La Thangue N B
Laboratory of Eukaryotic Molecular Genetics, MRC National Institute for Medical Research, Mill Hill, London.
Biochem Soc Trans. 1996 Feb;24(1):54-9. doi: 10.1042/bst0240054.
This is an exciting era in cell-cycle research. We are now uncovering the molecular details of a critical pathway which regulates early cell-cycle progression by integrating signals emanating from proteins that drive the cell cycle with the transcription apparatus and the consequent control of target genes. Molecules that function to positively regulate, such as cyclin-cdk complexes, and negatively regulate, such as the cdk inhibitors, converge on the pathway and, in turn, regulate the activity of pRb and related proteins. A principal role of pRb is in the regulation of the E2F family of transcription factors, and activity of which determines cell-cycle progression. Importantly, many of the proteins in this pathway are encoded by genes which are frequently mutated in tumour cells, a feature which emphasizes the pathway's critical role in orchestrating early cell-cycle control. In fact, it seems likely that the pathway is, at some point, aberrantly regulated in most, if not all, human tumour cells. It is principally E2F that pRb seeks out to exert its effect on the cell cycle. However, it is unclear why there is such a plethora of E2F/DP heterodimers under the E2F umbrella: different genes, different targets or different pathways of control? In human tumour cells, why is Rb so frequently mutated, whereas the genes encoding p107 and p130 apparently not so? Does this imply that the physiological roles of p107 and p130 are of overwhelming importance that cells cannot accommodate mutation in either gene, or do they take on such minor roles that their mutation in tumour cells would be of incidental consequence? These questions, and many others, remain to be resolved. Finally, we should never forget that the increasing knowledge of cell-cycle control has profound implications for the treatment of proliferative disease. The progress and insights into the physiological pathways which regulate cell-cycle progression offer a new and exciting range of realistic targets through which oncogenesis may, in the near future, be effectively treated. The mechanistic and structural information that is rapidly accumulating offers new promise in the search for small-molecule clinically viable drugs.
这是细胞周期研究中一个令人兴奋的时代。我们现在正在揭示一条关键通路的分子细节，该通路通过整合来自驱动细胞周期的蛋白质发出的信号与转录装置以及对靶基因的后续控制来调节细胞周期的早期进程。起正向调节作用的分子，如细胞周期蛋白 - 细胞周期蛋白依赖性激酶（cyclin-cdk）复合物，以及起负向调节作用的分子，如细胞周期蛋白依赖性激酶抑制剂，都汇聚在这条通路上，进而调节视网膜母细胞瘤蛋白（pRb）及相关蛋白的活性。pRb的一个主要作用是调节E2F转录因子家族，其活性决定细胞周期进程。重要的是，这条通路中的许多蛋白质由在肿瘤细胞中频繁突变的基因编码，这一特征强调了该通路在协调细胞周期早期控制中的关键作用。事实上，在大多数（如果不是全部）人类肿瘤细胞中，这条通路似乎在某个时候受到了异常调节。pRb主要是通过寻找E2F来对细胞周期发挥作用。然而，目前尚不清楚为什么在E2F保护伞下会有如此众多的E2F/DP异二聚体：是不同的基因、不同的靶标还是不同的控制途径？在人类肿瘤细胞中，为什么Rb如此频繁地发生突变，而编码p107和p130的基因显然并非如此？这是否意味着p107和p130的生理作用极其重要，以至于细胞无法承受任何一个基因的突变，或者它们所起的作用如此微小，以至于在肿瘤细胞中的突变只是偶然结果？这些问题以及许多其他问题仍有待解决。最后，我们绝不能忘记，对细胞周期控制的认识不断增加对增殖性疾病的治疗具有深远意义。对调节细胞周期进程的生理通路的进展和见解提供了一系列新的、令人兴奋的现实靶点，通过这些靶点，在不久的将来，肿瘤发生可能会得到有效治疗。迅速积累的机制和结构信息为寻找临床上可行的小分子药物带来了新的希望。
