Abstract
Modulation of transcriptional elongation within the c-myc gene is thought to play a major role in determining levels of c-myc mRNA in both normal and tumor cells. A discrete site of blockage to transcriptional elongation has previously been localized at the 3' end of exon 1 of the mouse and human c-myc genes. We here identify an additional site of transcriptional attenuation that is located between the P1 and P2 promoters of the c-myc gene and that mediates premature termination of transcripts initiating from the P1 promoter. A 95-nucleotide DNA fragment derived from this region prematurely terminated transcription when placed downstream from the promoter of the H-2Kbm1 gene and assayed by expression in Xenopus oocytes. We also show that the previously identified attenuation signal in exon 1 of the mouse c-myc gene can mediate premature termination of P1-initiated transcripts. Premature termination of P1-initiated transcripts presumably increases transcription from the downstream P2 promoter; aberrant regulation of this termination may explain the increased use of the P1 promoter that is characteristic of certain tumors in which myc is overexpressed.
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- Alitalo K., Schwab M. Oncogene amplification in tumor cells. Adv Cancer Res. 1986;47:235–281. doi: 10.1016/s0065-230x(08)60201-8. [DOI] [PubMed] [Google Scholar]
- Barik S., Ghosh B., Whalen W., Lazinski D., Das A. An antitermination protein engages the elongating transcription apparatus at a promoter-proximal recognition site. Cell. 1987 Sep 11;50(6):885–899. doi: 10.1016/0092-8674(87)90515-0. [DOI] [PubMed] [Google Scholar]
- Bender T. P., Thompson C. B., Kuehl W. M. Differential expression of c-myb mRNA in murine B lymphomas by a block to transcription elongation. Science. 1987 Sep 18;237(4821):1473–1476. doi: 10.1126/science.3498214. [DOI] [PubMed] [Google Scholar]
- Bentley D. L., Brown W. L., Groudine M. Accurate, TATA box-dependent polymerase III transcription from promoters of the c-myc gene in injected Xenopus oocytes. Genes Dev. 1989 Aug;3(8):1179–1189. doi: 10.1101/gad.3.8.1179. [DOI] [PubMed] [Google Scholar]
- Bentley D. L., Groudine M. A block to elongation is largely responsible for decreased transcription of c-myc in differentiated HL60 cells. Nature. 1986 Jun 12;321(6071):702–706. doi: 10.1038/321702a0. [DOI] [PubMed] [Google Scholar]
- Bentley D. L., Groudine M. Sequence requirements for premature termination of transcription in the human c-myc gene. Cell. 1988 Apr 22;53(2):245–256. doi: 10.1016/0092-8674(88)90386-8. [DOI] [PubMed] [Google Scholar]
- Cesarman E., Dalla-Favera R., Bentley D., Groudine M. Mutations in the first exon are associated with altered transcription of c-myc in Burkitt lymphoma. Science. 1987 Nov 27;238(4831):1272–1275. doi: 10.1126/science.3685977. [DOI] [PubMed] [Google Scholar]
- Chen Z., Harless M. L., Wright D. A., Kellems R. E. Identification and characterization of transcriptional arrest sites in exon 1 of the human adenosine deaminase gene. Mol Cell Biol. 1990 Sep;10(9):4555–4564. doi: 10.1128/mcb.10.9.4555. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cole M. D. The myc oncogene: its role in transformation and differentiation. Annu Rev Genet. 1986;20:361–384. doi: 10.1146/annurev.ge.20.120186.002045. [DOI] [PubMed] [Google Scholar]
- Cory S. Activation of cellular oncogenes in hemopoietic cells by chromosome translocation. Adv Cancer Res. 1986;47:189–234. doi: 10.1016/s0065-230x(08)60200-6. [DOI] [PubMed] [Google Scholar]
- Cullen B. R., Lomedico P. T., Ju G. Transcriptional interference in avian retroviruses--implications for the promoter insertion model of leukaemogenesis. Nature. 1984 Jan 19;307(5948):241–245. doi: 10.1038/307241a0. [DOI] [PubMed] [Google Scholar]
- Dani C., Blanchard J. M., Piechaczyk M., El Sabouty S., Marty L., Jeanteur P. Extreme instability of myc mRNA in normal and transformed human cells. Proc Natl Acad Sci U S A. 1984 Nov;81(22):7046–7050. doi: 10.1073/pnas.81.22.7046. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dani C., Mechti N., Piechaczyk M., Lebleu B., Jeanteur P., Blanchard J. M. Increased rate of degradation of c-myc mRNA in interferon-treated Daudi cells. Proc Natl Acad Sci U S A. 1985 Aug;82(15):4896–4899. doi: 10.1073/pnas.82.15.4896. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Eick D., Berger R., Polack A., Bornkamm G. W. Transcription of c-myc in human mononuclear cells is regulated by an elongation block. Oncogene. 1987;2(1):61–65. [PubMed] [Google Scholar]
- Eick D., Bornkamm G. W. Transcriptional arrest within the first exon is a fast control mechanism in c-myc gene expression. Nucleic Acids Res. 1986 Nov 11;14(21):8331–8346. doi: 10.1093/nar/14.21.8331. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Einat M., Resnitzky D., Kimchi A. Close link between reduction of c-myc expression by interferon and, G0/G1 arrest. Nature. 1985 Feb 14;313(6003):597–600. doi: 10.1038/313597a0. [DOI] [PubMed] [Google Scholar]
- Faus I., Richardson J. P. Structural and functional properties of the segments of lambda cro mRNA that interact with transcription termination factor Rho. J Mol Biol. 1990 Mar 5;212(1):53–66. doi: 10.1016/0022-2836(90)90304-5. [DOI] [PubMed] [Google Scholar]
- Fort P., Rech J., Vie A., Piechaczyk M., Bonnieu A., Jeanteur P., Blanchard J. M. Regulation of c-fos gene expression in hamster fibroblasts: initiation and elongation of transcription and mRNA degradation. Nucleic Acids Res. 1987 Jul 24;15(14):5657–5667. doi: 10.1093/nar/15.14.5657. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gottlieb E., Steitz J. A. Function of the mammalian La protein: evidence for its action in transcription termination by RNA polymerase III. EMBO J. 1989 Mar;8(3):851–861. doi: 10.1002/j.1460-2075.1989.tb03446.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gottlieb E., Steitz J. A. The RNA binding protein La influences both the accuracy and the efficiency of RNA polymerase III transcription in vitro. EMBO J. 1989 Mar;8(3):841–850. doi: 10.1002/j.1460-2075.1989.tb03445.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Grayhack E. J., Yang X. J., Lau L. F., Roberts J. W. Phage lambda gene Q antiterminator recognizes RNA polymerase near the promoter and accelerates it through a pause site. Cell. 1985 Aug;42(1):259–269. doi: 10.1016/s0092-8674(85)80121-5. [DOI] [PubMed] [Google Scholar]
- Gurdon J. B., Wickens M. P. The use of Xenopus oocytes for the expression of cloned genes. Methods Enzymol. 1983;101:370–386. doi: 10.1016/0076-6879(83)01028-9. [DOI] [PubMed] [Google Scholar]
- Hann S. R., King M. W., Bentley D. L., Anderson C. W., Eisenman R. N. A non-AUG translational initiation in c-myc exon 1 generates an N-terminally distinct protein whose synthesis is disrupted in Burkitt's lymphomas. Cell. 1988 Jan 29;52(2):185–195. doi: 10.1016/0092-8674(88)90507-7. [DOI] [PubMed] [Google Scholar]
- Hernandez N., Lucito R. Elements required for transcription initiation of the human U2 snRNA gene coincide with elements required for snRNA 3' end formation. EMBO J. 1988 Oct;7(10):3125–3134. doi: 10.1002/j.1460-2075.1988.tb03179.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Horwitz R. J., Li J., Greenblatt J. An elongation control particle containing the N gene transcriptional antitermination protein of bacteriophage lambda. Cell. 1987 Nov 20;51(4):631–641. doi: 10.1016/0092-8674(87)90132-2. [DOI] [PubMed] [Google Scholar]
- Kuhn A., Bartsch I., Grummt I. Specific interaction of the murine transcription termination factor TTF I with class-I RNA polymerases. Nature. 1990 Apr 5;344(6266):559–562. doi: 10.1038/344559a0. [DOI] [PubMed] [Google Scholar]
- Lazinski D., Grzadzielska E., Das A. Sequence-specific recognition of RNA hairpins by bacteriophage antiterminators requires a conserved arginine-rich motif. Cell. 1989 Oct 6;59(1):207–218. doi: 10.1016/0092-8674(89)90882-9. [DOI] [PubMed] [Google Scholar]
- McStay B., Reeder R. H. A DNA-binding protein is required for termination of transcription by RNA polymerase I in Xenopus laevis. Mol Cell Biol. 1990 Jun;10(6):2793–2800. doi: 10.1128/mcb.10.6.2793. [DOI] [PMC free article] [PubMed] [Google Scholar]
- McStay B., Reeder R. H. An RNA polymerase I termination site can stimulate the adjacent ribosomal gene promoter by two distinct mechanisms in Xenopus laevis. Genes Dev. 1990 Jul;4(7):1240–1251. doi: 10.1101/gad.4.7.1240. [DOI] [PubMed] [Google Scholar]
- Middleton K. M., Morgan G. T. Premature termination of transcription can be induced on an injected alpha-tubulin gene in Xenopus oocytes. Mol Cell Biol. 1990 Feb;10(2):727–735. doi: 10.1128/mcb.10.2.727. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Miller H., Asselin C., Dufort D., Yang J. Q., Gupta K., Marcu K. B., Nepveu A. A cis-acting element in the promoter region of the murine c-myc gene is necessary for transcriptional block. Mol Cell Biol. 1989 Dec;9(12):5340–5349. doi: 10.1128/mcb.9.12.5340. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nepveu A., Levine R. A., Campisi J., Greenberg M. E., Ziff E. B., Marcu K. B. Alternative modes of c-myc regulation in growth factor-stimulated and differentiating cells. Oncogene. 1987;1(3):243–250. [PubMed] [Google Scholar]
- Nepveu A., Marcu K. B. Intragenic pausing and anti-sense transcription within the murine c-myc locus. EMBO J. 1986 Nov;5(11):2859–2865. doi: 10.1002/j.1460-2075.1986.tb04580.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nepveu A., Marcu K. B., Skoultchi A. I., Lachman H. M. Contributions of transcriptional and post-transcriptional mechanisms to the regulation of c-myc expression in mouse erythroleukemia cells. Genes Dev. 1987 Nov;1(9):938–945. doi: 10.1101/gad.1.9.938. [DOI] [PubMed] [Google Scholar]
- Pfleiderer C., Smid A., Bartsch I., Grummt I. An undecamer DNA sequence directs termination of human ribosomal gene transcription. Nucleic Acids Res. 1990 Aug 25;18(16):4727–4736. doi: 10.1093/nar/18.16.4727. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Platt T. Transcription termination and the regulation of gene expression. Annu Rev Biochem. 1986;55:339–372. doi: 10.1146/annurev.bi.55.070186.002011. [DOI] [PubMed] [Google Scholar]
- Proudfoot N. J. Transcriptional interference and termination between duplicated alpha-globin gene constructs suggests a novel mechanism for gene regulation. Nature. 1986 Aug 7;322(6079):562–565. doi: 10.1038/322562a0. [DOI] [PubMed] [Google Scholar]
- Ramamurthy V., Maa M. C., Harless M. L., Wright D. A., Kellems R. E. Sequence requirements for transcriptional arrest in exon 1 of the murine adenosine deaminase gene. Mol Cell Biol. 1990 Apr;10(4):1484–1491. doi: 10.1128/mcb.10.4.1484. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Schwab M., Amler L. C. Amplification of cellular oncogenes: a predictor of clinical outcome in human cancer. Genes Chromosomes Cancer. 1990 Jan;1(3):181–193. doi: 10.1002/gcc.2870010302. [DOI] [PubMed] [Google Scholar]
- Spandidos D. A., Paul J. Transfer of human globin genes to erythroleukemic mouse cells. EMBO J. 1982;1(1):15–20. doi: 10.1002/j.1460-2075.1982.tb01117.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Spencer C. A., LeStrange R. C., Novak U., Hayward W. S., Groudine M. The block to transcription elongation is promoter dependent in normal and Burkitt's lymphoma c-myc alleles. Genes Dev. 1990 Jan;4(1):75–88. doi: 10.1101/gad.4.1.75. [DOI] [PubMed] [Google Scholar]
- Taub R., Kelly K., Battey J., Latt S., Lenoir G. M., Tantravahi U., Tu Z., Leder P. A novel alteration in the structure of an activated c-myc gene in a variant t(2;8) Burkitt lymphoma. Cell. 1984 Jun;37(2):511–520. doi: 10.1016/0092-8674(84)90381-7. [DOI] [PubMed] [Google Scholar]
- Taub R., Moulding C., Battey J., Murphy W., Vasicek T., Lenoir G. M., Leder P. Activation and somatic mutation of the translocated c-myc gene in burkitt lymphoma cells. Cell. 1984 Feb;36(2):339–348. doi: 10.1016/0092-8674(84)90227-7. [DOI] [PubMed] [Google Scholar]
- Varmus H. E. The molecular genetics of cellular oncogenes. Annu Rev Genet. 1984;18:553–612. doi: 10.1146/annurev.ge.18.120184.003005. [DOI] [PubMed] [Google Scholar]
- Watson R. J. A transcriptional arrest mechanism involved in controlling constitutive levels of mouse c-myb mRNA. Oncogene. 1988 Mar;2(3):267–272. [PubMed] [Google Scholar]
- Wright S., Bishop J. M. DNA sequences that mediate attenuation of transcription from the mouse protooncogene myc. Proc Natl Acad Sci U S A. 1989 Jan;86(2):505–509. doi: 10.1073/pnas.86.2.505. [DOI] [PMC free article] [PubMed] [Google Scholar]
- de Vegvar H. E., Lund E., Dahlberg J. E. 3' end formation of U1 snRNA precursors is coupled to transcription from snRNA promoters. Cell. 1986 Oct 24;47(2):259–266. doi: 10.1016/0092-8674(86)90448-4. [DOI] [PubMed] [Google Scholar]