Actively transcribed genes in the raf oncogene group, located on the X chromosome in mouse and human.

Abstract

Murine and human cDNAs, related to but distinct from c-raf-1, have been isolated and designated mA-raf and hA-raf, respectively. The mA-raf and hA-raf cDNAs detect the same murine and human fragments in Southern blots of restriction enzyme-cleaved murine and human cellular DNA. The murine restriction enzyme fragments homologous to mA-raf cDNA cosegregate with mouse chromosome X in a panel of Chinese hamster-mouse hybrid cells, thus localizing the mA-raf locus to mouse chromosome X. Two independently segregating loci, detected by the hA-raf cDNA (or mA-raf cDNA), hA-raf-l and hA-raf-2, are located on human chromosomes X and 7, respectively. The mA-raf locus and the hA-raf-1 locus are actively transcribed in several mouse and human cell lines.The normal precursors to activated oncogenes, the protooncogenes, presumably serve important growth-regulatory functions, since at least 4 of the more than 25 known oncogenes derive from components ofthe signal transduction pathway of growth factors: erbB, which derives from a portion of the receptor gene for epidermal growth factor (1); sis, which is homologous to part of the gene for plateletderived growth factor (2-4); the cellular homolog of the McDonough feline sarcoma oncogene, c-fms, which is related to the receptor for the colony-stimulating factor CSF-1 (5); and myc, which can mediate signal transduction for a variety of growth factors (6-8). Most oncogenes have been isolated as part of the genomes of transducing retroviruses (9-12), by molecular cloning of retrovirus integration sites in virusinduced tumor cells (13), or by DNA transfection using tumor-cell DNA (14). Additional oncogene-related genes (N-myc and r-fos) were identified by virtue of their nucleic acid sequence relatedness to known oncogenes (15-17), and putative oncogenes have been identified by virtue of their presence at the junction between chromosomes involved in specific translocations in leukemia and lymphoma (18)(19)(20).The v-raf oncogene was originally isolated as part of the genome of 3611 murine sarcoma virus, an acutely transforming murine retrovirus (21). Subsequently, the avian homolog of v-raf, v-mil (or mht) was identified in the avian carcinoma virus MH2 (22, 23). v-raf and v-mil derive from the 3'-terminal two-thirds of the same cellular gene, c-raf-1. c-raf-l encodes a 74-kDa protein that is predominantly cytoplasmic (24). The deduced amino acid sequence of c-raf-l shows a distant relationship to the src family of oncogenes (25); however, in contrast to many src-family gene products, which have tyrosine-specific protein kinase activity, the proteins encoded by transforming versions of c-raf-1 have protein kinase activity with specificity for serine or threonine residues (26). A role of c-raf-1 in human tumors is suggested by its chromosomal location at 3p25 (27), a region that is commonly altered in small-cell lung carcinoma (28). Moreover, activation of c-raf-J occurs in primary stomach cancer (29).Recently, on screening a mouse cDNA library with a v-raf oncogene probe, we h...

RG7204 (PLX4032), a Selective BRAFV600E Inhibitor, Displays Potent Antitumor Activity in Preclinical Melanoma Models

“…RG7204 may also be effective in treating cancers other than melanoma, as shown by its antiproliferative activity in colorectal cancer and other tumor cell lines with the BRAF V600E mutation and by its RG7204 antitumor activity in BRAF V600E -bearing colorectal cancer xenograft models. 6 However, it seems that the specific molecular effect of RG7204 may differ in different cell types. A previous study in a thyroid cancer cell line showed inhibition of cell growth but very little induction of apoptosis (16).…”

Raf kinases: Oncogenesis and drug discovery

“…27 Our finding that constitutive MAP kinase activity in v-raf transformed cells quickly led to the identification of the mitogen-activated kinase kinase MEK as first physiological Raf substrate, thereby completing the description of the classical mitogenic cascade. [28][29][30] Subsequently, the paralogues A-Raf [31][32][33] and B-Raf 34,35 were identified. Although all 3 Raf isoforms share considerable sequence similarity, 36 they exhibit beneath common also individual functions, which are still far from being fully understood.…”

BRAFE600 in benign and malignant human tumours

“…Around the same time, chicken Raf was cloned from an avian virus (Mill-Hill No 2) and termed v-mil (Jansen et al, 1983(Jansen et al, , 1984. Cloning of human CRAF, ARAF and BRAF followed shortly afterwards (Bonner et al, 1985;Huebner et al, 1986;Beck et al, 1987;Ikawa et al, 1988;reviewed in Wellbrock et al, 2004). In 2003, an omission of three nucleotides from the first exon in the sequence of the human BRAF gene in NCBI was identified and corrected, resulting in the change of the numbering of protein residues (Kumar et al, 2003a).…”