MYC Protein Interactome Profiling Reveals Functionally Distinct Regions that Cooperate to Drive Tumorigenesis
MYC Protein Interactome Profiling Reveals Functionally Distinct Regions that Cooperate to Drive Tumorigenesis
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DOI：
10.1016/j.molcel.2018.09.031
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发表时间：
2018-12-06
期刊：
影响因子：
16
通讯作者：
Penn, Linda Z.
中科院分区：
文献类型：
--
作者：
Kalkat, Manpreet;Resetca, Diana;Penn, Linda Z.
MYC 家族的转化成员（MYC、MYCL1 和 MYCN）编码包含六个高度保守区域的转录因子，称为 MYC 同源盒 (MB)。通过对 MB 相互作用组进行蛋白质组学分析，我们证明一半的 MYC 相互作用子需要一个或多个 MB 进行结合。综合表型分析表明，MBO 和 MBII 两种 MB 是转化普遍需要的。 MBII 介导与含有乙酰转移酶的复合物的相互作用，使组蛋白乙酰化，并且对于 MYC 依赖性肿瘤的发生至关重要。相比之下，MBO 通过直接结合通用转录因子 TFIIF 来介导与转录延伸因子的相互作用。 MBO 对于肿瘤的发生来说是可有可无的，但却是肿瘤生长的主要加速器。值得注意的是，MYC 的完全转化活性可以通过非转化 MBO 和 MBII 缺失蛋白的共表达来恢复，表明这两个区域赋予不同的分子功能，这两者都是致癌 MYC 活性所必需的。
Transforming members of the MYC family (MYC, MYCL1, and MYCN) encode transcription factors containing six highly conserved regions, termed MYC homology boxes (MBs). By conducting proteomic profiling of the MB interactomes, we demonstrate that half of the MYC interactors require one or more MBs for binding. Comprehensive phenotypic analyses reveal that two MBs, MBO and MBII, are universally required for transformation. MBII mediates interactions with acetyltransferase-containing complexes, enabling histone acetylation, and is essential for MYC-dependent tumor initiation. By contrast, MBO mediates interactions with transcription elongation factors via direct binding to the general transcription factor TFIIF. MBO is dispensable for tumor initiation but is a major accelerator of tumor growth. Notably, the full transforming activity of MYC can be restored by co-expression of the non-transforming MBO and MBII deletion proteins, indicating that these two regions confer separate molecular functions, both of which are required for oncogenic MYC activity.