Department of Biochemistry and Molecular Biology, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
Oncogene. 2017 Aug 17;36(33):4732-4738. doi: 10.1038/onc.2017.81. Epub 2017 Apr 10.
Microphthalmia transcription factor (MITF) is a basic helix-loop-helix leucine zipper (bHLH-Zip) DNA-binding protein. This transcription factor plays a crucial role in the physiological and pathological functions of distinct cell types. MITF transcriptional activity is inhibited by the histidine triad nucleotide-binding protein 1 (HINT1) through direct binding. We previously reported that this association is disrupted by the binding of the second messenger ApA to HINT1. ApA is mainly produced in the mammalian cells by S207-phosphorylated Lysyl-tRNA synthetase. In this study, we found first that HINT1 was subjected to K21 acetylation and Y109 phosphorylation in activated mast cells, together with the ApA-triggered HINT1 dissociation from MITF. Mutational analysis confirmed that these modifications promote MITF transcriptional and oncogenic activity in melanoma cell lines, derived from human melanoma patients. Thus, we provided here an example that manipulation of the LysRS-ApA-HINT1-MITF signalling pathway in melanoma through post-translational modifications of HINT1 can affect the activity of the melanoma oncogene MITF.
小眼畸形相关转录因子（MITF）是一种碱性螺旋-环-螺旋亮氨酸拉链（bHLH-Zip）DNA 结合蛋白。该转录因子在不同细胞类型的生理和病理功能中发挥着关键作用。组氨酸三核苷酸结合蛋白 1（HINT1）通过直接结合抑制 MITF 的转录活性。我们之前的研究报道，这种结合通过第二信使 ApA 与 HINT1 的结合而被破坏。ApA 主要由 S207 磷酸化的赖氨酰-tRNA 合成酶在哺乳动物细胞中产生。在这项研究中，我们首先发现活化的肥大细胞中 HINT1 受到 K21 乙酰化和 Y109 磷酸化的作用，同时 ApA 触发 HINT1 与 MITF 解离。突变分析证实，这些修饰促进了源自人类黑色素瘤患者的黑色素瘤细胞系中 MITF 的转录和致癌活性。因此，我们在这里提供了一个示例，即通过 HINT1 的翻译后修饰来操纵黑色素瘤中的 LysRS-ApA-HINT1-MITF 信号通路，可以影响黑色素瘤致癌基因 MITF 的活性。
