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Gene Review

RFC4  -  replication factor C (activator 1) 4, 37kDa

Homo sapiens

Synonyms: A1, A1 37 kDa subunit, Activator 1 37 kDa subunit, Activator 1 subunit 4, RF-C 37 kDa subunit, ...
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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


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].


  1. RNA interference targeting of A1 receptor-overexpressing breast carcinoma cells leads to diminished rates of cell proliferation and induction of apoptosis. Mirza, A., Basso, A., Black, S., Malkowski, M., Kwee, L., Pachter, J.A., Lachowicz, J.E., Wang, Y., Liu, S. Cancer Biol. Ther. (2005) [Pubmed]
  2. Retroviral insertions downstream of the heterogeneous nuclear ribonucleoprotein A1 gene in erythroleukemia cells: evidence that A1 is not essential for cell growth. Ben-David, Y., Bani, M.R., Chabot, B., De Koven, A., Bernstein, A. Mol. Cell. Biol. (1992) [Pubmed]
  3. Monoclonal antibodies against the adeno-associated virus type 2 (AAV-2) capsid: epitope mapping and identification of capsid domains involved in AAV-2-cell interaction and neutralization of AAV-2 infection. Wobus, C.E., Hügle-Dörr, B., Girod, A., Petersen, G., Hallek, M., Kleinschmidt, J.A. J. Virol. (2000) [Pubmed]
  4. Serpin A1 is overexpressed in ALK+ anaplastic large cell lymphoma and its expression correlates with extranodal dissemination. Duplantier, M.M., Lamant, L., Sabourdy, F., de Reynies, A., Delsol, G., Espinos, E. Leukemia (2006) [Pubmed]
  5. A1 adenosine receptor of human and mouse adipose tissues: cloning, expression, and characterization. Tatsis-Kotsidis, I., Erlanger, B.F. Biochem. Pharmacol. (1999) [Pubmed]
  6. The myb-homologous P gene controls phlobaphene pigmentation in maize floral organs by directly activating a flavonoid biosynthetic gene subset. Grotewold, E., Drummond, B.J., Bowen, B., Peterson, T. Cell (1994) [Pubmed]
  7. Modulation of exon skipping by high-affinity hnRNP A1-binding sites and by intron elements that repress splice site utilization. Blanchette, M., Chabot, B. EMBO J. (1999) [Pubmed]
  8. Influence of transposable elements on the structure and function of the A1 gene of Zea mays. Schwarz-Sommer, Z., Shepherd, N., Tacke, E., Gierl, A., Rohde, W., Leclercq, L., Mattes, M., Berndtgen, R., Peterson, P.A., Saedler, H. EMBO J. (1987) [Pubmed]
  9. Studies of the cloned 37-kDa subunit of activator 1 (replication factor C) of HeLa cells. Chen, M., Pan, Z.Q., Hurwitz, J. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  10. Interaction of heterogeneous nuclear ribonucleoprotein A1 with cytochrome P450 2A6 mRNA: implications for post-transcriptional regulation of the CYP2A6 gene. Christian, K., Lang, M., Maurel, P., Raffalli-Mathieu, F. Mol. Pharmacol. (2004) [Pubmed]
  11. Carotid artery diameter correlates with risk factors for cardiovascular disease in a population of 55-year-old subjects. Jensen-Urstad, K., Jensen-Urstad, M., Johansson, J. Stroke (1999) [Pubmed]
  12. Acetylation and phosphorylation of high-mobility group A1 proteins in PC-3 human tumor cells. Jiang, X., Wang, Y. Biochemistry (2006) [Pubmed]
  13. Identification of five MAGE-A1 epitopes recognized by cytolytic T lymphocytes obtained by in vitro stimulation with dendritic cells transduced with MAGE-A1. Chaux, P., Luiten, R., Demotte, N., Vantomme, V., Stroobant, V., Traversari, C., Russo, V., Schultz, E., Cornelis, G.R., Boon, T., van der Bruggen, P. J. Immunol. (1999) [Pubmed]
  14. Growth-dependent and growth-independent translation of messengers for heterogeneous nuclear ribonucleoproteins. Camacho-Vanegas, O., Weighardt, F., Ghigna, C., Amaldi, F., Riva, S., Biamonti, G. Nucleic Acids Res. (1997) [Pubmed]
  15. Human hnRNP protein A1 gene expression. Structural and functional characterization of the promoter. Biamonti, G., Bassi, M.T., Cartegni, L., Mechta, F., Buvoli, M., Cobianchi, F., Riva, S. J. Mol. Biol. (1993) [Pubmed]
  16. Shielding the front-strand beta 3 of the von Willebrand factor A1 domain inhibits its binding to platelet glycoprotein Ibalpha. Bonnefoy, A., Yamamoto, H., Thys, C., Kito, M., Vermylen, J., Hoylaerts, M.F. Blood (2003) [Pubmed]
  17. Glucocorticoid modulation of Bcl-2 family members A1 and Bak during delayed spontaneous apoptosis of bovine blood neutrophils. Madsen-Bouterse, S.A., Rosa, G.J., Burton, J.L. Endocrinology (2006) [Pubmed]
  18. Cloning of a gene (SR-A1), encoding for a new member of the human Ser/Arg-rich family of pre-mRNA splicing factors: overexpression in aggressive ovarian cancer. Scorilas, A., Kyriakopoulou, L., Katsaros, D., Diamandis, E.P. Br. J. Cancer (2001) [Pubmed]
  19. A key role for replication factor C in DNA replication checkpoint function in fission yeast. Reynolds, N., Fantes, P.A., MacNeill, S.A. Nucleic Acids Res. (1999) [Pubmed]
  20. The second subunit of the replication factor C complex (RFC40) and the regulatory subunit (RIalpha) of protein kinase A form a protein complex promoting cell survival. Gupte, R.S., Weng, Y., Liu, L., Lee, M.Y. Cell Cycle (2005) [Pubmed]
  21. cDNA expression array analysis of DNA repair genes in human glioma cells that lack or express DNA-PK. Galloway, A.M., Allalunis-Turner, J. Radiat. Res. (2000) [Pubmed]
  22. The elusive role of the N-terminal extension of beta A3- and beta A1-crystallin. Werten, P.J., Carver, J.A., Jaenicke, R., de Jong, W.W. Protein Eng. (1996) [Pubmed]
  23. Blood group A antigen expression in platelets is prominently associated with glycoprotein Ib and IIb. Evidence for an A1/A2 difference. Hou, M., Stockelberg, D., Rydberg, L., Kutti, J., Wadenvik, H. Transfusion medicine (Oxford, England) (1996) [Pubmed]
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