Poulogiannis George, Luo Feijun, Arends Mark J
Department of Systems Biology, Harvard Medical School, and Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
Cell Commun Adhes. 2012 Feb;19(1):1-9. doi: 10.3109/15419061.2011.649380. Epub 2012 Jan 10.
RAS proteins act as molecular switches between several homeostatic inputs and signal transduction pathways that regulate important cellular processes including cell growth, differentiation and survival. Activating mutations change the function of normal proto-oncogenic RAS proteins to oncogenic RAS proteins that trigger a wide range of downstream effectors altering expression of transcription factors that together stimulate cell proliferation and modulate apoptosis and differentiation. RAS genes are amongst the most frequently mutated genes in human cancers, in particular KRAS is mutated in 40-50% of colorectal cancers. Mutation of this gene has a significant impact on treatment management and patients' survival, particularly in relation to anti-EGFR therapy, which is only effective in KRAS wild-type cases. Here, we discuss the regulation of KRAS signalling in the colorectum, some of the post-transcriptional and post-translational modifications that control its activity, the mutations and other DNA alterations that are found in this tumour type and the implications that they have for disease progression and current drug treatments.
RAS蛋白充当多种稳态输入与信号转导途径之间的分子开关，这些信号转导途径调节包括细胞生长、分化和存活在内的重要细胞过程。激活突变会将正常的原癌基因RAS蛋白功能转变为致癌性RAS蛋白，后者触发多种下游效应器，改变转录因子的表达，共同刺激细胞增殖并调节细胞凋亡和分化。RAS基因是人类癌症中最常发生突变的基因之一，尤其是KRAS在40%-50%的结直肠癌中发生突变。该基因的突变对治疗管理和患者生存有重大影响，特别是在抗表皮生长因子受体（EGFR）治疗方面，该治疗仅对KRAS野生型病例有效。在此，我们讨论结直肠癌中KRAS信号传导的调控、一些控制其活性的转录后和翻译后修饰、在这种肿瘤类型中发现的突变及其他DNA改变，以及它们对疾病进展和当前药物治疗的影响。
