Identification and characterization of R-ras3: a novel member of the RAS gene family with a non-ubiquitous pattern of tissue distribution
Identification and characterization of R-ras3: a novel member of the RAS gene family with a non-ubiquitous pattern of tissue distribution
复制标题
DOI：
10.1038/sj.onc.1201674
复制
发表时间：
1997-11-27
期刊：
影响因子：
8
通讯作者：
Chan, AML
中科院分区：
文献类型：
--
作者：
Kimmelman, A;Tolkacheva, T;Chan, AML
gtp结合蛋白的Ras亚家族成员，包括Ras (H-， K-和N-)， TC21和R-ras，已被证明具有转化活性，并在人类肿瘤中检测到激活病变。我们已经确定了Ras基因家族的另一个成员，显示出与人类TC21基因显著的序列相似性。这个新的人类Ras相关基因R-rad编码209个氨基酸的蛋白质，在n端催化区域与gtp结合蛋白Ras亚家族成员的序列相似性为60-75%。当将ras癌基因的亮氨酸61致癌病变对应的激活突变引入R-ras3时，激活其转化潜能。R-ras3微弱地刺激丝裂原活化蛋白激酶（MAPK）的活性，但这种作用被c-raf- 1的共表达大大增强。通过酵母双杂交系统，R-rad仅与已知的Ras效应物（如Raf和RalGDS）弱相互作用，而与RglII不相互作用。此外，R-ras3对结合转录因子的不同核反应元件（如SRF、ETS/TCF、Jun/Fos和NF-kappa B/Rel）的反式激活表现出适度的刺激作用。有趣的是，从各种组织中分离的总RNA的Northern blot分析显示，R-rad的3.8千碱基对（kb）转录本高度局限于大脑和心脏。与其生物活性和组织表达模式的显著差异相比，R-rad与Ras家族成员之间的密切进化保守性提高了R-rad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。
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-rad, encodes for a protein of 209 amino acids, and shows similar to 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-l. By the yeast two-hybrid system, R-rad interacts only weakly with known Ras effecters, 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-kappa B/Rel. Interestingly, Northern blot analysis of total RNA isolated from various tissues revealed that the 3.8 kilobasepair (kb) transcript of R-rad is highly restricted to the brain and heart. The close evolutionary conservation between R-rad 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-rad may control novel cellular functions previously not described for other GTP-binding proteins.