THE REGULATION OF P53 FUNCTION - STEINER-AWARD LECTURE
THE REGULATION OF P53 FUNCTION - STEINER-AWARD LECTURE
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DOI：
10.1002/ijc.2910570502
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发表时间：
1994-06-01
影响因子：
6.4
通讯作者：
LANE, DP
中科院分区：
文献类型：
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作者：
LANE, DP
p53肿瘤抑制基因用于防止癌症的发展（Donehower等人，1992年）。它作为“基因组的守护者”（Lane，1992）通过阻断已经持续DNA损伤的细胞的分裂并且在某些情况下通过细胞凋亡触发细胞死亡（Lane，1993）来这样做。p53的这种功能通常必须是速率限制性的，因为p53的失活是癌症发展中最常见的分子步骤之一（Hollstein等人，1991年）。对p53功能调节的研究表明，该蛋白至少受3种一般机制的控制。第一种是蛋白质半衰期的翻译后调节（Maltzman和Czyzyk，1984），第二种是通过特异性病毒和宿主蛋白的结合（Lane和Crawford，1979;萨尔诺et al.，1982; Scheffner等人，1990），第三种是由翻译后修饰引起的变构调节形式（Hupp等，1992年）。p53的发现;病毒-宿主相互作用pS3蛋白首先通过其与SV 40大T抗原形成紧密、稳定复合物的能力而被鉴定（Lane和Crawford，1979）。大T抗原是一种多功能蛋白质，具有转化多种脊椎动物细胞的有效能力，还可启动病毒DNA复制（Rigby和Lane，1983; Fried和Prives，1986）。当我们最初使用免疫化学方法鉴定该复合物时，我们推测p53“可能作为与生长控制相关的某些细胞功能的调节剂，并且本身通过与T抗原结合而被中和”（Lane和Crawford，1979）。现在有明确的生物学和生物化学证据支持这一观点，因为大T可以阻断pS3作为DNA结合蛋白和作为转录因子的作用（Mietz et al.，1992年）。大T还起到阻断p53的生长停滞和凋亡功能的作用。这些效应可能对DNA病毒非常有益，因为它们将允许病毒复制进行而不诱导细胞自杀反应，从而增加病毒产量。毫不奇怪，其他病毒也可能开发出中和p53功能的策略。腺病毒E1 B 55 kDa蛋白也可以结合并中和p53（Kao等人，1990; Berk和Yew，1992），高危人乳头瘤病毒血清型的E6基因产物也可以（Mietz等，1992年）。然而，仍有一些未解之谜;例如，多瘤病毒的大T蛋白不与p53结合，并且目前还不清楚这种高度相关的Papova病毒如何处理p53途径（Manfredi和Prives，1993）。这些调节p53功能的蛋白质-蛋白质相互作用，在我的同事A。Levine发现了一种细胞p53结合蛋白MDM 2，它可以像病毒蛋白一样结合并中和p53（Momand et al.，1992; Olson等人，1993年）。这些病毒和细胞蛋白在p35上的结合位点正在使用抗体、突变分析和合成肽方法进行详细分析。这使得我们能够鉴定出可以阻断甚至逆转这些蛋白质相互作用的抗体（Lane和Gannon，1986; Gannon和Lane，1990），并且这些试剂可以作为开发新型治疗化合物的模型。这在与乳头状瘤病毒E6蛋白表达相关的人类癌症中特别重要，因为E6-p53相互作用的破坏可能以非常特异的方式恢复这些肿瘤细胞的p53功能。
Thep53 tumour suppressor gene acts to prevent the development of cancer (Donehower et al., 1992). It does so as “the guardian of the genome”(Lane, 1992) by blocking the division of cells that have sustained DNA damage and in some cases triggering cell death by apoptosis (Lane, 1993). This function ofp53 must often be rate limiting as inactivation ofp53 is one of the most common molecular steps in the development of cancer (Hollstein et al., 1991). Study of the regulation ofp53 function has shown that the protein is controlled by at least 3 general mechanisms. The first is a post-translational regulation of the protein’s half-life (Maltzman and Czyzyk, 1984), the second is by the binding of specific viral and host proteins (Lane and Crawford, 1979; Sarnow et al., 1982; Scheffner et al., 1990) and the third is a form of allosteric regulation brought about by post-translational modification (Hupp et al., 1992). A full understanding of the operation of these mechanisms will lead the way forward to the clinical application of novel diagnostic and therapeutic approaches based on thep53 system.THE DISCOVERY OF p53; VIRUS-HOST INTERACTIONS The pS3 protein was first identified through its ability to form a tight, stable complex with the SV40 large T antigen (Lane and Crawford, 1979). The large T antigen is a multifunctional protein that has a potent capacity to transform a wide range of vertebrate cells and also acts to initiate viral DNA replication (Rigby and Lane, 1983; Fried and Prives, 1986). When we originally identified the complex using immunochemical methods we speculated that p53 “might act as a regulator of certain cellular functions related to growth control and itself be neutralised by binding to T antigen”(Lane and Crawford, 1979). There is now clear biological and biochemical evidence to support this idea since large T can block the action of pS3 as a DNA-binding protein and as a transcription factor (Mietz et al., 1992). Large T also acts to block the growth arrest and apoptotic functions of p53. These effects may be very beneficial for a DNA virus as they will allow viral replication to proceed without inducing a cell suicide response and thus increase viral yield. Not surprisingly then other viruses may have also developed strategies which act to neutralise p53 function. The adenovirus E1B 55 kDa protein can also bind and neutralise p53 (Kao et al., 1990; Berk and Yew, 1992) as can the E6 gene product of the high-risk human papilloma virus serotypes (Mietz et al., 1992). Some enigmas remain unresolved, however; for example, the polyoma virus large T protein does not bind to p53, and it is as yet quite unclear how this highly related Papova virus deals with the p53 pathway (Manfredi and Prives, 1993). These protein-protein interactions that modulate p53 function have taken on fresh significance with my colleague Dr. A. Levine’s discovery of a cellular p53-binding protein, MDM2, that can, like the viral proteins, bind and neutralise p53 (Momand et al., 1992; Olson et al., 1993). The binding sites for these viral and cellular proteins on p35 are being analysed in great detail using antibodies, mutational analyses and synthetic peptide approaches. This has allowed us to identify antibodies that can block or even reverse these protein interactions (Lane and Gannon, 1986; Gannon and Lane, 1990), and such agents may act as models for the development of novel therapeutic compounds. This is of particular importance in human cancers associated with papilloma virus E6 protein expression since disruption of the E6-p53 interaction might restore p53 function to these tumour cells in a very specific manner.