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Gene Review

ORF1  -  uncharacterized protein, clone pT-Adv JuaX22

Homo sapiens

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Disease relevance of ORF1

  • ORF1 encoded a retrovirus-like major homology region and a Cys/His box motif, also present in Gag polyproteins of related retrotransposons and retroviruses [1].
  • Interestingly, in contrast to other adenoviruses, in which oncogenic viral functions are entirely encoded within the E1 region, Ad9 requires an E4 region transforming protein (ORF1) for its unique mammary oncogenicity [2].
  • Adenovirus type 9 (Ad9) is distinct among human adenoviruses because it elicits solely mammary tumors in animals and its primary oncogenic determinant is the E4 region-encoded ORF1 (E4-ORF1) protein [3].
  • P40 is the protein encoded by the first open reading frame (ORF1) of the human LINE-1 (L1Hs) retrotransposon; it is 338 amino acids long, has a leucine zipper motif and has been found in human teratocarcinoma cell lines and some tumor cells [4].
  • VP10, a minor structural protein of the calicivirus rabbit hemorrhagic disease virus, is encoded in the small 3'-terminal open reading frame (ORF) 2 and is translated with an efficiency of approximately 20% of the preceding ORF1 [5].

High impact information on ORF1

  • Using a site-directed mutagenesis approach, we found that this clone recognized a transframe epitope generated by an internal +1 frameshifting in the IL-10 sequence and so derived partly from ORF1, partly from ORF2 [6].
  • Based on our results, we propose a model wherein E4-ORF1 binding to Dlg1 triggers the resulting complex to translocate to the plasma membrane and, at this site, to promote Ras-mediated PI3K activation [7].
  • Despite a general belief that such interactions function solely to inactivate this suspected human tumor suppressor protein, we demonstrate here that E4-ORF1 specifically requires endogenous Dlg1 to provoke oncogenic activation of phosphatidylinositol 3-kinase (PI3K) in cells [7].
  • The retrotransposition requires conserved domains in both open reading frames (ORFs), including the ORF1 cysteine- histidine motifs [8].
  • Link of the unique oncogenic properties of adenovirus type 9 E4-ORF1 to a select interaction with the candidate tumor suppressor protein ZO-2 [3].

Chemical compound and disease context of ORF1


Biological context of ORF1

  • A nucleotide alignment of 10 full-length SaV genome sequences was subjected to similarity plot analysis, which indicated that the most conserved site was the polymerase-capsid junction in open reading frame 1 (ORF1) [14].
  • Although the predicted amino acid sequence of ORF1 is not closely related to any known proteins, it is highly basic; thus, it has long been hypothesized that ORF1 protein functions to bind LINE-1 (L1) RNA during retrotransposition [15].
  • We found that novel (i.e., unrelated) regulatory regions (5'UTR) have been frequently recruited during the evolution of L1, whereas the two open-reading frames (ORF1 and ORF2) have remained relatively conserved [16].
  • The RNA sequence of the 3'-terminal 84 nucleotides of ORF1 but not the encoded peptide was found to be crucial for VP10 expression [5].
  • One of gene products (ORF1) catalyzed the methylation reactions of glycine and sarcosine with S-adenosylmethionine acting as the methyl donor [17].

Anatomical context of ORF1

  • The results are compatible with a model for ORF1 translation initiation in which the majority of ribosomes scan from a point 5' of nt 661 but suggest that ORF2 is not translated by attached ribosomes that reinitiate after the termination of ORF1 translation [18].
  • The presence of both ORF1- and ORF2-encoded proteins in vascular endothelial cells and its apparent association with certain stages of differentiation and maturation of blood vessels may have functional relevance for vasculogenesis and/or angiogenesis [19].
  • The ORF1 polypeptide targets EGFP to cytosol and nucleus whereas ORF2 targets EGFP to mitochondria [20].
  • Immunohistochemical analyses revealed coexpression of ORF1 and ORF2 in prespermatogonia of fetal testis, in germ cells of adult testis, and in distinct somatic cell types, such as Leydig, Sertoli, and vascular endothelial cells [19].
  • While PDZ domain-containing proteins represent cellular targets for several different viral oncoproteins, including human papillomavirus E6, human T-cell leukemia virus type 1 Tax, and human adenovirus E4-ORF1, the functional consequences for such interactions have not been elucidated [21].

Associations of ORF1 with chemical compounds

  • This protein, termed Tip (tyrosine kinase interacting protein), is identified as a viral protein encoded by the open reading frame 1 (ORF1) [22].
  • Disruption of ORF1 with a chloramphenicol-resistance cassette (CAT) rendered the H. pylori mutants more susceptible to cupric ion than their parental strains, whereas there is no significant alteration of susceptibility to Ni2+, Cd2d+ and Hg2+ between the mutants and the parental strains [23].
  • The first open reading frame (ORF1) of PsCR1 has two unusual arrangements of Cys residues [24].
  • Rather, the lysine substitutions alter the delicate balance between the ORF1 protein's melting and reannealing activities, thereby reducing its nucleic acid chaperone activity [25].
  • An in-frame fusion of ORF1 to the malE gene of the expression vector, pMAL-c2, yielded a protein that was immunostained with antibodies raised against the maltose binding protein and A. naeslundii T14V whole bacteria [26].

Other interactions of ORF1

  • Galectin-3 mRNA and L1-related ORF1/ p40 protein showed similar expression patterns [27].
  • The induction of p38delta appears to be mediated by an ORF1/p40-dependent process [28].
  • The fact that several different human virus oncoproteins, including adenovirus type 9 E4-ORF1, evolved to target the Dlg1 mammalian homolog of the membrane-associated Drosophila discs-large tumor suppressor has implicated this cellular factor in human cancer [7].
  • Two ORFs were predicted within human MGC9753 mRNA, and ORF1 (nucleotide position 18-980 of NM_033419.1) was predicted as the coding region of human MGC9753 mRNA based on comparative genomics [29].
  • A database search revealed that 2P1 was 91% identical to ORF1 of E3-3, a rat gene probably involved in the regulation of alternative splicing [30].

Analytical, diagnostic and therapeutic context of ORF1


  1. Boudicca, a retrovirus-like long terminal repeat retrotransposon from the genome of the human blood fluke Schistosoma mansoni. Copeland, C.S., Brindley, P.J., Heyers, O., Michael, S.F., Johnston, D.A., Williams, D.L., Ivens, A.C., Kalinna, B.H. J. Virol. (2003) [Pubmed]
  2. Mammary tumors induced by human adenovirus type 9: a role for the viral early region 4 gene. Javier, R., Shenk, T. Breast Cancer Res. Treat. (1996) [Pubmed]
  3. Link of the unique oncogenic properties of adenovirus type 9 E4-ORF1 to a select interaction with the candidate tumor suppressor protein ZO-2. Glaunsinger, B.A., Weiss, R.S., Lee, S.S., Javier, R. EMBO J. (2001) [Pubmed]
  4. Cytoplasmic ribonucleoprotein complexes containing human LINE-1 protein and RNA. Hohjoh, H., Singer, M.F. EMBO J. (1996) [Pubmed]
  5. Translation of the minor capsid protein of a calicivirus is initiated by a novel termination-dependent reinitiation mechanism. Meyers, G. J. Biol. Chem. (2003) [Pubmed]
  6. +1 Frameshifting as a novel mechanism to generate a cryptic cytotoxic T lymphocyte epitope derived from human interleukin 10. Saulquin, X., Scotet, E., Trautmann, L., Peyrat, M.A., Halary, F., Bonneville, M., Houssaint, E. J. Exp. Med. (2002) [Pubmed]
  7. Oncogenic function for the Dlg1 mammalian homolog of the Drosophila discs-large tumor suppressor. Frese, K.K., Latorre, I.J., Chung, S.H., Caruana, G., Bernstein, A., Jones, S.N., Donehower, L.A., Justice, M.J., Garner, C.C., Javier, R.T. EMBO J. (2006) [Pubmed]
  8. Transplantation of target site specificity by swapping the endonuclease domains of two LINEs. Takahashi, H., Fujiwara, H. EMBO J. (2002) [Pubmed]
  9. Early region 1 transforming functions are dispensable for mammary tumorigenesis by human adenovirus type 9. Thomas, D.L., Shin, S., Jiang, B.H., Vogel, H., Ross, M.A., Kaplitt, M., Shenk, T.E., Javier, R.T. J. Virol. (1999) [Pubmed]
  10. A picorna-like virus from the red imported fire ant, Solenopsis invicta: initial discovery, genome sequence, and characterization. Valles, S.M., Strong, C.A., Dang, P.M., Hunter, W.B., Pereira, R.M., Oi, D.H., Shapiro, A.M., Williams, D.F. Virology (2004) [Pubmed]
  11. The nodD locus from Azorhizobium caulinodans is flanked by two repetitive elements. Geelen, D., Goethals, K., Van Montagu, M., Holsters, M. Gene (1995) [Pubmed]
  12. Regulated expression of the Streptococcus mutans dlt genes correlates with intracellular polysaccharide accumulation. Spatafora, G.A., Sheets, M., June, R., Luyimbazi, D., Howard, K., Hulbert, R., Barnard, D., el Janne, M., Hudson, M.C. J. Bacteriol. (1999) [Pubmed]
  13. Orchid fleck virus is a rhabdovirus with an unusual bipartite genome. Kondo, H., Maeda, T., Shirako, Y., Tamada, T. J. Gen. Virol. (2006) [Pubmed]
  14. Detection of human sapovirus by real-time reverse transcription-polymerase chain reaction. Oka, T., Katayama, K., Hansman, G.S., Kageyama, T., Ogawa, S., Wu, F.T., White, P.A., Takeda, N. J. Med. Virol. (2006) [Pubmed]
  15. In vitro properties of the first ORF protein from mouse LINE-1 support its role in ribonucleoprotein particle formation during retrotransposition. Kolosha, V.O., Martin, S.L. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  16. Molecular evolution and tempo of amplification of human LINE-1 retrotransposons since the origin of primates. Khan, H., Smit, A., Boissinot, S. Genome Res. (2006) [Pubmed]
  17. Isolation and functional characterization of N-methyltransferases that catalyze betaine synthesis from glycine in a halotolerant photosynthetic organism Aphanothece halophytica. Waditee, R., Tanaka, Y., Aoki, K., Hibino, T., Jikuya, H., Takano, J., Takabe, T., Takabe, T. J. Biol. Chem. (2003) [Pubmed]
  18. Translation of the human LINE-1 element, L1Hs. McMillan, J.P., Singer, M.F. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  19. Cell type-specific expression of LINE-1 open reading frames 1 and 2 in fetal and adult human tissues. Ergün, S., Buschmann, C., Heukeshoven, J., Dammann, K., Schnieders, F., Lauke, H., Chalajour, F., Kilic, N., Strätling, W.H., Schumann, G.G. J. Biol. Chem. (2004) [Pubmed]
  20. Identification of an internal gene to the human Galectin-3 gene with two different overlapping reading frames that do not encode Galectin-3. Guittaut, M., Charpentier, S., Normand, T., Dubois, M., Raimond, J., Legrand, A. J. Biol. Chem. (2001) [Pubmed]
  21. Selective PDZ protein-dependent stimulation of phosphatidylinositol 3-kinase by the adenovirus E4-ORF1 oncoprotein. Frese, K.K., Lee, S.S., Thomas, D.L., Latorre, I.J., Weiss, R.S., Glaunsinger, B.A., Javier, R.T. Oncogene (2003) [Pubmed]
  22. The product of the Herpesvirus saimiri open reading frame 1 (tip) interacts with T cell-specific kinase p56lck in transformed cells. Biesinger, B., Tsygankov, A.Y., Fickenscher, H., Emmrich, F., Fleckenstein, B., Bolen, J.B., Bröker, B.M. J. Biol. Chem. (1995) [Pubmed]
  23. Nucleotide sequence and mutational analysis indicate that two Helicobacter pylori genes encode a P-type ATPase and a cation-binding protein associated with copper transport. Ge, Z., Hiratsuka, K., Taylor, D.E. Mol. Microbiol. (1995) [Pubmed]
  24. Determination of the entire sequence of turtle CR1: the first open reading frame of the turtle CR1 element encodes a protein with a novel zinc finger motif. Kajikawa, M., Ohshima, K., Okada, N. Mol. Biol. Evol. (1997) [Pubmed]
  25. LINE-1 retrotransposition requires the nucleic acid chaperone activity of the ORF1 protein. Martin, S.L., Cruceanu, M., Branciforte, D., Wai-Lun Li, P., Kwok, S.C., Hodges, R.S., Williams, M.C. J. Mol. Biol. (2005) [Pubmed]
  26. Synthesis and function of Actinomyces naeslundii T14V type 1 fimbriae require the expression of additional fimbria-associated genes. Yeung, M.K., Ragsdale, P.A. Infect. Immun. (1997) [Pubmed]
  27. Retrotransposable L1 elements expressed in rheumatoid arthritis synovial tissue: association with genomic DNA hypomethylation and influence on gene expression. Neidhart, M., Rethage, J., Kuchen, S., Künzler, P., Crowl, R.M., Billingham, M.E., Gay, R.E., Gay, S. Arthritis Rheum. (2000) [Pubmed]
  28. The L1 retroelement-related p40 protein induces p38delta MAP kinase. Kuchen, S., Seemayer, C.A., Rethage, J., von Knoch, R., Kuenzler, P., Beat, A.M., Gay, R.E., Gay, S., Neidhart, M. Autoimmunity (2004) [Pubmed]
  29. MGC9753 gene, located within PPP1R1B-STARD3-ERBB2-GRB7 amplicon on human chromosome 17q12, encodes the seven-transmembrane receptor with extracellular six-cystein domain. Katoh, M., Katoh, M. Int. J. Oncol. (2003) [Pubmed]
  30. 2P1, a novel male mouse cDNA specifically expressed during meiosis. Hammami-Hamza, S., Doussau, M., Allemand, I., Segretain, D., Gasc, J.M., Finaz, C. Int. J. Dev. Biol. (2003) [Pubmed]
  31. Sequence heterogeneity of TT virus and closely related viruses. Khudyakov, Y.E., Cong, M.E., Nichols, B., Reed, D., Dou, X.G., Viazov, S.O., Chang, J., Fried, M.W., Williams, I., Bower, W., Lambert, S., Purdy, M., Roggendorf, M., Fields, H.A. J. Virol. (2000) [Pubmed]
  32. Conservation and developmental control of alternative splicing in maebl among malaria parasites. Singh, N., Preiser, P., Rénia, L., Balu, B., Barnwell, J., Blair, P., Jarra, W., Voza, T., Landau, I., Adams, J.H. J. Mol. Biol. (2004) [Pubmed]
  33. Norwalk virus N-terminal nonstructural protein is associated with disassembly of the Golgi complex in transfected cells. Fernandez-Vega, V., Sosnovtsev, S.V., Belliot, G., King, A.D., Mitra, T., Gorbalenya, A., Green, K.Y. J. Virol. (2004) [Pubmed]
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