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. 1997 Mar;17(3):1490–1502. doi: 10.1128/mcb.17.3.1490

bic, a novel gene activated by proviral insertions in avian leukosis virus-induced lymphomas, is likely to function through its noncoding RNA.

W Tam 1, D Ben-Yehuda 1, W S Hayward 1
PMCID: PMC231875  PMID: 9032277

Abstract

The bic locus is a common retroviral integration site in avian leukosis virus (ALV)-induced B-cell lymphomas originally identified by infection of chickens with ALVs of two different subgroups (Clurman and Hayward, Mol. Cell. Biol. 9:2657-2664, 1989). Based on its frequent association with c-myc activation and its preferential activation in metastatic tumors, the bic locus is thought to harbor a gene that can collaborate with c-myc in lymphomagenesis and presumably plays a role in late stages of tumor progression. In the present study, we have cloned and characterized two novel genes, bdw and bic, at the bic locus. bdw encoded a putative novel protein of 345 amino acids. However, its expression did not appear to be altered in tumor tissues, suggesting that it is not involved in oncogenesis. The bic gene consisted of two exons and was expressed as two spliced and alternatively polyadenylated transcripts at low levels in lymphoid/hematopoietic tissues. In tumors harboring bic integrations, proviruses drove bic gene expression by promoter insertion, resulting in high levels of expression of a chimeric RNA containing bic exon 2. Interestingly, bic lacked an extensive open reading frame, implying that it may function through its RNA. Computer analysis of RNA from small exon 2 of bic predicted extensive double-stranded structures, including a highly ordered RNA duplex between nucleotides 316 and 461. The possible role of bic in cell growth and differentiation is discussed in view of the emerging evidence that untranslated RNAs play a role in growth control.

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Selected References

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  1. Adams J. M., Cory S. Oncogene co-operation in leukaemogenesis. Cancer Surv. 1992;15:119–141. [PubMed] [Google Scholar]
  2. Adams J. M., Harris A. W., Pinkert C. A., Corcoran L. M., Alexander W. S., Cory S., Palmiter R. D., Brinster R. L. The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice. Nature. 1985 Dec 12;318(6046):533–538. doi: 10.1038/318533a0. [DOI] [PubMed] [Google Scholar]
  3. Alexander W. S., Bernard O., Cory S., Adams J. M. Lymphomagenesis in E mu-myc transgenic mice can involve ras mutations. Oncogene. 1989 May;4(5):575–581. [PubMed] [Google Scholar]
  4. Altschul S. F., Gish W., Miller W., Myers E. W., Lipman D. J. Basic local alignment search tool. J Mol Biol. 1990 Oct 5;215(3):403–410. doi: 10.1016/S0022-2836(05)80360-2. [DOI] [PubMed] [Google Scholar]
  5. Askew D. S., Li J., Ihle J. N. Retroviral insertions in the murine His-1 locus activate the expression of a novel RNA that lacks an extensive open reading frame. Mol Cell Biol. 1994 Mar;14(3):1743–1751. doi: 10.1128/mcb.14.3.1743. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Baba T. W., Humphries E. H. Formation of a transformed follicle is necessary but not sufficient for development of an avian leukosis virus-induced lymphoma. Proc Natl Acad Sci U S A. 1985 Jan;82(1):213–216. doi: 10.1073/pnas.82.1.213. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Brannan C. I., Dees E. C., Ingram R. S., Tilghman S. M. The product of the H19 gene may function as an RNA. Mol Cell Biol. 1990 Jan;10(1):28–36. doi: 10.1128/mcb.10.1.28. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Brockdorff N., Ashworth A., Kay G. F., McCabe V. M., Norris D. P., Cooper P. J., Swift S., Rastan S. The product of the mouse Xist gene is a 15 kb inactive X-specific transcript containing no conserved ORF and located in the nucleus. Cell. 1992 Oct 30;71(3):515–526. doi: 10.1016/0092-8674(92)90519-i. [DOI] [PubMed] [Google Scholar]
  9. Brown C. J., Hendrich B. D., Rupert J. L., Lafrenière R. G., Xing Y., Lawrence J., Willard H. F. The human XIST gene: analysis of a 17 kb inactive X-specific RNA that contains conserved repeats and is highly localized within the nucleus. Cell. 1992 Oct 30;71(3):527–542. doi: 10.1016/0092-8674(92)90520-m. [DOI] [PubMed] [Google Scholar]
  10. Brunkow M. E., Tilghman S. M. Ectopic expression of the H19 gene in mice causes prenatal lethality. Genes Dev. 1991 Jun;5(6):1092–1101. doi: 10.1101/gad.5.6.1092. [DOI] [PubMed] [Google Scholar]
  11. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  12. Clemens M. J., Laing K. G., Jeffrey I. W., Schofield A., Sharp T. V., Elia A., Matys V., James M. C., Tilleray V. J. Regulation of the interferon-inducible eIF-2 alpha protein kinase by small RNAs. Biochimie. 1994;76(8):770–778. doi: 10.1016/0300-9084(94)90081-7. [DOI] [PubMed] [Google Scholar]
  13. Clemson C. M., McNeil J. A., Willard H. F., Lawrence J. B. XIST RNA paints the inactive X chromosome at interphase: evidence for a novel RNA involved in nuclear/chromosome structure. J Cell Biol. 1996 Feb;132(3):259–275. doi: 10.1083/jcb.132.3.259. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Clurman B. E., Hayward W. S. Multiple proto-oncogene activations in avian leukosis virus-induced lymphomas: evidence for stage-specific events. Mol Cell Biol. 1989 Jun;9(6):2657–2664. doi: 10.1128/mcb.9.6.2657. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Cooper M. D., Payne L. N., Dent P. B., Burmester B. R., Good R. A. Pathogenesis of avian lymphoid leukosis. I. Histogenesis. J Natl Cancer Inst. 1968 Aug;41(2):373–378. [PubMed] [Google Scholar]
  16. Cory S., Adams J. M. Transgenic mice and oncogenesis. Annu Rev Immunol. 1988;6:25–48. doi: 10.1146/annurev.iy.06.040188.000325. [DOI] [PubMed] [Google Scholar]
  17. Davis S., Watson J. C. In vitro activation of the interferon-induced, double-stranded RNA-dependent protein kinase PKR by RNA from the 3' untranslated regions of human alpha-tropomyosin. Proc Natl Acad Sci U S A. 1996 Jan 9;93(1):508–513. doi: 10.1073/pnas.93.1.508. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Douc-Rasy S., Barrois M., Fogel S., Ahomadegbe J. C., Stéhelin D., Coll J., Riou G. High incidence of loss of heterozygosity and abnormal imprinting of H19 and IGF2 genes in invasive cervical carcinomas. Uncoupling of H19 and IGF2 expression and biallelic hypomethylation of H19. Oncogene. 1996 Jan 18;12(2):423–430. [PubMed] [Google Scholar]
  19. Edwards J. B., Delort J., Mallet J. Oligodeoxyribonucleotide ligation to single-stranded cDNAs: a new tool for cloning 5' ends of mRNAs and for constructing cDNA libraries by in vitro amplification. Nucleic Acids Res. 1991 Oct 11;19(19):5227–5232. doi: 10.1093/nar/19.19.5227. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Ewert D. L., de Boer G. F. Avian lymphoid leukosis: mechanisms of lymphomagenesis. Adv Vet Sci Comp Med. 1988;32:37–55. doi: 10.1016/b978-0-12-039232-2.50006-2. [DOI] [PubMed] [Google Scholar]
  21. Farabaugh P. J. Alternative readings of the genetic code. Cell. 1993 Aug 27;74(4):591–596. doi: 10.1016/0092-8674(93)90507-M. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Feinberg A. P., Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem. 1983 Jul 1;132(1):6–13. doi: 10.1016/0003-2697(83)90418-9. [DOI] [PubMed] [Google Scholar]
  23. Fini M. E., Bendena W. G., Pardue M. L. Unusual behavior of the cytoplasmic transcript of hsr omega: an abundant, stress-inducible RNA that is translated but yields no detectable protein product. J Cell Biol. 1989 Jun;108(6):2045–2057. doi: 10.1083/jcb.108.6.2045. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Frohman M. A., Dush M. K., Martin G. R. Rapid production of full-length cDNAs from rare transcripts: amplification using a single gene-specific oligonucleotide primer. Proc Natl Acad Sci U S A. 1988 Dec;85(23):8998–9002. doi: 10.1073/pnas.85.23.8998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Hao Y., Crenshaw T., Moulton T., Newcomb E., Tycko B. Tumour-suppressor activity of H19 RNA. Nature. 1993 Oct 21;365(6448):764–767. doi: 10.1038/365764a0. [DOI] [PubMed] [Google Scholar]
  26. Haupt Y., Alexander W. S., Barri G., Klinken S. P., Adams J. M. Novel zinc finger gene implicated as myc collaborator by retrovirally accelerated lymphomagenesis in E mu-myc transgenic mice. Cell. 1991 May 31;65(5):753–763. doi: 10.1016/0092-8674(91)90383-a. [DOI] [PubMed] [Google Scholar]
  27. Haupt Y., Bath M. L., Harris A. W., Adams J. M. bmi-1 transgene induces lymphomas and collaborates with myc in tumorigenesis. Oncogene. 1993 Nov;8(11):3161–3164. [PubMed] [Google Scholar]
  28. Haupt Y., Harris A. W., Adams J. M. Moloney virus induction of T-cell lymphomas in a plasmacytomagenic strain of E mu-v-abl transgenic mice. Int J Cancer. 1993 Oct 21;55(4):623–629. doi: 10.1002/ijc.2910550418. [DOI] [PubMed] [Google Scholar]
  29. Hayward W. S., Neel B. G., Astrin S. M. Activation of a cellular onc gene by promoter insertion in ALV-induced lymphoid leukosis. Nature. 1981 Apr 9;290(5806):475–480. doi: 10.1038/290475a0. [DOI] [PubMed] [Google Scholar]
  30. Hibi K., Nakamura H., Hirai A., Fujikake Y., Kasai Y., Akiyama S., Ito K., Takagi H. Loss of H19 imprinting in esophageal cancer. Cancer Res. 1996 Feb 1;56(3):480–482. [PubMed] [Google Scholar]
  31. Humphrey T., Proudfoot N. J. A beginning to the biochemistry of polyadenylation. Trends Genet. 1988 Sep;4(9):243–245. doi: 10.1016/0168-9525(88)90028-5. [DOI] [PubMed] [Google Scholar]
  32. Kay G. F., Penny G. D., Patel D., Ashworth A., Brockdorff N., Rastan S. Expression of Xist during mouse development suggests a role in the initiation of X chromosome inactivation. Cell. 1993 Jan 29;72(2):171–182. doi: 10.1016/0092-8674(93)90658-d. [DOI] [PubMed] [Google Scholar]
  33. Kondo M., Suzuki H., Ueda R., Osada H., Takagi K., Takahashi T., Takahashi T. Frequent loss of imprinting of the H19 gene is often associated with its overexpression in human lung cancers. Oncogene. 1995 Mar 16;10(6):1193–1198. [PubMed] [Google Scholar]
  34. Koromilas A. E., Cantin C., Craig A. W., Jagus R., Hiscott J., Sonenberg N. The interferon-inducible protein kinase PKR modulates the transcriptional activation of immunoglobulin kappa gene. J Biol Chem. 1995 Oct 27;270(43):25426–25434. doi: 10.1074/jbc.270.43.25426. [DOI] [PubMed] [Google Scholar]
  35. Koromilas A. E., Roy S., Barber G. N., Katze M. G., Sonenberg N. Malignant transformation by a mutant of the IFN-inducible dsRNA-dependent protein kinase. Science. 1992 Sep 18;257(5077):1685–1689. doi: 10.1126/science.1382315. [DOI] [PubMed] [Google Scholar]
  36. Kozak M. Effects of intercistronic length on the efficiency of reinitiation by eucaryotic ribosomes. Mol Cell Biol. 1987 Oct;7(10):3438–3445. doi: 10.1128/mcb.7.10.3438. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Kozak M. Structural features in eukaryotic mRNAs that modulate the initiation of translation. J Biol Chem. 1991 Oct 25;266(30):19867–19870. [PubMed] [Google Scholar]
  38. Kozak M. The scanning model for translation: an update. J Cell Biol. 1989 Feb;108(2):229–241. doi: 10.1083/jcb.108.2.229. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Kumar A., Haque J., Lacoste J., Hiscott J., Williams B. R. Double-stranded RNA-dependent protein kinase activates transcription factor NF-kappa B by phosphorylating I kappa B. Proc Natl Acad Sci U S A. 1994 Jul 5;91(14):6288–6292. doi: 10.1073/pnas.91.14.6288. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Langdon W. Y., Harris A. W., Cory S. Acceleration of B-lymphoid tumorigenesis in E mu-myc transgenic mice by v-H-ras and v-raf but not v-abl. Oncogene Res. 1989;4(4):253–258. [PubMed] [Google Scholar]
  41. Largaespada D. A., Kaehler D. A., Mishak H., Weissinger E., Potter M., Mushinski J. F., Risser R. A retrovirus that expresses v-abl and c-myc oncogenes rapidly induces plasmacytomas. Oncogene. 1992 Apr;7(4):811–819. [PubMed] [Google Scholar]
  42. McCarrey J. R., Dilworth D. D. Expression of Xist in mouse germ cells correlates with X-chromosome inactivation. Nat Genet. 1992 Nov;2(3):200–203. doi: 10.1038/ng1192-200. [DOI] [PubMed] [Google Scholar]
  43. McDonnell T. J., Korsmeyer S. J. Progression from lymphoid hyperplasia to high-grade malignant lymphoma in mice transgenic for the t(14; 18). Nature. 1991 Jan 17;349(6306):254–256. doi: 10.1038/349254a0. [DOI] [PubMed] [Google Scholar]
  44. Meurs E. F., Galabru J., Barber G. N., Katze M. G., Hovanessian A. G. Tumor suppressor function of the interferon-induced double-stranded RNA-activated protein kinase. Proc Natl Acad Sci U S A. 1993 Jan 1;90(1):232–236. doi: 10.1073/pnas.90.1.232. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Neiman P. E. Retrovirus-induced B cell neoplasia in the bursa of Fabricius. Adv Immunol. 1994;56:467–484. doi: 10.1016/s0065-2776(08)60457-5. [DOI] [PubMed] [Google Scholar]
  46. Neiman P. E., Thomas S. J., Loring G. Induction of apoptosis during normal and neoplastic B-cell development in the bursa of Fabricius. Proc Natl Acad Sci U S A. 1991 Jul 1;88(13):5857–5861. doi: 10.1073/pnas.88.13.5857. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Neiman P., Wolf C., Enrietto P. J., Cooper G. M. A retroviral myc gene induces preneoplastic transformation of lymphocytes in a bursal transplantation assay. Proc Natl Acad Sci U S A. 1985 Jan;82(1):222–226. doi: 10.1073/pnas.82.1.222. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Pearson W. R., Lipman D. J. Improved tools for biological sequence comparison. Proc Natl Acad Sci U S A. 1988 Apr;85(8):2444–2448. doi: 10.1073/pnas.85.8.2444. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Penny G. D., Kay G. F., Sheardown S. A., Rastan S., Brockdorff N. Requirement for Xist in X chromosome inactivation. Nature. 1996 Jan 11;379(6561):131–137. doi: 10.1038/379131a0. [DOI] [PubMed] [Google Scholar]
  50. Proud C. G. PKR: a new name and new roles. Trends Biochem Sci. 1995 Jun;20(6):241–246. doi: 10.1016/s0968-0004(00)89025-8. [DOI] [PubMed] [Google Scholar]
  51. Rastan S. X chromosome inactivation and the Xist gene. Curr Opin Genet Dev. 1994 Apr;4(2):292–297. doi: 10.1016/s0959-437x(05)80056-5. [DOI] [PubMed] [Google Scholar]
  52. Rastinejad F., Blau H. M. Genetic complementation reveals a novel regulatory role for 3' untranslated regions in growth and differentiation. Cell. 1993 Mar 26;72(6):903–917. doi: 10.1016/0092-8674(93)90579-f. [DOI] [PubMed] [Google Scholar]
  53. Rastinejad F., Conboy M. J., Rando T. A., Blau H. M. Tumor suppression by RNA from the 3' untranslated region of alpha-tropomyosin. Cell. 1993 Dec 17;75(6):1107–1117. doi: 10.1016/0092-8674(93)90320-p. [DOI] [PubMed] [Google Scholar]
  54. Richler C., Soreq H., Wahrman J. X inactivation in mammalian testis is correlated with inactive X-specific transcription. Nat Genet. 1992 Nov;2(3):192–195. doi: 10.1038/ng1192-192. [DOI] [PubMed] [Google Scholar]
  55. Salido E. C., Yen P. H., Mohandas T. K., Shapiro L. J. Expression of the X-inactivation-associated gene XIST during spermatogenesis. Nat Genet. 1992 Nov;2(3):196–199. doi: 10.1038/ng1192-196. [DOI] [PubMed] [Google Scholar]
  56. Schwartz R. C., Stanton L. W., Riley S. C., Marcu K. B., Witte O. N. Synergism of v-myc and v-Ha-ras in the in vitro neoplastic progression of murine lymphoid cells. Mol Cell Biol. 1986 Sep;6(9):3221–3231. doi: 10.1128/mcb.6.9.3221. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Schägger H., von Jagow G. Tricine-sodium dodecyl sulfate-polyacrylamide gel electrophoresis for the separation of proteins in the range from 1 to 100 kDa. Anal Biochem. 1987 Nov 1;166(2):368–379. doi: 10.1016/0003-2697(87)90587-2. [DOI] [PubMed] [Google Scholar]
  58. Shapiro M. B., Senapathy P. RNA splice junctions of different classes of eukaryotes: sequence statistics and functional implications in gene expression. Nucleic Acids Res. 1987 Sep 11;15(17):7155–7174. doi: 10.1093/nar/15.17.7155. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Shinto Y., Morimoto M., Katsumata M., Uchida A., Aozasa K., Okamoto M., Kurosawa T., Ochi T., Greene M. I., Tsujimoto Y. Moloney murine leukemia virus infection accelerates lymphomagenesis in E mu-bcl-2 transgenic mice. Oncogene. 1995 Nov 2;11(9):1729–1736. [PubMed] [Google Scholar]
  60. Strasser A., Harris A. W., Bath M. L., Cory S. Novel primitive lymphoid tumours induced in transgenic mice by cooperation between myc and bcl-2. Nature. 1990 Nov 22;348(6299):331–333. doi: 10.1038/348331a0. [DOI] [PubMed] [Google Scholar]
  61. Taniguchi T., Sullivan M. J., Ogawa O., Reeve A. E. Epigenetic changes encompassing the IGF2/H19 locus associated with relaxation of IGF2 imprinting and silencing of H19 in Wilms tumor. Proc Natl Acad Sci U S A. 1995 Mar 14;92(6):2159–2163. doi: 10.1073/pnas.92.6.2159. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Thompson C. B., Humphries E. H., Carlson L. M., Chen C. L., Neiman P. E. The effect of alterations in myc gene expression on B cell development in the bursa of Fabricius. Cell. 1987 Nov 6;51(3):371–381. doi: 10.1016/0092-8674(87)90633-7. [DOI] [PubMed] [Google Scholar]
  63. Uberbacher E. C., Mural R. J. Locating protein-coding regions in human DNA sequences by a multiple sensor-neural network approach. Proc Natl Acad Sci U S A. 1991 Dec 15;88(24):11261–11265. doi: 10.1073/pnas.88.24.11261. [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. Verbeek S., van Lohuizen M., van der Valk M., Domen J., Kraal G., Berns A. Mice bearing the E mu-myc and E mu-pim-1 transgenes develop pre-B-cell leukemia prenatally. Mol Cell Biol. 1991 Feb;11(2):1176–1179. doi: 10.1128/mcb.11.2.1176. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Wickens M. How the messenger got its tail: addition of poly(A) in the nucleus. Trends Biochem Sci. 1990 Jul;15(7):277–281. doi: 10.1016/0968-0004(90)90054-f. [DOI] [PubMed] [Google Scholar]
  66. Zuker M., Stiegler P. Optimal computer folding of large RNA sequences using thermodynamics and auxiliary information. Nucleic Acids Res. 1981 Jan 10;9(1):133–148. doi: 10.1093/nar/9.1.133. [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. van Gurp R. J., Oosterhuis J. W., Kalscheuer V., Mariman E. C., Looijenga L. H. Biallelic expression of the H19 and IGF2 genes in human testicular germ cell tumors. J Natl Cancer Inst. 1994 Jul 20;86(14):1070–1075. doi: 10.1093/jnci/86.14.1070. [DOI] [PubMed] [Google Scholar]
  68. van Lohuizen M., Berns A. Tumorigenesis by slow-transforming retroviruses--an update. Biochim Biophys Acta. 1990 Dec 11;1032(2-3):213–235. doi: 10.1016/0304-419x(90)90005-l. [DOI] [PubMed] [Google Scholar]
  69. van Lohuizen M., Verbeek S., Krimpenfort P., Domen J., Saris C., Radaszkiewicz T., Berns A. Predisposition to lymphomagenesis in pim-1 transgenic mice: cooperation with c-myc and N-myc in murine leukemia virus-induced tumors. Cell. 1989 Feb 24;56(4):673–682. doi: 10.1016/0092-8674(89)90589-8. [DOI] [PubMed] [Google Scholar]
  70. van Lohuizen M., Verbeek S., Scheijen B., Wientjens E., van der Gulden H., Berns A. Identification of cooperating oncogenes in E mu-myc transgenic mice by provirus tagging. Cell. 1991 May 31;65(5):737–752. doi: 10.1016/0092-8674(91)90382-9. [DOI] [PubMed] [Google Scholar]

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