A role for tyrosinase-related protein 1 in 4-tert-butyl phenol-induced toxicity in melanocytes -: Implications for vitiligo
A role for tyrosinase-related protein 1 in 4-tert-butyl phenol-induced toxicity in melanocytes -: Implications for vitiligo
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DOI：
10.2353/ajpath.2006.050769
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发表时间：
2006-11-01
影响因子：
6
通讯作者：
Boissy, Raymond E.
中科院分区：
文献类型：
--
作者：
Manga, Prashiela;Sheyn, David;Boissy, Raymond E.
白癜风表现为局部黑素细胞死亡后的色素脱失性皮损。多种因素导致细胞死亡，包括遗传决定的创伤易感性和环境因素，如暴露于4-叔丁基苯酚（4-TBP）。我们证明，4-TBP诱导的氧化应激，是更容易克服黑素细胞色素正常的个人比两个人白癜风。抗氧化剂过氧化氢酶选择性和显着减少死亡的黑素细胞来自两个人白癜风，表明氧化应激在白癜风发病机制中的作用。在正常黑素细胞中，氧化应激导致小眼症相关转录因子（MITF）的表达减少。黑素细胞刺激性黑素瘤诱导的MITF蛋白表达导致对4-TBP的敏感性增加，而黑素瘤的敏感性与MITF表达相关。MITF通过上调黑素生成酶如酪氨酸酶相关蛋白-1（Tyrp 1）的表达来刺激黑素合成。虽然黑色素含量本身并不影响对4-TBP的敏感性，但Tyrp 1的表达显著增加了敏感性。表达功能性TYrp 1的黑色素细胞和黑色素瘤对4-TBP的敏感性显著高于Tyrp 1缺失细胞。因此，正常黑素细胞通过降低MITF和Tyrp 1的表达来响应4-TBP。我们推测白癜风患者的黑素细胞表现出抵抗氧化应激的能力降低，部分原因是MITF对Tyrp 1的调节受到破坏。
Vitiligo presents with depigmented cutaneous lesions following localized melanocyte death. Multiple factors contribute to cell death, including genetically determined susceptibility to trauma, and environmental factors, such as exposure to 4-tert-butylphenol (4-TBP). We demonstrate that 4-TBP induces oxidative stress that is more readily overcome by melanocytes from normally pigmented individuals than from two individuals with vitiligo. The antioxidant catalase selectively and significantly reduced death of melanocytes derived from two individuals with vitiligo, indicating a role for oxidative stress in vitiligo, pathogenesis. in normal melanocytes, oxidative stress results in reduced expression of microphthalmia-associated transcription factor (MITF). Melanocyte-stimulating hormone-induced expression of MITF protein caused increased sensitivity to 4-TBP, whereas sensitivity of melanomas correlated with MITF expression. MITF stimulates melanin synthesis by up-regulating expression of melanogenic enzymes such as tyrosinase-related protein-1 (Tyrp1). Although melanin content per se did not affect sensitivity to 4-TBP, expression of Tyrp1 significantly increased sensitivity. Melanocytes, and melanomas that express functional TYrp1 were significantly more sensitive to 4-TBP than Tyrp1-null cells. Thus, normal melanocytes respond to 4-TBP by reducing expression of MITF and Tyrp1. We hypothesize that melanocytes in vitiligo demonstrate reduced ability to withstand oxidative stress due, partly, to a disruption in MITF regulation of Tyrp1.