UV transmission to the nuclear content (Kobayashi et al, 1998).…”

Section: Ontogeny and Function Of Normal Human Melanocytesmentioning

confidence: 99%