Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status

Genes of the RAF family encode kinases that are regulated by Ras and mediate cellular responses to growth signals. Activating mutations in one RAF gene, BRAF, have been found in a high proportion of melanomas and in a small fraction of other cancers. Here we show that BRAF mutations in colorectal cancers occur only in tumours that do not carry mutations in a RAS gene known as KRAS, and that BRAF mutation is linked to the proficiency of these tumours in repairing mismatched bases in DNA. Our results not only provide genetic support for the idea that mutations in BRAF and KRAS exert equivalent effects in tumorigenesis, but also emphasize the role of repair processes in establishing the mutation spectra that underpin human cancer.     

Mutations of the BRAF gene in human cancer

Cancers arise owing to the accumulation of mutations in critical genes that alter normal programmes of cell proliferation, differentiation and death. As the first stage of a systematic genome-wide screen for these genes, we have prioritized for analysis signalling pathways in which at least one gene is mutated in human cancer. The RAS RAF MEK ERK MAP kinase pathway mediates cellular responses to growth signals. RAS is mutated to an oncogenic form in about 15% of human cancer. The three RAF genes code for cytoplasmic serine/threonine kinases that are regulated by binding RAS. Here we report BRAF somatic missense mutations in 66% of malignant melanomas and at lower frequency in a wide range of human cancers. All mutations are within the kinase domain, with a single substitution (V599E) accounting for 80%. Mutated BRAF proteins have elevated kinase activity and are transforming in NIH3T3 cells. Furthermore, RAS function is not required for the growth of cancer cell lines with the V599E mutation. As BRAF is a serine/threonine kinase that is commonly activated by somatic point mutation in human cancer, it may provide new therapeutic opportunities in malignant melanoma.     

数值学报（2003年第12卷）

本书是由英国剑桥大学出版、发行的不定期专题论文集，每年出版一卷，登载数值分析、计算方法及其应用等方面的高水平创造性研究论文或综述报告，论文作者多为当代相关领域的国际性学术带头人。     

Study on molecular interaction between NifA and NifL of Pseudomonas stutzeri A1501 by using the yeast two-hybrid system

Pseudomonas stutzeri AI501 (formerly Alcaligenes faecalis A1501), which was isolated from rice paddies in South China in 1980, can colonize tightly on rhizoplane of the host plants or invade the roots of plants for growth and nitrogen fixation. But A1501 can fix nitrogen only under the micro-aerobic and nitrogen-free conditions. The oxygen concentration and the availability of fixed nitrogen are therefore important factors in the regulation of nitrogenase biosynthesis of associative nitrogen-fixing bacteria.