生物谷報(bào)道：P53腫瘤抑制基因是細(xì)胞分子信號(hào)級(jí)聯(lián)指導(dǎo)發(fā)生致死性DNA損傷的細(xì)胞進(jìn)行自我毀滅的關(guān)鍵,。如果p53基因失活（一如在一半以上的人類癌癥中見到的那樣）,，細(xì)胞生長的檢測和平衡都會(huì)無法進(jìn)行，并且體細(xì)胞開始積累突變以至于最終導(dǎo)致癌癥的發(fā)生,。P53在很多細(xì)胞凋亡信號(hào)通路中都扮演著十分重要的作用,，包括膜凋亡信號(hào)，線粒體凋亡通路,，以及它在細(xì)胞核內(nèi)影響著很多與凋亡相關(guān)的因子的轉(zhuǎn)錄與表達(dá),。
雖然這種基因的調(diào)節(jié)已經(jīng)研究的比較多,，但是大部分研究都是在組織培養(yǎng)或離體模型中進(jìn)行的。最新Salk生物研究所的研究人員創(chuàng)造出的一個(gè)新小鼠模型顯示研究人員從離體研究獲得的有關(guān)p53活性調(diào)節(jié)的信息可能不適用于生活著的,、呼吸著的生物體,。這項(xiàng)研究的結(jié)果公布在PNAS雜志上，引起了人們對(duì)P53的新一輪的關(guān)注,。
到目前為止,，研究人員根據(jù)培養(yǎng)細(xì)胞的實(shí)驗(yàn)結(jié)果推測p53必定通過被附著在蛋白質(zhì)特定位置的化學(xué)基團(tuán)修飾，從而在身體中正常行使其功能,。但是,，新的研究表明在壓力條件下，這些修飾對(duì)活化p53不是必須的,。
之前人們認(rèn)為對(duì)其正常功能至關(guān)重要的p53蛋白的化學(xué)修飾可能只是在活體生物中的生理?xiàng)l件下的這種蛋白活性的一種微調(diào),。這項(xiàng)新研究將人們的眼光吸引到了p53的調(diào)節(jié)因子網(wǎng)絡(luò)和它的調(diào)節(jié)機(jī)制上。
人類的細(xì)胞容易因UV光照射,、電離輻射,、毒性化合物或其他環(huán)境損傷而發(fā)生DNA斷裂。如果不加以修復(fù),，這些DNA缺口能夠使細(xì)胞分裂發(fā)生失控并最終導(dǎo)致癌癥的發(fā)生,。正常情況下，p53蛋白很不穩(wěn)定并且在細(xì)胞中的水平非常低,。但是,，當(dāng)細(xì)胞感覺到它的DNA出現(xiàn)了損傷時(shí)，它就會(huì)放慢p53的降解,，因此p53蛋白水平增加并起始保護(hù)性措施,。當(dāng)較高水平的p53腫瘤抑制因子存在時(shí)，就有足夠的p53與細(xì)胞的基因組中的調(diào)節(jié)位點(diǎn)結(jié)合以活化其他終止細(xì)胞分裂的蛋白的制造（如果這種DNA損傷還能修復(fù)）,。如果這種損傷太嚴(yán)重以至于無法修復(fù)時(shí),，由p53腫瘤抑制蛋白控制的關(guān)鍵后備保護(hù)作用就會(huì)將這個(gè)細(xì)胞剔除。它會(huì)起始程序性細(xì)胞死亡或凋亡過程將這種受損的DNA永久地從生物體內(nèi)消除掉,。
這項(xiàng)研究表明先前通過組織培養(yǎng)方法獲得的有關(guān)p53基因的調(diào)節(jié)信息可能在活體生物中并不是重要的調(diào)節(jié)形式,，因此增加了人們對(duì)p53基因的新認(rèn)識(shí)。
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P53家族的成員
The p53 tumor suppressor protein
The p53 gene like the Rb gene, is a tumor suppressor gene, i.e., its activity stops the formation of tumors. If a person inherits only one functional copy of the p53 gene from their parents, they are predisposed to cancer and usually develop several independent tumors in a variety of tissues in early adulthood. This condition is rare, and is known as Li-Fraumeni syndrome. However, mutations in p53 are found in most tumor types, and so contribute to the complex network of molecular events leading to tumor formation.
The p53 gene has been mapped to chromosome 17. In the cell, p53 protein binds DNA, which in turn stimulates another gene to produce a protein called p21 that interacts with a cell division-stimulating protein (cdk2). When p21 is complexed with cdk2 the cell cannot pass through to the next stage of cell division. Mutant p53 can no longer bind DNA in an effective way, and as a consequence the p21 protein is not made available to act as the 'stop signal' for cell division. Thus cells divide uncontrollably, and form tumors.
Help with unraveling the molecular mechanisms of cancerous growth has come from the use of mice as models for human cancer, in which powerful 'gene knockout' techniques can be used. The amount of information that exists on all aspects of p53 normal function and mutant expression in human cancers is now vast, reflecting its key role in the pathogenesis of human cancers. It is clear that p53 is just one component of a network of events that culminate in tumor formation
p53 Folding Biophysics
In the folding reaction of p53, the rate-limiting step is the association of the two dimers with native-like structures into the tetrameric native structure. The highlighted amino acid residues were found to be involved in the early association events. This result was obtained with the so-called F-value analysis, a methods in which mutations serve as reporters of structural consolidation of the protein molecule in the course of its folding reaction - see B. Nolting "Protein Folding Kinetics: Biophysical Methods" (Springer, 1999, 2000) and B. Nolting "Methods in Modern Biophysics" (Springer, 2003). For further results of this research on p53 and for details of the application of such F-value analysis methods on 5 further proteins see B. Nolting & K. Andert, "Mechanism of Protein Folding", Proteins (2000) 41, 288-298. [Figure prepared with the program MOLMOL: Koradi, R., Billeter, M., and Wüthrich, K. (1996) J Mol Graphics 14, 51-55. MOLMOL: a program for display and analysis of macromolecular structures.]
P53 結(jié)構(gòu)域:
