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Gene Review

ref(2)P  -  refractory to sigma P

Drosophila melanogaster

Synonyms: CG10360, Dmel\CG10360, Protein ref(2)P, Ref(2)P, Ref(2)p, ...
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Disease relevance of ref(2)P

  • Molecular analysis of ref(2)P, a Drosophila gene implicated in sigma rhabdovirus multiplication and necessary for male fertility [1].
  • We identified the protein encoded by the ref(2)P gene and produced polyclonal antibodies directed against the whole ref(2)P protein obtained from a recombinant baculovirus and against a part of the protein expressed as a fusion protein [2].
  • The injection of purified Rous sarcoma virus (RSV) (Prague strain) into Drosophila melanogaster (Oregon R line) eggs changes the fly phenotype in certain cases, and RSV-specific sequences can be identified in the Drosophila genome (ref. 1 and preceding paper) [3].

High impact information on ref(2)P

  • Prevalence is estimated to be as high as 1 in 10,000 (ref. 4). We carried out genome-wide linkage exclusion analysis in 12 families with CdLS and identified four candidate regions, of which chromosome 5p13.1 gave the highest multipoint lod score of 2 [4].
  • Previous studies have demonstrated a locus for JP mapping to 18q21.1 (ref. 3) and germline mutations in the homolog of the gene for mothers against decapentaplegic, Drosophila, (MADH4, also known as SMAD4) in several JP families [5].
  • Here we show that the epigenetic activator Ash1 (ref. 5) is a multi-catalytic histone methyl-transferase (HMTase) that methylates lysine residues 4 and 9 in H3 and 20 in H4 [6].
  • Here we report that Cnd2 (ref. 6), a non-SMC subunit of fission yeast similar to Drosophila Barren and the budding yeast protein Brn1 (refs 8, 9), is required for both interphase and mitotic condensation [7].
  • The N terminus of syntaxin also binds the presynaptic protein UNC-13 (ref. 5). Studies in mouse, Drosophila and Caenorhabditis elegans suggest that UNC-13 functions at a post-docking step of exocytosis, most likely during synaptic vesicle priming [8].

Biological context of ref(2)P

  • The putative ref(2)P protein contains internal repeats, PEST regions which may be signals for protein degradation, and interesting structural motifs such as zinc finger and amphiphilic helices [1].
  • The amino acid sequence of the ref(2)P product shows no homology with any known protein from the data banks [1].
  • Molecular population genetics of ref(2)P, a locus which confers viral resistance in Drosophila [9].
  • Nevertheless, nucleotide sequence comparison with the Drosophila erecta ref(2)P gene shows that selective pressures are exerted to maintain the existence of a functional protein [10].
  • (ii) They were modified in the N protein of the haP7 sigma virus mutant selected as being adapted to the restrictive alleles of the ref(2)P gene; only one mutation in the N gene, leading to an amino acid substitution, distinguished the haP7 mutant from the original virus [11].

Anatomical context of ref(2)P

  • Using expression cloning, we have isolated a complementary DNA clone from a BALB/c 3T3 mouse fibroblast variant, A31-I-13 (ref. 10), which specifies a factor determining the susceptibility of BALB/c3T3 to chemically and physically induced transformation [12].
  • Posterior activity can be recovered at an early stage (stage 10, ref. 5) from the oocyte-nurse cell complex, but anterior activity can only be detected in the mature oocytes (stage 14) [13].

Associations of ref(2)P with chemical compounds

  • Loss-of-function alleles of ref(2)P (called null) were selected following DEB mutagenesis [14].
  • This probably stimulates p21ras activity through the mammalian homologue of the Drosophila guanine-nucleotide-exchange factor Sos (reviewed in ref. 11) [15].

Other interactions of ref(2)P

  • The unusual variability of the ref(2)P locus was confirmed by the high ratio of amino acid replacements to synonymous mutations (7:1), as compared to that of other genes, such as the Adh (2:42) [10].
  • Here we report the nucleotide sequence of TcD37 and the similarity of its deduced protein product to the catalytic domain of mammalian GTPase-activating proteins (GAPs); GAPs stimulate the GTPase activity of Ras (ref. 6), which are plasma membrane-bound proteins involved in the regulation of cell proliferation and differentiation [16].

Analytical, diagnostic and therapeutic context of ref(2)P

  • Genetic analysis and cytoplasmic transplantation experiments suggested that these maternal genes are required to generate a 'posterior activity' that is thought to activate the expression of kni (reviewed in ref. 2). The molecular nature of the members of the posterior group is still unknown [17].
  • Using cloned cDNA probes of the Antp+ (ref. 6) locus and an improved in situ hybridization method, we found that the neural cells of the embryonic and larval mesothorax possess higher levels of Antp+ transcripts than the neural tissue of the other segments [18].


  1. Molecular analysis of ref(2)P, a Drosophila gene implicated in sigma rhabdovirus multiplication and necessary for male fertility. Dezelee, S., Bras, F., Contamine, D., Lopez-Ferber, M., Segretain, D., Teninges, D. EMBO J. (1989) [Pubmed]
  2. Immunological cross-reactions and interactions between the Drosophila melanogaster ref(2)P protein and sigma rhabdovirus proteins. Wyers, F., Dru, P., Simonet, B., Contamine, D. J. Virol. (1993) [Pubmed]
  3. Detection of virus-specific sequences in Drosophila melanogaster mutants induced by injection of RSV DNA into early embryos. Tatosyan, A.G., Nabirochkin, S.D., Shakhbazyan, A.K., Gazaryan, K.G., Kisseljov, F.L. Nature (1984) [Pubmed]
  4. Cornelia de Lange syndrome is caused by mutations in NIPBL, the human homolog of Drosophila melanogaster Nipped-B. Krantz, I.D., McCallum, J., DeScipio, C., Kaur, M., Gillis, L.A., Yaeger, D., Jukofsky, L., Wasserman, N., Bottani, A., Morris, C.A., Nowaczyk, M.J., Toriello, H., Bamshad, M.J., Carey, J.C., Rappaport, E., Kawauchi, S., Lander, A.D., Calof, A.L., Li, H.H., Devoto, M., Jackson, L.G. Nat. Genet. (2004) [Pubmed]
  5. Germline mutations of the gene encoding bone morphogenetic protein receptor 1A in juvenile polyposis. Howe, J.R., Bair, J.L., Sayed, M.G., Anderson, M.E., Mitros, F.A., Petersen, G.M., Velculescu, V.E., Traverso, G., Vogelstein, B. Nat. Genet. (2001) [Pubmed]
  6. Histone methylation by the Drosophila epigenetic transcriptional regulator Ash1. Beisel, C., Imhof, A., Greene, J., Kremmer, E., Sauer, F. Nature (2002) [Pubmed]
  7. Cnd2 has dual roles in mitotic condensation and interphase. Aono, N., Sutani, T., Tomonaga, T., Mochida, S., Yanagida, M. Nature (2002) [Pubmed]
  8. An open form of syntaxin bypasses the requirement for UNC-13 in vesicle priming. Richmond, J.E., Weimer, R.M., Jorgensen, E.M. Nature (2001) [Pubmed]
  9. Molecular population genetics of ref(2)P, a locus which confers viral resistance in Drosophila. Wayne, M.L., Contamine, D., Kreitman, M. Mol. Biol. Evol. (1996) [Pubmed]
  10. Unusual variability of the Drosophila melanogaster ref(2)P protein which controls the multiplication of sigma rhabdovirus. Dru, P., Bras, F., Dezélée, S., Gay, P., Petitjean, A.M., Pierre-Deneubourg, A., Teninges, D., Contamine, D. Genetics (1993) [Pubmed]
  11. Localization of domains within the Drosophila Ref(2)P protein involved in the intracellular control of sigma rhabdovirus multiplication. Wyers, F., Petitjean, A.M., Dru, P., Gay, P., Contamine, D. J. Virol. (1995) [Pubmed]
  12. Elongation factor-1 alpha gene determines susceptibility to transformation. Tatsuka, M., Mitsui, H., Wada, M., Nagata, A., Nojima, H., Okayama, H. Nature (1992) [Pubmed]
  13. Drosophila nurse cells produce a posterior signal required for embryonic segmentation and polarity. Sander, K., Lehmann, R. Nature (1988) [Pubmed]
  14. Study of the ref(2)P locus of Drosophila melanogaster. II. Genetic studies of the 37DF region. Gay, P., Contamine, D. Mol. Gen. Genet. (1993) [Pubmed]
  15. Transformation by polyoma virus middle T-antigen involves the binding and tyrosine phosphorylation of Shc. Dilworth, S.M., Brewster, C.E., Jones, M.D., Lanfrancone, L., Pelicci, G., Pelicci, P.G. Nature (1994) [Pubmed]
  16. A product of the prune locus of Drosophila is similar to mammalian GTPase-activating protein. Teng, D.H., Engele, C.M., Venkatesh, T.R. Nature (1991) [Pubmed]
  17. Abdominal segmentation of the Drosophila embryo requires a hormone receptor-like protein encoded by the gap gene knirps. Nauber, U., Pankratz, M.J., Kienlin, A., Seifert, E., Klemm, U., Jäckle, H. Nature (1988) [Pubmed]
  18. Regulation of Antennapedia transcript distribution by the bithorax complex in Drosophila. Hafen, E., Levine, M., Gehring, W.J. Nature (1984) [Pubmed]
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