Disease relevance of Araf

• When incorporated into a retrovirus, the resulting gag-A-raf fusion gene causes transformation in vitro and induces tumors in newborn mice [1].
• Using a phage display library to identify basic residues in A-Raf required to mediate binding to the Src homology 2 domains of the p85 subunit of phosphatidylinositol 3'-kinase [2].

High impact information on Araf

• Braf -/- embryos, unlike Araf -/- or Craf1 -/- embryos (L.W. et al., unpublished), show an increased number of endothelial precursor cells, dramatically enlarged blood vessels and apoptotic death of differentiated endothelial cells [3].
• However, genetic studies of C. elegans and Drosophila, as well as the targeted mutagenesis of the murine Araf gene, have failed to support such a role [3].
• Moreover, raf-1(-/-) megakaryocytes do not have a compensatory increase in A-Raf or B-Raf expression, and thrombopoietin-induced ERK1/2 phosphorylation is similar in raf-1(-/-) and raf-1(+/+) megakaryocytes [4].
• Conditionally oncogenic forms of the A-Raf and B-Raf protein kinases display different biological and biochemical properties in NIH 3T3 cells [5].
• In contrast to raf, A-raf shows a highly restricted tissue distribution of expression, with highest levels observed in epididymis, followed by intestine [1].

Chemical compound and disease context of Araf

• A cysteine-rich region located near the amino terminus, which is highly conserved in A-raf and c-raf, shows significant homology with protein kinase C. A 5' deleted fragment of the cDNA has been incorporated into a murine retrovirus which endows the virus with the ability to transform cells in vivo and in vitro [6].

Biological context of Araf

• Detailed genetic mapping of the A-raf proto-oncogene on the mouse X chromosome [7].
• The transcribed murine A-raf proto-oncogene has been localized to the proximal region of the mouse X chromosome, within the context of four other active genes in this region which together constitute a conserved linkage group between mouse and man [7].
• This localization on the mouse X chromosome is compatible with the presence of the A-raf oncogene on the short arm of the human X chromosome between the centromere and Xp21 [8].
• Methylation analysis indicated that DAP-4I-1a mainly comprised 4-linked Gal and 3-, 4-, and 6-linked Glc, whereas DAP-4IIa-1 consisted mainly of terminal Araf, 3-linked Glc, and 3,6-branched Gal [9].
• Characterization of murine A-raf, a new oncogene related to the v-raf oncogene [1].

Anatomical context of Araf

• In contrast, A-raf showed wider variation in its range of expression, with the 2.6 kb transcripts being most abundant in epididymis and ovary [10].
• We have introduced into the mouse germ line a loss-of-function mutation in the X-chromosomal A-Raf gene, by homologous recombination in embryonic stem cells [11].
• A-raf expression in Leydig cells appears to be elevated in testes undergoing spermatogenesis [12].
• These studies indicated that testicular products, such as spermatozoa, or substances that require germ cells for their production in the testis modulate the androgen-dependent expression of A-raf in the initial segment of the caput epididymis [13].

Associations of Araf with chemical compounds

• A-raf oncogene localizes on mouse X chromosome to region some 10-17 centimorgans proximal to hypoxanthine phosphoribosyltransferase gene [8].
• Methylation analysis of these degradation products indicated that they contained terminal Rha, Araf, Fuc, Xyl, and Gal, 4-linked Rha, 3-linked Fuc, 3-linked Ara, and 3'-linked Api [14].
• Approximately 50% of the clones identified encoded portions of the c-Raf and A-Raf serine/threonine kinases [15].
• A fivefold dexamethasone-dependent induction of A-raf promoter activity was observed using constructs containing all three GRE motifs whereas point mutations in the GREs either diminished or abolished dexamethasone induction [16].
• These results demonstrate that the A-raf promoter is regulated in part by members of the glucocorticoid family of steroid hormone receptors and suggest a model for the regulation of A-raf expression in urogenital tissues [16].

Other interactions of Araf

• Detailed restriction mapping shows that Timp is transcribed in the same direction as Araf but in the opposite direction to the Syn-1 gene [17].
• The proto-oncogene c-raf-1 and the related genes A-raf and B-raf encode serine/threonine protein kinases thought to be involved in regulating gene expression by transducing extracellular signals into the cell [12].
• Interestingly, B-Raf and Raf-1 activity towards MEK as measured by the immunoprecipitation kinase cascade assay are both significantly increased in the A-Raf deficient MEFs [18].
• M-Ras interacted poorly in a yeast two-hybrid assay with multiple Ras effectors, including c-Raf-1, A-Raf, B-Raf, phosphoinositol-3 kinase delta, RalGDS, and Rin1 [19].
• Transformation of NIH 3T3 cells with Ha-ras, v-raf, or A-raf enhanced the stimulatory effect of PMA on the phospholipase D-mediated hydrolysis of PtdEtn [20].

Analytical, diagnostic and therapeutic context of Araf

• Castration abolished detectable A-raf expression throughout the epididymis [13].
• Southern blot analysis of transformant DNAs showed that the transforming activity was not due to the acquisition of a ras (Ha, Ki, or N), neu, myc, A-raf, v-raf, erbA, or erbB gene of rat origin [21].

References