Kimmelman A, Tolkacheva T, Lorenzi M V, Osada M, Chan A M
The Derald H. Ruttenberg Cancer Center, Mount Sinai School of Medicine, New York, New York 10029, USA.
Oncogene. 1997 Nov 27;15(22):2675-85. doi: 10.1038/sj.onc.1201674.
Members of the Ras subfamily of GTP-binding proteins, including Ras (H-, K-, and N-), TC21, and R-ras have been shown to display transforming activity, and activating lesions have been detected in human tumors. We have identified an additional member of the Ras gene family which shows significant sequence similarity to the human TC21 gene. This novel human ras-related gene, R-ras3, encodes for a protein of 209 amino acids, and shows approximately 60-75% sequence identity in the N-terminal catalytic domain with members of the Ras subfamily of GTP-binding proteins. An activating mutation corresponding to the leucine 61 oncogenic lesion of the ras oncogenes when introduced into R-ras3, activates its transforming potential. R-ras3 weakly stimulates the mitogen-activated protein kinase (MAPK) activity, but this effect is greatly potentiated by the co-expression of c-raf-1. By the yeast two-hybrid system, R-ras3 interacts only weakly with known Ras effectors, such as Raf and RalGDS, but not with RglII. In addition, R-ras3 displays modest stimulatory effects on trans-activation from different nuclear response elements which bind transcription factors, such as SRF, ETS/TCF, Jun/Fos, and NF-kappaB/Rel. Interestingly, Northern blot analysis of total RNA isolated from various tissues revealed that the 3.8 kilobasepair (kb) transcript of R-ras3 is highly restricted to the brain and heart. The close evolutionary conservation between R-ras3 and Ras family members, in contrast to the significant differences in its biological activities and the pattern of tissue expression, raise the possibility that R-ras3 may control novel cellular functions previously not described for other GTP-binding proteins.
GTP结合蛋白Ras亚家族的成员，包括Ras（H-、K-和N-）、TC21和R-ras已被证明具有转化活性，并且在人类肿瘤中检测到了激活损伤。我们鉴定出了Ras基因家族的另一个成员，它与人类TC21基因具有显著的序列相似性。这个新的人类ras相关基因R-ras3编码一个209个氨基酸的蛋白质，并且在N端催化结构域与GTP结合蛋白Ras亚家族的成员具有大约60-75%的序列同一性。当将与ras癌基因的亮氨酸61致癌损伤相对应的激活突变引入R-ras3时，可激活其转化潜能。R-ras3对丝裂原活化蛋白激酶（MAPK）活性的刺激作用较弱，但c-raf-1的共表达可大大增强这种作用。通过酵母双杂交系统，R-ras3仅与已知的Ras效应器（如Raf和RalGDS）弱相互作用，而不与RglII相互作用。此外，R-ras3对来自结合转录因子（如SRF、ETS/TCF、Jun/Fos和NF-κB/Rel）的不同核反应元件的反式激活显示出适度的刺激作用。有趣的是，对从各种组织中分离的总RNA进行的Northern印迹分析表明，R-ras3的3.8千碱基对（kb）转录本高度局限于脑和心脏。与R-ras3和Ras家族成员之间紧密的进化保守性形成对比的是，其生物学活性和组织表达模式存在显著差异，这增加了R-ras3可能控制其他GTP结合蛋白以前未描述的新细胞功能的可能性。
