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首页> 外文期刊>Pigment cell research >Dynamic regulation of the human dopachrome tautomerase promoter by MITF, ER-alpha and chromatin remodelers during proliferation and senescence of human melanocytes
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Dynamic regulation of the human dopachrome tautomerase promoter by MITF, ER-alpha and chromatin remodelers during proliferation and senescence of human melanocytes

机译：MITF，ER-α和染色质重塑剂在人黑素细胞增殖和衰老过程中动态调节人多巴色素互变异构酶启动子

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Senescent cells are known to display altered gene expression of differentiation-associated genes. We have previously demonstrated that the melanocyte transcriptional regulator microphthalmia-associated protein (MITF) is down-regulated in senescent melanocytes. Since virtually nothing is known regarding the differentiated function of senescent melanocytes, we analyzed the transcriptional regulation of Dopachrome tautomerase (DCT), a member of the tyrosinase gene family, in proliferating and in senescent human melanocytes. Computational analysis of the region containing the M-box that includes the MITF CATGTG binding motif demonstrated that this sequence overlaps with the estrogen receptor alpha (ER-α), USF-1, TFE-3, Isl-1 and AP-1 binding elements. Electrophoresis gel-shift analysis using an oligonucleotide containing MITF and ERE elements identified MITF and ER-α complexes in proliferating melanocytes, whereas only ER-α complexes were detected in senescent cells. Importantly, a promoter-reporter analysis demonstrated that the coactivator p300/CBP switched MITF from a repressor to an activator of DCT transcription. p300/CBP was also required by ER-α and MITF to induce high, synergistic activation of the DCT promoter. We have also found that transcription of the DCT gene is differentially regulated by major melanocyte mitogens. In contrast to the activating effect of cAMP inducers, 12-O-tetradecanoylphorbolacetate (TPA) was a potent repressor of DCT transcription, suggesting that this gene can be differentially regulated by multiple environmental signals and promoter context. In support of this conclusion, trichostatin A, a histone deacetylase inhibitor, counteracted the TPA-mediated repression, and restored high levels of DCT protein in cultured melanocytes. We conclude that senescent melanocytes display dramatic changes in the expression of differentiation-related proteins; such changes may in turn result in altered melanocyte function and survival to environmental stresses.
机译：已知衰老细胞显示分化相关基因的基因表达改变。我们以前已经证明，衰老的黑素细胞中黑素细胞转录调节剂小眼症相关蛋白（MITF）被下调。由于实际上对衰老黑素细胞的分化功能一无所知，因此我们分析了酪氨酸酶基因家族成员多巴色素互变异构酶（DCT）在增殖和衰老的人类黑素细胞中的转录调控。对包含带有MITF CATGTG结合基序的M-box的区域的计算分析表明，该序列与雌激素受体α（ER-α），USF-1，TFE-3，Isl-1和AP-1结合元件重叠。使用包含MITF和ERE元素的寡核苷酸进行的电泳凝胶移分析确定了增殖的黑素细胞中的MITF和ER-α复合物，而在衰老细胞中仅检测到ER-α复合物。重要的是，启动子-报告子分析表明，共激活因子p300 / CBP将MITF从抑制因子转换为DCT转录激活因子。 ER-α和MITF也需要p300 / CBP来诱导DCT启动子的高协同激活。我们还发现DCT基因的转录受主要的黑色素细胞有丝分裂原的差异调节。与cAMP诱导剂的激活作用相反，12-O-十四烷酰佛波乙酸酯（TPA）是DCT转录的有效阻遏物，表明该基因可以受到多种环境信号和启动子环境的差异调节。支持该结论的是，组蛋白脱乙酰基酶抑制剂曲古抑菌素A抵消了TPA介导的阻遏作用，并在培养的黑素细胞中恢复了高水平的DCT蛋白。我们得出的结论是，衰老的黑素细胞在分化相关蛋白的表达中显示出巨大的变化。这样的变化可能反过来导致黑素细胞功能的改变和对环境压力的生存。

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