αmelanocyte-stimulating hormone protects from ultraviolet radiation-induced apoptosis and DNA damage
αmelanocyte-stimulating hormone protects from ultraviolet radiation-induced apoptosis and DNA damage
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DOI：
10.1074/jbc.m406334200
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发表时间：
2005-02-18
影响因子：
4.8
通讯作者：
Schwarz, A
中科院分区：
文献类型：
--
作者：
Böhm, M;Wolff, I;Schwarz, A
紫外线辐射是恶性黑色素瘤的一个公认的流行病学危险因素。这一观察结果与正常黑素细胞对紫外线B(UVB)辐射诱导的细胞凋亡的相对抵抗力有关，从而导致UVB辐射诱导的黑素细胞DNA损伤的积累。因此，确定调控UVB辐射诱导黑素细胞凋亡和DNA损伤的生理因素具有重要的生物学意义。我们发现神经肽a-黑素细胞刺激素(α-MSH)在体外可以阻断UVB辐射诱导的正常人黑素细胞的凋亡。A-MSH的抗凋亡活性不是通过过滤或诱导黑素细胞合成黑素来介导的。A-MSH不改变细胞周期分布，也不影响细胞凋亡相关蛋白Bcl2、Bclx、Bax、P53、CD95(Fas/APO-1)和CD95L(FasL)的表达。相反，α-MSH显著减少了UVB辐射诱导的DNA损伤，减少了环丁烷嘧啶二聚体的数量，最终导致了细胞凋亡的减少。α-MSH减少紫外线辐射诱导的DNA损伤可能与诱导核苷酸切除修复有关，因为在核苷酸切除修复缺陷的成纤维细胞中，紫外线诱导的细胞凋亡不被α-MSH阻断。这些数据首次证明了一种在表皮中生理性表达的神经肽对UVB辐射诱导的人类黑素细胞凋亡的调节。除了诱导光保护性黑色素合成的能力外，α-MSH似乎还具有减少紫外线辐射诱导的DNA损伤的能力，因此，可能作为一种有效的保护因子来抵御紫外线辐射对表皮细胞基因组稳定性的有害影响。
Ultraviolet radiation is a well established epidemiologic risk factor for malignant melanoma. This observation has been linked to the relative resistance of normal melanocytes to ultraviolet B (UVB) radiation-induced apoptosis, which consequently leads to accumulation of UVB radiation-induced DNA lesions in melanocytes. Therefore, identification of physiologic factors regulating UVB radiation-induced apoptosis and DNA damage of melanocytes is of utmost biological importance. We show that the neuropeptide a-melanocyte-stimulating hormone (alpha-MSH) blocks UVB radiation-induced apoptosis of normal human melanocytes in vitro. The antiapoptotic activity of a-MSH is not mediated by filtering or by induction of melanin synthesis in melanocytes. a-MSH neither leads to changes in the cell cycle distribution nor induces alterations in the expression of the apoptosis-related proteins Bcl(2), Bcl(x), Bax, p53, CD95 (Fas/APO-1), and CD95L (FasL). In contrast, alpha-MSH markedly reduces the formation of UVB radiation-induced DNA damage as demonstrated by reduced amounts of cyclobutane pyrimidine dimers, ultimately leading to reduced apoptosis. The reduction of UV radiation-induced DNA damage by a-MSH appears to be related to induction of nucleotide excision repair, because UV radiation-mediated apoptosis was not blocked by alpha-MSH in nucleotide excision repair-deficient fibroblasts. These data, for the first time, demonstrate regulation of UVB radiation-induced apoptosis of human melanocytes by a neuropeptide that is physiologically expressed within the epidermis. Apart from its ability to induce photoprotective melanin synthesis, alpha-MSH appears to exert the capacity to reduce UV radiation-induced DNA damage and, thus, may act as a potent protection factor against the harmful effects of UV radiation on the genomic stability of epidermal cells.