SIGNALING PATHWAYS FOR UV-INDUCED MELANOGENIC RESPONSE

描述：日晒的标志是晒黑的反应， 表皮黑素细胞黑素合成增加和增强的转归 黑素小体从黑素细胞到角质形成细胞的转移。构成要素 色素沉着决定了黑色素对阳光的反应程度 暴露，以及患有I型或I型皮肤的人的晒黑反应差 II与皮肤癌风险增加有关。紫外光有 直接的遗传毒性效应，以及间接的细胞效应 由多种旁分泌/自分泌表皮合成增加所介导 各种因素。已知的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)，它们是有丝分裂和 人类黑素细胞的黑素生成，以及内皮素-1，它是一种丝裂原， 以及这些细胞中黑素合成的调节剂。最近，有报道称， 黑素皮质素-1受体基因的变异体按皮肤类型表达 I和II个体，提示该受体在决定 对日晒的色素反应。α-促黑素蛋白介导其 主要通过激活cAMP依赖的途径发挥作用。我们发现 人黑素细胞中cAMP通路的激活对 对紫外线的黑色素生成反应。内皮素-1激活多个 信号通路，包括cAMP、细胞内钙离子、蛋白激酶C、 和酪氨酸激酶依赖的通路。此外，内皮素-1似乎是 紫外线对人黑素细胞黑素生成反应的重要作用 灯。内皮素-1刺激人黑素细胞增殖的研究 呈剂量依赖关系，但对活性和蛋白质有双相影响 酪氨酸酶水平：亚纳摩尔浓度的刺激效应 在较高浓度时有抑制作用。这种调制 酪氨酸酶与细胞内Ca+2的动员程度相关 通过不同浓度的内皮素-1，这一机制可能是 在黑素生成的生理调节方面具有重要意义。内皮素-1 和α-促黑素激素协同作用，刺激人类 黑素细胞增殖，并上瘾地调节黑素的生成。我们 假设正常人黑素细胞对紫外线的反应 光由不同信号通路的串扰来调节，这些信号通路 由内皮素-1和α-促黑素激素激活。基于此，我们建议 为了阐明黑素皮质素-1受体的意义，黑素皮质素-1受体在 内皮素-1与cAMP和钙依赖通路的参与 在调节人类黑素细胞增殖和黑素生成方面。 尤其是对紫外线的反应。

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.