SIGNALING PATHWAYS FOR UV-INDUCED MELANOGENIC RESPONSE

描述：阳光照射的标志是晒黑反应， 表皮黑素细胞黑素合成增加的结果， 将黑素体从黑素细胞转移到角质形成细胞。 本构 色素沉着决定了黑色素对阳光的反应程度 暴露，和个人与皮肤类型I或 II与皮肤癌风险增加有关。 紫外光具有 直接遗传毒性效应，以及间接细胞效应， 通过增加各种旁分泌/自分泌表皮 因素 已知调节色素沉着的因子是α-促黑素 （α-MSH）和促肾上腺皮质激素（ACTH），它们是促有丝分裂的， 人黑素细胞的黑素原，以及内皮素-1，内皮素-1是人黑素细胞的促分裂原， 和黑素生成的调节剂。 近日有消息称 黑素皮质素-1受体基因的变体在不同的皮肤类型中表达， I和II个体，这表明该受体在决定 皮肤对阳光照射的反应。 α-促黑激素介导其 主要通过激活cAMP依赖性途径发挥作用。 我们发现 人黑素细胞中cAMP途径的激活对于 对紫外线的黑素反应。 内皮素-1激活多种 信号传导途径，包括cAMP，细胞内Ca+2，蛋白激酶C， 和酪氨酸激酶依赖性途径。 此外，内皮素-1似乎是 对人类黑素细胞对紫外线的黑素生成反应很重要 光 内皮素-1刺激人黑素细胞增殖， 剂量依赖性，但对活性和蛋白质有双相影响 酪氨酸酶水平：在亚纳摩尔浓度下的刺激作用， 在较高浓度下有抑制作用。 的这种调制 酪氨酸酶与细胞内Ca+2的动员程度相关 不同浓度的内皮素-1，这可能是一种机制， 在黑素生成的生理调节中具有重要意义。 内皮素-1 和α-促黑素激素协同相互作用以刺激人类 黑素细胞增殖和调节黑素生成。 我们 假设正常人黑色素细胞对紫外线的反应 光由不同信号通路的串扰调节， 由内皮素-1和α-促黑素素激活。 基于此，我们建议 为了阐明黑皮质素-1受体的重要性， 内皮素-1，以及cAMP和Ca+2依赖性通路的参与 在人类黑素细胞增殖和黑素生成的调节中。 特别是对紫外光的响应。

DESCRIPTION: The hallmark of sun exposure is the tanning response, the outcome of increased melanin synthesis by epidermal melanocytes and enhanced transfer of melanosomes from melanocytes to keratinocytes. Constitutive pigmentation determines the extent of the melanogenic response to sun exposure, and the poor tanning response of individuals with skin type I or II is associated with increased risk for skin cancer. Ultraviolet light has direct genotoxic effects, as well as indirect cellular effects which are mediated by increased synthesis of various paracrine/autocrine epidermal factors. Factors known to regulate pigmentation are alpha-melanotropin (alpha-MSH) and adrenocorticotropic hormone (ACTH) which are mitogenic and melanogenic for human melanocytes, and endothelin-1 which is a mitogen for, and a modulator of melanogenesis in, these cells. Recently, it was reported that variants of the melanocortin-1 receptor gene are expressed by skin type I and II individuals, suggesting a role for this receptor in determining the pigmentary response to sun exposure. alpha-Melanotropin mediates its effects primarily by activating the cAMP-dependent pathway. We found that activation of the cAMP pathway in human melanocytes is pivotal for the melanogenic response to ultraviolet light. Endothelin-1 activates multiple signaling pathways, including cAMP, intracellular Ca+2, protein kinase C, and tyrosine kinase-dependent pathways. Also, endothelin-1 seems to be important for the melanogenic response of human melanocytes to ultraviolet light. Endothelin-1 stimulates human melanocyte proliferation in a dose-dependent manner, but has a biphasic effect on the activity and protein level of tyrosinase: a stimulatory effect at subnanomolar concentrations, and an inhibitory effect at higher concentrations. This modulation of tyrosinase correlates with the extent of mobilization of intracellular Ca+2 by different concentrations of endothelin-1, a mechanism that might be significant in the physiologic regulation of melanogenesis. Endothelin-1 and alpha-melanotropin interact synergistically to stimulate human melanocyte proliferation and addictively to modulate melanogenesis. We hypothesize that the response of normal human melanocytes to ultraviolet light is regulated by the crosstalk of different signaling pathways that are activated by endothelin-1 and alpha-melanotropin. Based on this, we propose to elucidate the significance of the melanocortin-1 receptor, the role of endothelin-1, and the participation of the cAMP and Ca+2-dependent pathways in the regulation of human melanocyte proliferation and melanogenesis. particularly in response to ultraviolet light.