新托福阅读背景知识汇总（五十）

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What is p53 ?

After the identification of the p53 protein and the subsequent cloning of p53 genes from several species, early observations suggested that p53 may function as an oncogene, because overexpression of p53 appeared to cause oncogenic transformation of cells. In the late 1980s, however, several critical discoveries defined the normal function of p53 to be anti-oncogenic. Wild-type p53 genes, when introduced into cells, were found to be growth suppressive. The screening of DNA from colon cancer patients revealed that p53 mutations occur with unusually high frequency in tumor tissue, an observation that was extended to most of the other major forms of human cancer. Indeed, members of Li-Fraumeni cancer-prone families were shown to carry germ-line p53 mutations. The importance of these observations was underscored by the finding that mice that are homozygous null for p53, although developmentally competent, are highly predisposed to tumors.

The functional character of the p53 protein was determined by experiments showing that p53 contains a strong transcriptional activation domain within its amino terminus and that it is a tetrameric, sequence-specific DNA-biding protein with a defined cognate binding site containing two copies of the 10-mer (5'-RRRCA/TT/AGYYY-3'). Although the p53 protein acts as a transcriptional activator of genes containing p53-binding sites, it is also capable of strongly inhibiting transcription from many genes lacking p53-binding sites. Several oncogenic DNA viruses express viral gene products that associate with and inhibit the trans-activation function of p53, notably SV40 large T antigen, the adenovirus E1B 55-kD protein, and the E6 protein of oncogenic forms of human papillomavirus (HPV E6). In cells, p53 can associate with a 90-kD protein, identified as the product of the mdm-2 oncogene, which is amplified in some types of tumors. When bound to mdm-2, p53 can no longer function as an activator of transcription.

p53 plays multiple roles in cells. Expression of high levels of wild-type (but not mutant) p53 has two outcomes: cell cycle arrest or apoptosis. The observation that DNA-damaging agents induce levels of p53 in cells led to the definition of p53 as a checkpoint factor, akin, perhaps, to the product of the fad9 gene in yeast. While dispensable for viability, in response to genotoxic stress, p53 acts as an "emergency brake" inducing either arrest or apoptosis, protecting the genome from accumulating excess mutations. Consistent with this notion, cells lacking p53 were shown to be genetically unstable and thus more prone to tumors.

(中文版)

p53是存在人体细胞内的一种抗癌白质，它有抑制细胞生长及维持遗传物质完整性的功能。事实上，半数以上的癌症细胞内都有p53的突变，可见其在细胞生长控制上扮演了重要的角色。在正常状况下，p53的半衰期约只有30分鐘，相当不稳定;然而当细胞经紫外线，离子化射线(如X光，伽傌照射)，或当细胞缺氧、缺养时，p53被活化，同时它的稳定性提高，造成细胞内的p53大量增加，除了上述刺激外，化学治疗上常用的药物也有同效。这种p53的活化与增加常导致两种可能的结果：一是细胞长停止在G1或G2期;另一是细胞採自杀行为(apoptosis)而死亡。细胞由此得以修补损坏(前者)，或过度受损的细胞得以从人体除去(后者)。这种依赖p53的"自卫措施"在一些细胞中常因p53的突变而失去功能，使得这些有"缺陷"的细胞能继续不受控制的生长分裂，导致突变的累积和癌症的生长。

虽然环境因子影响p53活性及稳定性的事实已知已久，其间的分子机转仍不清楚。蛋白质的磷酸化(phosphorylation)一向被认为在讯息传递上扮演重要的角色。事实上，经由我们及其他实验室的研究发现，p53在经过紫外线，伽傌射线照射后，其N端的数个胺基酸(第15，20，33，37)有磷酸化的现象。这种磷酸化发生极为快速，几乎是在照射后数分鐘内即已产生，而持续多久则视胺基酸位置、刺激型态，及细胞种类而异。至于这些磷酸化与p53的反应之关联性则仍有待证明。最近我们发现有两个在细胞分裂(Cell cycle)的检查点(checkpoint)上扮演着重要调控功能的磷酸化酵素(kinase) hCHK1，CHK2可以有效的磷酸化p53。有趣的是，磷酸化的胺基酸中包括了那些可以被紫外线、伽傌线引起的位置，即第15，20及37胺基酸。我们正着手研究可能的CHKs的上游分子及p53在CHKs磷酸化后功能之变化。此外， 不同的环境因子与p53联繫的方式可能各异，有些可能透过磷酸化以外的方式进行。 我们希望能先定出p53序列中与环境因子互动有关的区域(domain)，再由此找出与调节p53稳定性有关的机制及分子。

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