Disease relevance of RFC4

• To explore its cellular function, the A1 adenosine receptor was depleted by small interfering RNA (siRNA) in MDA-MB-468 human breast tumor cells [1].
• In one erythroleukemia cell line, A1 expression was undetectable as a result of F-MuLV integration in one allele and loss of the other allele [2].
• The previously characterized monoclonal antibodies (MAbs) A1, A69, B1, and A20 are directed against assembled or nonassembled adeno-associated virus type 2 (AAV-2) capsid proteins (A. Wistuba, A. Kern, S. Weger, D. Grimm, and J. A. Kleinschmidt, J. Virol. 71:1341-1352, 1997) [3].
• Serpin A1 is overexpressed in ALK+ anaplastic large cell lymphoma and its expression correlates with extranodal dissemination [4].
• The aberrant functioning of the A1 adenosine receptor of adipose tissue has been implicated as a factor in obesity [5].

High impact information on RFC4

• P binds to and activates transcription of the A1 gene required for 3-deoxy flavonoid and phlobaphene biosynthesis, but not the Bz1 gene required for anthocyanin biosynthesis [6].
• The maize C1 gene, which also encodes a Myb homolog, activates both the A1 and Bz1 genes, but only in the presence of a basic-helix-loop-helix coactivator encoded by the maize genes R or B [6].
• Based on the distribution of putative A1-binding sites in various pre-mRNAs, an A1-mediated change in pre-mRNA conformation may help define the borders of mammalian introns [7].
• Sequence analysis of these revertant alleles indicates that frame-shift mutations abolish A1 gene function, whereas one additional amino acid within the protein sequence still allows wild-type gene expression [8].
• The 40.1-kd A1 protein is an NADPH-dependent reductase [8].

Biological context of RFC4

• The amino acid sequence shows a high degree of homology to the 40-kDa subunit of A1; they both contain the identical ATP-binding motif, but in contrast to the bacterial expressed 40-kDa protein, the 37-kDa expressed protein did not bind ATP [9].
• Mapping of the hnRNP A1 binding site within CYP2A6 3'-UTR reveals that the smallest portion of RNA supporting significant binding consists of 111 central nucleotides of the 3'-UTR [10].
• RESULTS: In the whole group the CCA diameter was correlated with gender (P<0.001), cholesterol (P=0.007), triglycerides (P<0.001), apoB (P<0.001), apoB/A-1 (P<0.001), systolic blood pressure (P=0. 001), and glucose (P=0.006) [11].
• Acetylation and phosphorylation of high-mobility group A1 proteins in PC-3 human tumor cells [12].
• RNA interference targeting of A1 receptor-overexpressing breast carcinoma cells leads to diminished rates of cell proliferation and induction of apoptosis [1].

Anatomical context of RFC4

• A1 receptor mRNA expression is upregulated in all breast tumor cell lines examined (n=7) compared to normal mammary epithelial cells/cell lines (n=3) as determined by quantitative RT-PCR analysis [1].
• To determine if A1 adenosine receptors mediate breast tumorigenesis, we evaluated A1 receptor expression in human tumor cell lines and human primary breast tumor tissues using both quantitative RT-PCR and Western blot analysis [1].
• Monocyte-derived dendritic cells infected with a recombinant canarypoxvirus (ALVAC) containing the entire MAGE-A1 gene were used to stimulate CD8+ T lymphocytes from the blood of individuals without cancer [13].
• As expected from the role of the pyrimidine tract in the translational regulation of TOP mRNAs, the A1 mRNA is more efficiently loaded onto polysomes in growing than in resting cells [14].
• Transformed cell lines exhibit very high (proliferation independent) A1 mRNA levels compared to differentiated tissues [15].

Associations of RFC4 with chemical compounds

• The His563Arg, Ile566Leu, and Asp570Ala mutations also impaired the binding of heparin, which competes with AJvW-2 for binding to A1 [16].
• The hnRNP A1 transcript has a relatively short 5'- untranslated region (UTR) starting with a pyrimidine tract similar to that of mRNAs encoded by the TOP [terminal oligo(pyrimidine)] genes in vertebrates [14].
• Also, dexamethasone increased A1 and decreased Bak mRNA abundance [17].
• A1 adenosine receptor of human and mouse adipose tissues: cloning, expression, and characterization [5].
• By using the positional cloning gene approach, we were able to identify a novel gene encoding for a serine/arginine-rich protein, which appears to be the human homologue of the rat A1 gene [18].

Other interactions of RFC4

• Here we describe the genetic analysis of the rfc2 +gene of the fission yeast Schizosaccharomyces pombe encoding a structural homologue of the budding yeast Rfc2p and human hRFC37 proteins [19].
• Furthermore, RFC37, the third subunit of the RFC complex, competes with RIalpha and displaces it from the RFC40-RIalpha complex [20].
• Antibodies against the 37-kDa protein maximally inhibited (by 50%) the A1-dependent synthesis of DNA by DNA polymerase delta; antibodies against the 40-kDa protein quantitatively inhibited the same reaction [9].
• Our results indicate that the post-transcriptional regulation involves interaction of the hnRNP A1 protein with CYP2A6 mRNA [10].
• Northern blotting confirmed relatively greater expression of replication factor C 37-kDa subunit mRNA in M059J cells compared to M059K cells and reduced expression of DNA ligase IV compared to ligase III in both cell lines independent of irradiation [21].

Analytical, diagnostic and therapeutic context of RFC4

• In women the CCA diameter was correlated with a combined risk factor score (P=0.010), systolic blood pressure (P=0. 033), body mass index (P<0.001), cholesterol (P=0.009), triglycerides (P=0.14), apoB (P=0.002), and apoB/A1 (P=0.003) [11].
• Western blot analysis indicates that protein expression of A1 adenosine receptor is higher in 15 (62.5%) of 24 human primary breast tumor tissues than in matched normal breast tissue [1].
• Gel filtration and analytical ultracentrifugation established that beta A3 and beta A1 both form homodimers [22].
• By immunoprecipitation, a murine monoclonal anti-A antibody precipitated surface-biotin-labelled blood group A1 platelet membrane proteins with electrophoretic characteristics identical to those of GPIb/IX and GPIIb/IIIa [23].
• By immunoblotting of SDS-PAGE separated blood group A1 platelet proteins the monoclonal anti-A antibody bound to proteins with electrophoretic characteristics identical to those of GPIb and GPIIb [23].

References