The identification and functional characterization of a novel mast cell isoform of the microphthalmia-associated transcription factor
The identification and functional characterization of a novel mast cell isoform of the microphthalmia-associated transcription factor
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DOI：
10.1074/jbc.m201441200
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发表时间：
2002-08-16
影响因子：
4.8
通讯作者：
Fisher, DE
中科院分区：
文献类型：
--
作者：
Takemoto, CM;Yoon, YH;Fisher, DE
小眼症相关转录因子（Mitf）是肥大细胞发育的关键，这是基于在Mitf突变小鼠中观察到的严重肥大细胞缺乏。Mitf对黑素细胞、破骨细胞和视网膜色素上皮的发育也很重要。Mitf突变的谱系限制性表型与Mitf的组织限制性表达相关，这一特征部分是由于存在几种不同的Mitf同种型。我们报告的一种新的肥大细胞亚型，Mitf-mc的鉴定和表征。该同种型由一个新的5 '外显子选择性剪接到基因的共同体上产生，预计在其氨基末端编码一个独特的43个氨基酸序列。它在肥大细胞中特异性表达。肥大细胞同种型在其激活细胞类型特异性Mitf基因靶标的能力方面与黑素细胞同种型功能不同。Mitf-me仅在肥大细胞靶向启动子上起作用，尽管与其E-box元件结合，但不能激活黑素细胞靶向启动子。此外，Mitf-me异源二聚化与密切相关的转录因子，Tfe 3，并显性抑制Tfe 3的能力，反式激活黑素细胞特异性启动子。这些研究确定了一种新的Mitf亚型，具有组织特异性特征，可能是Mitf突变的肥大细胞表型的关键方面。
The microphthalmia-associated transcription factor (Mitf) is critical for mast cell development based on the severe mast cell deficiency seen in Mitf mutant mice. Mitf also is important for the development of melanocytes, osteoclasts, and retinal pigment epithelium. The lineage-restricted phenotypes of Mitf mutations correlate with tissue-restricted expression of Mitf, a feature due in part to the presence of several distinct Mitf isoforms. We report the identification and characterization of a novel mast cell isoform, Mitf-mc. This isoform arises from alternative splicing of a novel 5'-exon onto the common body of the gene and is predicted to encode a unique 43-amino acid sequence at its amino terminus. It is specifically expressed in mast cells. The mast cell isoform functions differently from the melanocyte isoform in its ability to activate cell type-specific Mitf gene targets. Mitf-me functions only on a mast cell target promoter and fails to activate a melanocyte target promoter despite binding to its E-box element. Moreover, Mitf-me heterodimerizes with a closely related transcription factor, Tfe3, and dominantly inhibits the ability of Tfe3 to transactivate a melanocyte-specific promoter. These studies identify a new isoform of Mitf with tissue-specific features that may underlie key aspects of the mast cell phenotype of Mitf mutations.