KAPtain in charge of multiple missions: Emerging roles of KAP1.
KAPtain in charge of multiple missions: Emerging roles of KAP1.
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DOI：
10.4331/wjbc.v5.i3.308
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发表时间：
2014-08-26
期刊：
影响因子：
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通讯作者：
Ann, David K
中科院分区：
文献类型：
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作者：
Cheng, Chun-Ting;Kuo, Ching-Ying;Ann, David K
KAP 1/TRIM 28/TIF 1 β在近20年前被鉴定为通用的转录辅阻遏物，因为它与含KRAB的锌指蛋白（KRAB-ZFP）转录因子家族相互作用。许多研究表明，KAP 1通过调节KRAB-ZFP特异性位点的转录、作为转录共阻遏物的反式阻遏或表观遗传调节染色质结构来影响基因表达。新出现的证据表明，KAP 1也作为SUMO/泛素E3连接酶或信号支架蛋白介导信号转导，独立于基因调控发挥作用。KAP 1经历多种翻译后修饰（PTM），包括丝氨酸/酪氨酸磷酸化、SUMO化和乙酰化，其协调调节KAP 1功能及其蛋白质丰度。KAP 1参与细胞活动的多个方面，包括DNA损伤反应、病毒复制、细胞因子产生和干细胞多能性。此外，敲除KAP 1导致胚胎死亡，表明KAP 1对胚胎发育至关重要，并可能影响广泛的（病理）生理表现。事实上，来自条件性基因敲除小鼠模型的研究表明，KAP 1缺陷显著损害重要的生理过程，如免疫成熟、应激脆弱性、肝脏代谢、配子发育和红细胞生成。本文对KAP 1的生理生化功能进行了综述和评价。此外，还将讨论KAP 1在癌症中的临床相关性的研究。
KAP1/TRIM28/TIF1beta was identified nearly twenty years ago as a universal transcriptional co-repressor because it interacts with a large KRAB-containing zinc finger protein (KRAB-ZFP) transcription factor family. Many studies demonstrate that KAP1 affects gene expression by regulating the transcription of KRAB-ZFP-specific loci, trans-repressing as a transcriptional co-repressor or epigenetically modulating chromatin structure. Emerging evidence suggests that KAP1 also functions independent of gene regulation by serving as a SUMO/ubiquitin E3 ligase or signaling scaffold protein to mediate signal transduction. KAP1 is subjected to multiple post-translational modifications (PTMs), including serine/tyrosine phosphorylation, SUMOylation, and acetylation, which coordinately regulate KAP1 function and its protein abundance. KAP1 is involved in multiple aspects of cellular activities, including DNA damage response, virus replication, cytokine production and stem cell pluripotency. Moreover, knockout of KAP1 results in embryonic lethality, indicating that KAP1 is crucial for embryonic development and possibly impacts a wide-range of (patho)physiological manifestations. Indeed, studies from conditional knockout mouse models reveal that KAP1-deficiency significantly impairs vital physiological processes, such as immune maturation, stress vulnerability, hepatic metabolism, gamete development and erythropoiesis. In this review, we summarize and evaluate current literatures involving the biochemical and physiological functions of KAP1. In addition, increasing studies on the clinical relevance of KAP1 in cancer will also be discussed.