新托福閱讀背景知識匯總（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是存在人體細(xì)胞內(nèi)的一種抗癌白質(zhì)，它有抑制細(xì)胞生長及維持遺傳物質(zhì)完整性的功能。事實上，半數(shù)以上的癌癥細(xì)胞內(nèi)都有p53的突變，可見其在細(xì)胞生長控制上扮演了重要的角色。在正常狀況下，p53的半衰期約只有30分鐘，相當(dāng)不穩(wěn)定;然而當(dāng)細(xì)胞經(jīng)紫外線，離子化射線(如X光，伽傌照射)，或當(dāng)細(xì)胞缺氧、缺養(yǎng)時，p53被活化，同時它的穩(wěn)定性提高，造成細(xì)胞內(nèi)的p53大量增加，除了上述刺激外，化學(xué)治療上常用的藥物也有同效。這種p53的活化與增加常導(dǎo)致兩種可能的結(jié)果：一是細(xì)胞長停止在G1或G2期;另一是細(xì)胞採自殺行為(apoptosis)而死亡。細(xì)胞由此得以修補(bǔ)損壞(前者)，或過度受損的細(xì)胞得以從人體除去(后者)。這種依賴p53的"自衛(wèi)措施"在一些細(xì)胞中常因p53的突變而失去功能，使得這些有"缺陷"的細(xì)胞能繼續(xù)不受控制的生長分裂，導(dǎo)致突變的累積和癌癥的生長。

雖然環(huán)境因子影響p53活性及穩(wěn)定性的事實已知已久，其間的分子機(jī)轉(zhuǎn)仍不清楚。蛋白質(zhì)的磷酸化(phosphorylation)一向被認(rèn)為在訊息傳遞上扮演重要的角色。事實上，經(jīng)由我們及其他實驗室的研究發(fā)現(xiàn)，p53在經(jīng)過紫外線，伽傌射線照射后，其N端的數(shù)個胺基酸(第15，20，33，37)有磷酸化的現(xiàn)象。這種磷酸化發(fā)生極為快速，幾乎是在照射后數(shù)分鐘內(nèi)即已產(chǎn)生，而持續(xù)多久則視胺基酸位置、刺激型態(tài)，及細(xì)胞種類而異。至于這些磷酸化與p53的反應(yīng)之關(guān)聯(lián)性則仍有待證明。最近我們發(fā)現(xiàn)有兩個在細(xì)胞分裂(Cell cycle)的檢查點(checkpoint)上扮演著重要調(diào)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線、伽傌線引起的位置，即第15，20及37胺基酸。我們正著手研究可能的CHKs的上游分子及p53在CHKs磷酸化后功能之變化。此外， 不同的環(huán)境因子與p53聯(lián)繫的方式可能各異，有些可能透過磷酸化以外的方式進(jìn)行。 我們希望能先定出p53序列中與環(huán)境因子互動有關(guān)的區(qū)域(domain)，再由此找出與調(diào)節(jié)p53穩(wěn)定性有關(guān)的機(jī)制及分子。

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