生物谷报道：P53肿瘤抑制基因是细胞分子信号级联指导发生致死性DNA损伤的细胞进行自我毁灭的关键。如果p53基因失活（一如在一半以上的人类癌症中见到的那样），细胞生长的检测和平衡都会无法进行，并且体细胞开始积累突变以至于最终导致癌症的发生。P53在很多细胞凋亡信号通路中都扮演着十分重要的作用，包括膜凋亡信号，线粒体凋亡通路，以及它在细胞核内影响着很多与凋亡相关的因子的转录与表达。
虽然这种基因的调节已经研究的比较多，但是大部分研究都是在组织培养或离体模型中进行的。最新Salk生物研究所的研究人员创造出的一个新小鼠模型显示研究人员从离体研究获得的有关p53活性调节的信息可能不适用于生活着的、呼吸着的生物体。这项研究的结果公布在PNAS杂志上，引起了人们对P53的新一轮的关注。
到目前为止，研究人员根据培养细胞的实验结果推测p53必定通过被附着在蛋白质特定位置的化学基团修饰，从而在身体中正常行使其功能。但是，新的研究表明在压力条件下，这些修饰对活化p53不是必须的。
之前人们认为对其正常功能至关重要的p53蛋白的化学修饰可能只是在活体生物中的生理条件下的这种蛋白活性的一种微调。这项新研究将人们的眼光吸引到了p53的调节因子网络和它的调节机制上。
人类的细胞容易因UV光照射、电离辐射、毒性化合物或其他环境损伤而发生DNA断裂。如果不加以修复，这些DNA缺口能够使细胞分裂发生失控并最终导致癌症的发生。正常情况下，p53蛋白很不稳定并且在细胞中的水平非常低。但是，当细胞感觉到它的DNA出现了损伤时，它就会放慢p53的降解，因此p53蛋白水平增加并起始保护性措施。当较高水平的p53肿瘤抑制因子存在时，就有足够的p53与细胞的基因组中的调节位点结合以活化其他终止细胞分裂的蛋白的制造（如果这种DNA损伤还能修复）。如果这种损伤太严重以至于无法修复时，由p53肿瘤抑制蛋白控制的关键后备保护作用就会将这个细胞剔除。它会起始程序性细胞死亡或凋亡过程将这种受损的DNA永久地从生物体内消除掉。
这项研究表明先前通过组织培养方法获得的有关p53基因的调节信息可能在活体生物中并不是重要的调节形式，因此增加了人们对p53基因的新认识。
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P53家族的成员
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 结构域:
