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. 1996 Jul;16(7):3401–3409. doi: 10.1128/mcb.16.7.3401

Cell cycle regulation of the murine cyclin E gene depends on an E2F binding site in the promoter.

J Botz 1, K Zerfass-Thome 1, D Spitkovsky 1, H Delius 1, B Vogt 1, M Eilers 1, A Hatzigeorgiou 1, P Jansen-Dürr 1
PMCID: PMC231334  PMID: 8668155

Abstract

Cyclin E controls progression through the G1 phase of the cell cycle in mammalian fibroblasts and potentially in many other cell types. Cyclin E is a rate-limiting activator of cdk2 kinase in late G1. The abundance of cyclin E is controlled by phase-specific fluctuations in the mRNA level; in mammalian fibroblasts, mRNA is not detected under conditions of serum starvation and is accumulated upon serum stimulation, with expression starting in mid-G1. Here, we report the cloning of the murine cyclin E promoter. We isolated a 3.8-kb genomic fragment that contains several transcriptional start sites and confers cell cycle regulation on a luciferase reporter gene. This fragment also supports transcriptional activation by adenovirus E1A, a known upstream regulator of cyclin E gene expression. An E2F binding site which is required for G1-specific activation of the cyclin E promoter in synchronized NIH 3T3 cells was identified in this fragment.

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Selected References

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  1. Arcot S. S., Traina-Dorge V. L., Deininger P. L. The rat thymidine kinase gene 5' region: evolution of a promoter. DNA Seq. 1991;2(2):129–131. doi: 10.3109/10425179109039682. [DOI] [PubMed] [Google Scholar]
  2. Brunak S., Engelbrecht J., Knudsen S. Prediction of human mRNA donor and acceptor sites from the DNA sequence. J Mol Biol. 1991 Jul 5;220(1):49–65. doi: 10.1016/0022-2836(91)90380-o. [DOI] [PubMed] [Google Scholar]
  3. Burggraf S., Larsen N., Woese C. R., Stetter K. O. An intron within the 16S ribosomal RNA gene of the archaeon Pyrobaculum aerophilum. Proc Natl Acad Sci U S A. 1993 Mar 15;90(6):2547–2550. doi: 10.1073/pnas.90.6.2547. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Chang Z. F., Huang D. Y., Lai T. C. Different regulation of the human thymidine kinase promoter in normal human diploid IMR-90 fibroblasts and HeLa cells. J Biol Chem. 1995 Nov 10;270(45):27374–27379. doi: 10.1074/jbc.270.45.27374. [DOI] [PubMed] [Google Scholar]
  5. Damjanov I., Shan J., Wang R. F., Damjanov A., DeLoia J. A. Molecular cloning and characterization of murine cyclin E. Biochem Biophys Res Commun. 1994 Jun 15;201(2):994–1000. doi: 10.1006/bbrc.1994.1800. [DOI] [PubMed] [Google Scholar]
  6. Dou Q. P., Zhao S., Levin A. H., Wang J., Helin K., Pardee A. B. G1/S-regulated E2F-containing protein complexes bind to the mouse thymidine kinase gene promoter. J Biol Chem. 1994 Jan 14;269(2):1306–1313. [PubMed] [Google Scholar]
  7. Dulić V., Lees E., Reed S. I. Association of human cyclin E with a periodic G1-S phase protein kinase. Science. 1992 Sep 25;257(5078):1958–1961. doi: 10.1126/science.1329201. [DOI] [PubMed] [Google Scholar]
  8. Eick D. Elongation and maturation of c-myc RNA is inhibited by differentiation inducing agents in HL60 cells. Nucleic Acids Res. 1990 Mar 11;18(5):1199–1205. doi: 10.1093/nar/18.5.1199. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Henglein B., Chenivesse X., Wang J., Eick D., Bréchot C. Structure and cell cycle-regulated transcription of the human cyclin A gene. Proc Natl Acad Sci U S A. 1994 Jun 7;91(12):5490–5494. doi: 10.1073/pnas.91.12.5490. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Hsiao K. M., McMahon S. L., Farnham P. J. Multiple DNA elements are required for the growth regulation of the mouse E2F1 promoter. Genes Dev. 1994 Jul 1;8(13):1526–1537. doi: 10.1101/gad.8.13.1526. [DOI] [PubMed] [Google Scholar]
  11. Johnson D. G., Ohtani K., Nevins J. R. Autoregulatory control of E2F1 expression in response to positive and negative regulators of cell cycle progression. Genes Dev. 1994 Jul 1;8(13):1514–1525. doi: 10.1101/gad.8.13.1514. [DOI] [PubMed] [Google Scholar]
  12. Knoblich J. A., Sauer K., Jones L., Richardson H., Saint R., Lehner C. F. Cyclin E controls S phase progression and its down-regulation during Drosophila embryogenesis is required for the arrest of cell proliferation. Cell. 1994 Apr 8;77(1):107–120. doi: 10.1016/0092-8674(94)90239-9. [DOI] [PubMed] [Google Scholar]
  13. Koff A., Cross F., Fisher A., Schumacher J., Leguellec K., Philippe M., Roberts J. M. Human cyclin E, a new cyclin that interacts with two members of the CDC2 gene family. Cell. 1991 Sep 20;66(6):1217–1228. doi: 10.1016/0092-8674(91)90044-y. [DOI] [PubMed] [Google Scholar]
  14. Koff A., Giordano A., Desai D., Yamashita K., Harper J. W., Elledge S., Nishimoto T., Morgan D. O., Franza B. R., Roberts J. M. Formation and activation of a cyclin E-cdk2 complex during the G1 phase of the human cell cycle. Science. 1992 Sep 18;257(5077):1689–1694. doi: 10.1126/science.1388288. [DOI] [PubMed] [Google Scholar]
  15. La Thangue N. B. DRTF1/E2F: an expanding family of heterodimeric transcription factors implicated in cell-cycle control. Trends Biochem Sci. 1994 Mar;19(3):108–114. doi: 10.1016/0968-0004(94)90202-x. [DOI] [PubMed] [Google Scholar]
  16. Lam E. W., La Thangue N. B. DP and E2F proteins: coordinating transcription with cell cycle progression. Curr Opin Cell Biol. 1994 Dec;6(6):859–866. doi: 10.1016/0955-0674(94)90057-4. [DOI] [PubMed] [Google Scholar]
  17. Lam E. W., Morris J. D., Davies R., Crook T., Watson R. J., Vousden K. H. HPV16 E7 oncoprotein deregulates B-myb expression: correlation with targeting of p107/E2F complexes. EMBO J. 1994 Feb 15;13(4):871–878. doi: 10.1002/j.1460-2075.1994.tb06330.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Motokura T., Bloom T., Kim H. G., Jüppner H., Ruderman J. V., Kronenberg H. M., Arnold A. A novel cyclin encoded by a bcl1-linked candidate oncogene. Nature. 1991 Apr 11;350(6318):512–515. doi: 10.1038/350512a0. [DOI] [PubMed] [Google Scholar]
  19. Nordeen S. K. Luciferase reporter gene vectors for analysis of promoters and enhancers. Biotechniques. 1988 May;6(5):454–458. [PubMed] [Google Scholar]
  20. Ohtani K., DeGregori J., Nevins J. R. Regulation of the cyclin E gene by transcription factor E2F1. Proc Natl Acad Sci U S A. 1995 Dec 19;92(26):12146–12150. doi: 10.1073/pnas.92.26.12146. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Ohtsubo M., Theodoras A. M., Schumacher J., Roberts J. M., Pagano M. Human cyclin E, a nuclear protein essential for the G1-to-S phase transition. Mol Cell Biol. 1995 May;15(5):2612–2624. doi: 10.1128/mcb.15.5.2612. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Pagano M., Draetta G., Jansen-Dürr P. Association of cdk2 kinase with the transcription factor E2F during S phase. Science. 1992 Feb 28;255(5048):1144–1147. doi: 10.1126/science.1312258. [DOI] [PubMed] [Google Scholar]
  23. Pagano M., Pepperkok R., Verde F., Ansorge W., Draetta G. Cyclin A is required at two points in the human cell cycle. EMBO J. 1992 Mar;11(3):961–971. doi: 10.1002/j.1460-2075.1992.tb05135.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Resnitzky D., Gossen M., Bujard H., Reed S. I. Acceleration of the G1/S phase transition by expression of cyclins D1 and E with an inducible system. Mol Cell Biol. 1994 Mar;14(3):1669–1679. doi: 10.1128/mcb.14.3.1669. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Schulze A., Zerfass K., Spitkovsky D., Middendorp S., Bergès J., Helin K., Jansen-Dürr P., Henglein B. Cell cycle regulation of the cyclin A gene promoter is mediated by a variant E2F site. Proc Natl Acad Sci U S A. 1995 Nov 21;92(24):11264–11268. doi: 10.1073/pnas.92.24.11264. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Schwarz J. K., Devoto S. H., Smith E. J., Chellappan S. P., Jakoi L., Nevins J. R. Interactions of the p107 and Rb proteins with E2F during the cell proliferation response. EMBO J. 1993 Mar;12(3):1013–1020. doi: 10.1002/j.1460-2075.1993.tb05742.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Sherr C. J. G1 phase progression: cycling on cue. Cell. 1994 Nov 18;79(4):551–555. doi: 10.1016/0092-8674(94)90540-1. [DOI] [PubMed] [Google Scholar]
  28. Spitkovsky D., Steiner P., Lukas J., Lees E., Pagano M., Schulze A., Joswig S., Picard D., Tommasino M., Eilers M. Modulation of cyclin gene expression by adenovirus E1A in a cell line with E1A-dependent conditional proliferation. J Virol. 1994 Apr;68(4):2206–2214. doi: 10.1128/jvi.68.4.2206-2214.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Tommasi S., Pfeifer G. P. In vivo structure of the human cdc2 promoter: release of a p130-E2F-4 complex from sequences immediately upstream of the transcription initiation site coincides with induction of cdc2 expression. Mol Cell Biol. 1995 Dec;15(12):6901–6913. doi: 10.1128/mcb.15.12.6901. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Wimmel A., Lucibello F. C., Sewing A., Adolph S., Müller R. Inducible acceleration of G1 progression through tetracycline-regulated expression of human cyclin E. Oncogene. 1994 Mar;9(3):995–997. [PubMed] [Google Scholar]
  31. Zerfass K., Schulze A., Spitkovsky D., Friedman V., Henglein B., Jansen-Dürr P. Sequential activation of cyclin E and cyclin A gene expression by human papillomavirus type 16 E7 through sequences necessary for transformation. J Virol. 1995 Oct;69(10):6389–6399. doi: 10.1128/jvi.69.10.6389-6399.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Zindy F., Lamas E., Chenivesse X., Sobczak J., Wang J., Fesquet D., Henglein B., Bréchot C. Cyclin A is required in S phase in normal epithelial cells. Biochem Biophys Res Commun. 1992 Feb 14;182(3):1144–1154. doi: 10.1016/0006-291x(92)91851-g. [DOI] [PubMed] [Google Scholar]
  33. Zwicker J., Lucibello F. C., Wolfraim L. A., Gross C., Truss M., Engeland K., Müller R. Cell cycle regulation of the cyclin A, cdc25C and cdc2 genes is based on a common mechanism of transcriptional repression. EMBO J. 1995 Sep 15;14(18):4514–4522. doi: 10.1002/j.1460-2075.1995.tb00130.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

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