MLANA/MART1 and SlLV/PMEL17/GP100 are transcriptionally regulated by MITF in melanocytes and melanoma
MLANA/MART1 and SlLV/PMEL17/GP100 are transcriptionally regulated by MITF in melanocytes and melanoma
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DOI：
10.1016/s0002-9440(10)63657-7
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发表时间：
2003-07-01
影响因子：
6
通讯作者：
Fisher, DE
中科院分区：
文献类型：
--
作者：
Du, JY;Miller, AJ;Fisher, DE
临床重要的黑色素瘤诊断抗体HMB-45、melan-A和MITF （D5）分别识别黑色素细胞谱系基因SIELV/PMEL17/GP100、MLANA/MART1和MITF的基因产物。MITF编码一种转录因子，这种转录因子对正常的黑素细胞发育至关重要，似乎可以调节几种色素沉着基因的表达。在这篇报道中，研究了MITF可能额外调节SILV和MLANA基因表达的可能性。这两个基因都含有保守的MITF一致DNA序列，这些序列在体外和体内都被MITF结合，这是基于电泳迁移率转移测定和染色质免疫沉淀。此外，在报告子实验中，WIT调节了它们的启动子/增强子区域，MITF的上调或下调会对黑色素瘤细胞中的内源性SILV和MLANA产生相应的调节。将这些因子在一系列已知原癌基因BRAF突变状态的黑色素瘤细胞系中的表达模式进行了比较。SILV和MLANA的表达与MITF相关，而与BRAF突变无明显相关性。最后，人类原发性黑色素瘤的mRNA表达阵列分析显示，它们在临床肿瘤标本中的表达水平密切相关。总的来说，这项研究将三种重要的黑色素瘤抗原与MITF调节的共同转录途径联系起来。
The clinically important melanoma diagnostic antibodies HMB-45, melan-A, and MITF (D5) recognize gene products of the melanocyte-lineage genes SIELV/PMEL17/GP100, MLANA/MART1, and MITF, respectively. MITF encodes a transcription factor that is essential for normal melanocyte development and appears to regulate expression of several pigmentation genes. In this report, the possibility was examined that MITF might additionally regulate expression of the SILV and MLANA genes. Both genes contain conserved MITF consensus DNA sequences that were bound by MITF in vitro and in vivo, based on electrophoretic mobility shift assay and chromatin-immunoprecipitation. In addition, WIT regulated their promoter/enhancer regions in reporter assays, and up- or down-regulation of MITF produced corresponding modulation of endogenous SILV and MLANA in melanoma cells. Expression patterns were compared with these factors in a series of melanoma cell lines whose mutational status of the proto-oncogene BRAF was also known. SILV and MLANA expression correlated with MITF, while no clear correlation was seen relative to BRAF mutation. Finally, mRNA expression array analysis of primary human melanomas demonstrated a tight correlation in their expression levels in clinical tumor specimens. Collectively, this study links three important melanoma antigens into a common transcriptional pathway regulated by MITF.