Skip to main content

The Role of the Transcription Factor E2F in the Growth Regulation of DHFR

  • Chapter
The Cell Cycle

Abstract

As cells enter S phase of the growth cycle there is a transient increase in the transcription and translation of a number of genes that prepare the cell for DNA synthesis. Increased levels of enzymes such as dihydrofolate reductase (DHFR), thymidine kinase, thymidylate synthase, ribonucleotide reductase, CAD, and DNA polymerise alpha help to create an environment favorable for DNA synthesis. As is true for most genes critical for cell growth, expression of these genes is controlled on many levels. Our interests are to understand the control mechanisms that lead to increased transcription at the G1/S-phase boundary. Using the DHFR promoter as a model system, we mapped a cis-acting element necessary and sufficient for a transcriptional increase late in G11, 2. We propose a simple model in which the transcription factor E2F1 binds to and activates transcription from this element in a growth-regulated manner. However, this model is not complete and additional factors may play a role in the growth regulation of the DHFR gene.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

eBook
USD 16.99
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 54.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. A. L. Means, J. E. Slansky, S. L. McMahon, M. W. Knuth, and P. J. Farnham, The HIP1 binding site is required for growth regulation of the dihydrofolate reductase gene promoter, Mol. Cell. Biol. 12: 1054–1063 (1992).

    PubMed  CAS  Google Scholar 

  2. J. E. Slansky, Y. Li, W. G. Kaelin, and P. J. Farnham, A protein synthesis-dependent increase in E2F1 mRNA correlates with growth regulation of the DHFR promoter, Mol. Cell. Biol. 13: 1610–1618 (1993).

    PubMed  CAS  Google Scholar 

  3. P. J. Farnham and R. T. Schimke, Transcriptional regulation of mouse dihydrofolate reductase in the cell cycle, J. Biol. Chem. 260: 7675–7680 (1985).

    PubMed  CAS  Google Scholar 

  4. P. J. Farnham and R. T. Schimke, Murine dihydrofolate reductase transcripts through the cell cycle, Mol. Cell. Biol. 6: 365–371 (1986).

    Google Scholar 

  5. L. F. Johnson, C. L. Fuhrman, and L. M. Wiedemann, Regulation of dihydrofolate reductase gene expression in mouse fibroblasts during the transition from the resting to growing state, J. Cell. Physiol. 97: 397–406 (1978).

    Article  PubMed  CAS  Google Scholar 

  6. C. Santiago, M. Collins, and L. F. Johnson, in vitro and in vivo analysis of the control of dihydrofolate reductase gene transcription in serum-stimulated mouse fibroblasts, J. Cell. Physiol. 118: 79–86 (1984).

    Article  PubMed  CAS  Google Scholar 

  7. A. L. Means and P. J. Farnham, Transcription initiation from the dihydrofolate reductase promoter is positioned by HIP1 binding at the initiation site, Mol. Cell. Biol. 10: 653–661 (1990).

    PubMed  CAS  Google Scholar 

  8. M. C. Blake and J. C. Azizkhan, Transcription factor E2F is required for efficient expression of the hamster dihydrofolate reductase gene in vitro and in vivo, Mol. Cell. Biol. 9: 4994–5002 (1989).

    PubMed  CAS  Google Scholar 

  9. W. G. Kaelin, W. Krek, W. R. Sellers, J. A. DeCaprio, F. Ajchenbaum, C. S. Fuchs, T. Chittenden, Y. Li, P. J. Farnham, M. A. Blanar, D. M. Livingston, and E. K. Flemington, Expression cloning of a cDNA encoding a retinoblastoma-binding protein with E2F-like properties, Cell 70: 351–364 (1992).

    Article  PubMed  CAS  Google Scholar 

  10. K. Helin, J. A. Lees, M. Vidal, N. Dyson, E. Harlow, and A. Fattaey, A cDNA encoding a pRB-binding protein with properties of the transcription factor E2F, Cell 70: 337–350 (1992).

    Article  PubMed  CAS  Google Scholar 

  11. B. Shan, X. Zhu, P.-L. Chen, T. Durfee, Y. Yang, D. Sharp, and W.-H. Lee, Molecular cloning of cellular genes encoding retinoblastoma-associated proteins: identification of a gene with properties of the transcription factor E2F, Mol. Cell. Biol. 12: 5620–5631 (1992).

    PubMed  CAS  Google Scholar 

  12. E. Harlow. Personal communication.

    Google Scholar 

  13. R. Girling, J. F. Partridge, L. R. Bandara, N. Burden, N. F. Totty, J. J. Hsuan, and N. B. La Thangue, A new component of the transcription factor DRTF1/E2F, Nature 362: 83–87 (1993).

    Article  PubMed  CAS  Google Scholar 

  14. Y. Li and P. J. Farnham. Unpublished data.

    Google Scholar 

  15. P. J. Farnham and A. L. Means, Sequences downstream of the transcription initiation site modulate the activity of the murine dihydrofolate reductase promoter., Mol. Cell. Biol. 10: 1390–1398 (1990).

    PubMed  CAS  Google Scholar 

  16. B. E. Pearson, H.-P. Nasheuer, and T. S.-F. Wang, Human DNA polymerise a gene: sequences controlling expression in cycling and serum-stimulated cells., Mol. Cell. Biol. 11: 2081–2095 (1991).

    PubMed  CAS  Google Scholar 

  17. R. J. Miltenberges and P. J. Farnham. Unpublished data.

    Google Scholar 

  18. S. Bagchi, R. Weinmann, and P. Raychaudhuri, The retinoblastoma protein copurifies with E2F-I, an E1A-regulated inhibitor of the transcription factor E2F, Cell 65: 1063–1072 (1991).

    Article  PubMed  CAS  Google Scholar 

  19. S. P. Chellappan, S. W. Hiebert, M. Mudryj, J. M. Horowitz, and J. R. Nevins, The E2F transcription factor is a cellular target for the RB protein, Cell 65: 1053–1061 (1991).

    Article  PubMed  CAS  Google Scholar 

  20. S. H. Devoto, M. Mudryj, J. Pines, T. Hunter, and J. R. Nevins, A cyclin A-protein kinase complex possesses sequence-specific DNA binding activity: p33cdk2 is a component of the E2F-cyclin A complex, Cell 68: 167–176 (1992).

    Article  PubMed  CAS  Google Scholar 

  21. M. Pagano, G. Draetta, and P. Jansen-Durr, Association of cdk2 kinase with the transcription factor E2F during S phase, Science 255: 1144–1147 (1992).

    Article  PubMed  CAS  Google Scholar 

  22. M. Mudryj, S. H. Devoto, S. W. Hiebert, T. Hunter, J. Pines, and J. R. Nevins, Cell cycle regulation of the E2F transcription factor involves an interaction with cyclin A, Cell 65, 1243–1253 (1991).

    Article  PubMed  CAS  Google Scholar 

  23. E. Lees, B. Faha, V. Dulic, S. I. Reed, and E. Harlow, Cyclin E/cdk2 and cyclin A/cdk2 kinases associate with p107 and E2F in a temporally distinct manner, Genes and Dev. 6: 1874–1885 (1992).

    Article  PubMed  CAS  Google Scholar 

  24. S. J. Weintraub, C. A. Prater, and D. C. Dean, Retinoblastoma protein switches the E2F site from positive to negative element, Nature 358: 259–261 (1992).

    Article  PubMed  CAS  Google Scholar 

  25. J. K. Schwarz, S. H. Devoto, E. J. Smith, S. P. Chellappan, L. Jakoi, and J. R. Nevins, Interactions of the p107 and Rb proteins with E2F during the cell proliferation response, EMBO J. 12: 1013–1020 (1993).

    PubMed  CAS  Google Scholar 

  26. S. W. Hiebert, S. P. Chellappan, J. M. Horowitz, and J. R. Nevins, The interaction of RB with E2F coincides with an inhibition of the transcriptional activity of E2F, Genes Dev. 6: 177–185 (1992).

    Article  PubMed  CAS  Google Scholar 

  27. H. E. Huber, G. Edwards, P. J. Goodhart, D. R. Patrick, P. S. Huang, M. Ivey-Hoyle, S. F. Barnett, A. O1iff, and D. C. Heimbrook, Transcription factor E2F binds as a heterodimer, Proc. Natl. Acad. Sci. USA 90: 3525–3529 (1993).

    Article  CAS  Google Scholar 

  28. J. R. Nevins, E2F: A link between the Rb tumor suppressor protein aad viral oncoproteins, Science 258: 424–429 (1992).

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 1994 Springer Science+Business Media New York

About this chapter

Cite this chapter

Slansky, J.E., Farnham, P.J. (1994). The Role of the Transcription Factor E2F in the Growth Regulation of DHFR. In: Hu, V.W. (eds) The Cell Cycle. GWUMC Department of Biochemistry Annual Spring Symposia. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-2421-2_16

Download citation

  • DOI: https://doi.org/10.1007/978-1-4615-2421-2_16

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4613-6027-8

  • Online ISBN: 978-1-4615-2421-2

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics