Disease relevance of ARAF

• Mutation analysis of the BRAF, ARAF and RAF-1 genes in human colorectal adenocarcinomas [1].
• In this study we analyzed the genomic DNAs for the detection of somatic mutations of the ARAF gene in 60 human cancer cell lines and 323 primary human cancer tissues, including colorectal carcinomas, gastric carcinomas, ovarian tumors and acute leukemias [2].
• The complete coding sequence of the human A-raf-1 oncogene and transforming activity of a human A-raf carrying retrovirus [3].
• In mammals there are three isoforms, A-RAF, B-RAF and C-RAF, and recently it was shown that the B-RAF isoform is mutated in a high proportion of melanomas [4].
• PATIENTS AND METHODS: A retrospective study was performed of 37 consecutive patients with PKS and human immunodeficiency virus infection in the tumor registry at a large municipal hospital in New York City between 1994 to 1997 [5].

High impact information on ARAF

• The PPI motif is conserved in protein kinases of the SOS2 family (i.e., protein kinase S, PKS) and in the DNA damage repair and replication block checkpoint kinase, Chk1, from various organisms including humans [6].
• No recombination was observed between the disease and the marker loci DXS7 and MAOA, suggesting that the location of COD1 is in the region Xp11.3, distal to DXS84 and proximal to ARAF1 [7].
• A highly polymorphic dinucleotide repeat on the proximal short arm of the human X chromosome: linkage mapping of the synapsin I/A-raf-1 genes [8].
• The mA-raf locus and the hA-raf-1 locus are actively transcribed in several mouse and human cell lines [9].
• In contrast, protein 14-3-3, an abundant cytosolic protein that participates in many facets of signal transduction, was found to interact with C-RAF but not with A-RAF N-terminal domain [10].

Chemical compound and disease context of ARAF

• The antibiotic TA of Myxococcus xanthus is a complex macrocyclic polyketide, produced through successive condensations of acetate by a type I PKS (polyketide synthase) mechanism [11].

Biological context of ARAF

• In 129 Japanese patients with PTC, BRAF(T1799A) was detected in 65 cases (50.4%), and the remaining 64 tumor specimens were subjected to mutation analysis of kinase domains of ARAF, CRAF and MET genes, and hotspots of K- and N-RAS genes [12].
• The MOLT-4 leukemia cell line was found to harbor an ARAF gene mutation resulting in an amino acid substitution (A451T) at the activation segment in the kinase domain of ARAF [2].
• This information is discussed in view of the important role of mitochondria in cellular functions involving energy balance, proliferation, and apoptosis and the potential role of A-RAF in regulating these systems [10].
• Human c-raf-1 maps to chromosome 3p25 and A-raf-1 to Xp21. c-raf-1 RNA is present in many tissues, while A-raf and B-raf expression is restricted [13].
• 2. We have isolated human genomic DNA clones containing the expressed gene (ARAF1) on the X chromosome and a pseudogene (ARAF2) on chromosome 7p12-q11.21 [14].

Anatomical context of ARAF

• No Evidence of ARAF, CRAF and MET Mutations in BRAF(T1799A) Negative Human Papillary Thyroid Carcinoma [12].
• Isoform-specific localization of A-RAF in mitochondria [10].
• Using Western analysis and immunogold labeling, A-RAF was selectively localized in highly purified rat liver mitochondria [10].
• The jaspamide/chondramide family of depsipeptides are mixed PKS/NRPS natural products isolated from marine sponges and a terrestrial myxobacterium that potently affect the function of the actin cytoskeleton [15].
• Unexpectedly, a long terminal repeat-driven overexpression of ARAF1 mRNA was confirmed to induce transformed foci in fibroblasts [16].

Associations of ARAF with chemical compounds

• The compounds studied were PKS-1 (N-acetyl Sph), PKS-2 (N-chloroacetyl Sph), PKS-3 (N-dichloroacetyl Sph), PKS-4 (N-trichloroacetyl Sph), Lyso-GM1 (ganglioside GM1 lacking the N-linked fatty acyl chain and the N-acetyl group on the sialic acid), Liga-4 (N-acetyl, lyso[NeuAc]GM1) and Liga-20 (N-dichloroacetyl, lyso[NeuAc]GM1) [17].
• Melithiazol biosynthesis: further insights into myxobacterial PKS/NRPS systems and evidence for a new subclass of methyl transferases [18].
• In addition to the expected PKS and NRPS genes, the cluster encodes a rare tyrosine aminomutase for beta-tyrosine formation and a previously unknown tryptophan-2-halogenase [15].
• CONCLUSIONS: The impaired ability of Dis-1 and Dis-2, harboring modified FAS-1 enzymes, to carry out norsolorinic acid synthesis implies the need for FAS-1 (and possibly also FAS-2) to physically associate with the PKS before biosynthesis can begin [19].
• The failure of the unaffected PKS alone to be efficiently primed by hexanoylNAC, and the presumed requirement for at least one of the FAS proteins to bind and transfer the C6 unit to the PKS, is in contrast to behavior widely believed to occur for type I PKSs [19].

Other interactions of ARAF

• We also performed mutation analysis of the corresponding conserved regions in the ARAF and RAF-1 genes [1].
• The ARAF1 minimal promoter, located between nucleotides -59 and +93, has a low G + C content and lacks consensus TATA and Inr sequences but shows sequence similarity at position -1 to the E box that is known to interact with USF and TFII-I transcription factors [14].
• With the integration of both physical and genetic maps we have predicted the following marker order: Xpter-UBE1-SYN1/ARAF1/ TIMP1-DXS1367-ZNF81-DXS.6849-ZNF21-DXSy6616++ +-(OATL1, DXS6950-DXS6949)- WAS-(GATA, DXS1126)-DXS1240-Xcen.(ABSTRACT TRUNCATED AT 250 WORDS)[20]
• In the multicenter study, a parametric analysis resulted in positive lod scores (highest of 1.97 for dominant and 1.19 for recessive inheritance at a theta of 0.20) for locus DXS7, with scores below 0.50 for other markers in this region (MAOB, DXS228, and ARAF1) [21].
• PCR amplification of this synapsin I/A-raf-1 associated repeat by using total genomic DNA from members of the 40 reference pedigree families of the Centre d'Etude du Polymorphisme Humaine showed it to be highly polymorphic, with a PIC value of .84 and a minimum of eight alleles [8].

Analytical, diagnostic and therapeutic context of ARAF

• We studied whether the introduction of highly active antiretroviral therapy (HAART; triple antiretroviral therapy including a protease inhibitor and two reverse transcriptase inhibitors) has been associated with improved survival for AIDS patients with PKS [5].
• CONCLUSION: In patients with AIDS-associated PKS and undergoing chemotherapy, administration of HAART was associated with increased survival [5].
• Site-directed mutagenesis of the ketosynthase (KS) and acylcarrier protein (ACP) domains in the interpolated module has shown that skipping within the hybrid PKS involves passage of the growing polyketide through the interpolated module, by direct ACP-to-ACP transfer of the polyketide chain [22].
• The relative expression levels of the 2 X-linked proto-oncogenes ARAF1 and ELK1 were assayed by quantitative reverse transcriptase-polymerase chain reaction [23].
• Poor precision may be due to reliance on routine drug monitoring data alone, difficulties with expression of covariates in continuous modeling relationships in the PKS program, lack of accurate quantitative measures of liver function, or large, random intraindividual variability in the bioavailability of tacrolimus [24].

References