DNA damage enhances melanogenesis
DNA damage enhances melanogenesis
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DOI：
10.1073/pnas.93.3.1087
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发表时间：
1996-02-06
影响因子：
11.1
通讯作者：
Gilchrest, BA
中科院分区：
文献类型：
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作者：
Eller, MS;Ostrom, K;Gilchrest, BA
虽然紫外线照射在体内和体外诱导色素沉着的能力已经得到很好的证明，但触发这种反应的细胞内信号却知之甚少，我们最近已经证明，增加照射后的DNA修复可以增强紫外线诱导的黑化。此外，将小的DNA片段，特别是胸腺嘧啶二核苷酸(PTpT)，被选为模拟紫外线诱导的DNA光产物修复过程中被切除的序列，添加到体外未受辐射的色素细胞或体内的豚鼠皮肤中，会引起与紫外线诱导的晒黑没有区别的色素反应。在这里，我们提出了进一步的证据表明，DNA损伤和/或这种损伤的修复增加了黑化，(I)用限制酶PYRE II或DNA损伤化学试剂甲基甲磺酸(MMS)或4-硝基喹啉1-氧化物(4-NQO)处理后，Cloudman S91小鼠黑色素瘤细胞的黑色素含量增加了4-10倍，正常人类黑素细胞的黑色素含量增加了70%，(Ii)紫外线照射、MMS和pTpT都上调了酪氨酸酶的mRNA水平，酪氨酸酶是黑色素生物合成中的限速酶，(Iii)pTpT或MMS处理增加了S91细胞对黑素细胞刺激素(MSH)的反应，并增加了MSH与其细胞表面受体的结合，正如已报道的紫外线照射。综上所述，这些数据表明，紫外线诱导的DNA损伤和/或这种损伤的修复是紫外线照射下色素沉着反应中的一个重要信号，因为PVU II仅作用于DNA，并且由于MMS和4-NQO在所使用的浓度下主要与DNA相互作用，这样的刺激似乎足以诱导黑素生成，具有可能的实用重要性，二核苷酸pTpT模拟了大多数，如果不是全部的话，紫外线照射对色素形成的影响，酪氨酸酶mRNA的调节，以及对MSH的反应，而不需要先前的DNA损伤。
Although the ability of UV irradiation to induce pigmentation in vivo and in vitro is well documented, the intracellular signals that trigger this response are poorly understood, We have recently shown that increasing DNA repair after irradiation enhances UV-induced melanization. Moreover, addition of small DNA fragments, particularly thymine dinucleotides (pTpT), selected to mimic sequences excised during the repair of UV-induced DNA photoproducts, to unirradiated pigment cells in vitro or to guinea pig skin in vivo induces a pigment response indistinguishable from UV-induced tanning. Here we present further evidence that DNA damage and/or the repair of this damage increases melanization, (i) Treatment with the restriction enzyme Pyre II or the DNA-damaging chemical agents methyl methanesulfonate (MMS) or 4-nitroquinoline 1-oxide (4-NQO) produces a 4- to 10-fold increase in melanin content in Cloudman S91 murine melanoma cells and an up to 70% increase in normal human melanocytes, (ii) UV irradiation, MMS, and pTpT all up regulate the mRNA level for tyrosinase, the rate-limiting enzyme in melanin biosynthesis, (iii) Treatment with pTpT or MMS increases the response of S91 cells to melanocyte-stimulating hormone (MSH) and increases the binding of MSH to its cell surface receptor, as has been reported for UV irradiation. Together, these data suggest that UV-induced DNA damage and/or the repair of this damage is an important signal in the pigmentation response to UV irradiation, Because Pvu II acts exclusively on DNA and because MMS and 4-NQO, at the concentrations used, primarily interact with DNA, such a stimulus alone appears sufficient to induce melanogenesis, Of possible practical importance, the dinucleotide pTpT mimics most, if not all, of the effects of UV irradiation on pigmentation, tyrosinase mRNA regulation, and response to MSH without the requirement for antecedent DNA damage.