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Inhibition of MITF transcriptional activity independent of targeting p300/CBP coactivators

机译：抑制MITF转录活性独立于靶向p300 / CBP共激活因子

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Microphthalmia-associated transcription factor (MITF) activates the expression of melanocyte-specific markers and promotes the survival of embryonic, adult and malignant melanocytes. Although numerous MITF-dependent downstream genes have been identified, the mechanisms by which the MITF activity is coregulated remain elusive. Here we used a non-melanocytic cell line U2-OS as a model in which MITF evokes transcription of a paradigmatic MITF target tyrosinase and show that the adenoviral E1A protein represses the MITF-driven transcription in these cells. The E1A CR1 domain (which alone is insufficient to bind p300) was sufficient for repression, while the N-terminus, through which E1A binds the p300/CBP proteins and other coactivators, was unable to repress. Correspondingly, CR1 inhibited colony formation of MITF-positive, but not MITF-negative, melanoma cells. The repression by CR1 was largely independent of the PCAF-binding motif, previously recognized to be necessary for suppression of muscle-specific enhancer. Interestingly, CR1 conferred transcriptional competence to the MITF-CR1 chimera in which the MITF portion was rendered transcription-deficient. Moreover, MITF mutants defective in binding to p300/CBP in vivo still activated transcription, further supporting a p300/CBP-independent coactivation of MITF targets. MITF is amplified in a subset of melanomas and is thought to be required for sustained proliferation of malignant melanocytes. Our results suggest that understanding how CR1 represses Mitf activity may reveal a route to melanoma therapy.
机译：小眼症相关转录因子（MITF）激活黑素细胞特异性标志物的表达，并促进胚胎，成年和恶性黑素细胞的存活。尽管已鉴定出许多依赖MITF的下游基因，但MITF活性被调控的机制仍然难以捉摸。在这里，我们使用非黑素细胞系U2-OS作为模型，其中MITF引发了典型的MITF目标酪氨酸酶的转录，并表明腺病毒E1A蛋白抑制了这些细胞中MITF驱动的转录。 E1A CR1结构域（仅其不足以结合p300）足以抑制，而E1A通过其结合p300 / CBP蛋白和其他共激活因子的N端无法抑制。相应地，CR1抑制了MITF阳性而不是MITF阴性的黑色素瘤细胞的集落形成。 CR1的抑制作用很大程度上独立于PCAF结合基序，而PCAF结合基序先前被认为是抑制肌肉特异性增强剂所必需的。有趣的是，CR1赋予了MITF-CR1嵌合体转录能力，在该嵌合体中MITF部分被赋予了转录缺陷。此外，在体内与p300 / CBP结合缺陷的MITF突变体仍激活转录，进一步支持MITF靶标的不依赖p300 / CBP的共激活。 MITF在黑色素瘤的一个子集中被扩增，被认为是恶性黑色素细胞持续增殖所必需的。我们的结果表明，了解CR1如何抑制Mitf活性可能揭示了通向黑色素瘤治疗的途径。

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