The Myc oncoprotein: a critical evaluation of transactivation and target gene regulation
The Myc oncoprotein: a critical evaluation of transactivation and target gene regulation
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DOI：
10.1038/sj.onc.1202748
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发表时间：
1999-05-13
期刊：
影响因子：
8
通讯作者：
McMahon, SB
中科院分区：
文献类型：
--
作者：
Cole, MD;McMahon, SB
破坏c-myc基因的调节或表达水平的突变是在人类和动物癌症中最常见的（综述于参考文献科尔，1986; Henriksson和Luscher，1996; Marcu等人，1992年）。异位表达研究确定了c-myc基因的许多生物学活性，包括转化、永生化？阻断细胞分化和诱导凋亡（Askew等人，1991;科尔，1986;埃文和利特尔伍德，1993; Freytag等人，1990; Henriksson和Luscher，1996; Marcu等人，1992年）。此外，c-myc是通过细胞周期有效进展所需的（Goruppi et al.，1994; Prochownik等人，1988; Yokoyama和Imamoto，1987），尽管最近的研究表明它不是绝对必要的（Mateyak等人，1997年）。这种迷人的生物学活动使c-myc基因成为最有趣的癌基因之一，并提出了一个具有挑战性的问题，即单个基因如何表现出如此多的不同作用。当与其配偶体Max二聚化时，c-Myc蛋白表现出序列特异性DNA结合，并且DNA结合通过识别核心序列CACGTG的碱性区介导（Berberich et al.，1992; Blackwell等人，1993;黑木和艾森曼，1991;普伦德加斯特和齐夫，1991;普伦德加斯特等人，1991），但对更延伸的序列ACCACGTGGT表现出稍高的亲和力（Berberich等人，1992; Blackwell等人，1993; Halazonetis和Kandil，1991）。存在三种密切相关的Myc家族蛋白（c-Myc、N-Myc和L-Myc），每一种都具有记录的致癌潜力（Birrer等人，1988; Schwab等人，1985; Yancopoulos等人，1985）和类似的DNA结合特性（Mukherjee等人，1992年）。为了简单起见，我们将使用术语Myc来指代所有三种蛋白质，但在它们适用的情况下描绘任何不同的活性。这篇综述的目的是讨论Myc作为一种转录激活因子，并批判性地评估特定靶基因作为直接下游效应子的反式激活的证据。由于最近发表了关于Myc的全面综述（Facchini和Penn，1998; Henriksson和Luscher，1996），我们将重点关注提供反式激活和致癌转化机制的最新观察结果。
Mutations which disrupt the regulation or expression level of the c-myc gene are among the most common found in human and animal cancers (reviewed in ref. Cole, 1986; Henriksson and Luscher, 1996; Marcu et al., 1992). Ectopic expression studies define numerous biological activities of the c-myc gene, including transformation, immortalization? blockage of cell differentiation and induction of apoptosis (Askew et al., 1991; Cole, 1986; Evan and Littlewood, 1993; Freytag et al., 1990; Henriksson and Luscher, 1996; Marcu et al., 1992). Furthermore, c-myc is required for efficient progression through the cell cycle (Goruppi et al., 1994; Prochownik et al., 1988; Yokoyama and Imamoto, 1987), although recent studies indicate that it is not absolutely essential (Mateyak et al., 1997). This fascinating array of biological activities makes the c-myc gene one of the most intriguing oncogenes and presents the challenging question of how a single gene can manifest so many different effects. The c-Myc protein exhibits sequence-specific DNA binding when dimerized with its partner Max, and DNA binding is mediated through the basic region, which recognizes the core sequence CACGTG (Berberich et al., 1992; Blackwell et al., 1993; Blackwood and Eisenman, 1991; Prendergast and Ziff, 1991; Prendergast et al., 1991), but exhibits somewhat higher affinity for the more extended sequence ACCACGTGGT (Berberich et al., 1992; Blackwell et al., 1993; Halazonetis and Kandil, 1991). There are three closely related Myc family proteins (c-Myc, N-Myc and L-Myc), each with documented oncogenic potential (Birrer et al., 1988; Schwab et al., 1985; Yancopoulos et al., 1985) and similar DNA binding properties (Mukherjee et al., 1992). For simplicity, we will use the term Myc to refer to all three proteins, but delineate any distinct activities where they apply. The goal of this review is to discuss Myc as a transcriptional activator and critically evaluate the evidence for the transactivation of specific target genes as direct downstream effecters. Since excellent comprehensive reviews on Myc have been published recently (Facchini and Penn, 1998; Henriksson and Luscher, 1996), we will focus on the latest observations that offer mechanistic insight into transactivation and oncogenic transformation.