Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Regulation of cyclin D2 and the cyclin D2 promoter by protein kinase A and CREB in lymphocytes

Oncogene volume 25, pages 2170–2180 (2006)Cite this article

Abstract

Lymphocyte proliferation is key to the regulation of the immune system. Cyclin D2 is the first cell cycle protein induced following stimulation through the T-cell receptor, the B-cell receptor or cytokines. The promoter of this cyclin integrates a diverse range of signals. Through investigating the regulation of this promoter by interleukin-2 and phosphatidylinositol 3-kinase, we have identified a role for the transcription factor CREB, cAMP response element-binding protein. Mutation of the CREB-binding site reduced cyclin D2 promoter activity 5–10-fold. CREB-1 is phosphorylated at serine 133, a critical site for activity, in both T cells and Epstein–Barr virus immortalized B cells. The introduction of an S133A mutant of CREB-1 reduces IL-2 induction of cyclin D2 promoter activity, demonstrating a role for this phosphorylation site in promoter activity. Two inhibitors of protein kinase A reduce lymphocyte proliferation and CREB-1 phosphorylation. This study demonstrates that the cyclin D2 promoter is capable of being regulated by PI3K and CREB and identifies CREB-1 and protein kinase A as potential targets for altering lymphocyte proliferation.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  • Ajchenbaum F, Ando K, DeCaprio JA, Griffin JD . (1993). J Biol Chem 268: 4113–4119.

  • Appleman LJ, Berezovskaya A, Grass I, Boussiotis VA . (2000). J Immunol 164: 144–151.

  • Banerji L, Glassford J, Lea NC, Thomas NS, Klaus GG, Lam EW . (2001). Oncogene 20: 7352–7367.

  • Barton K, Muthusamy N, Chanyangam M, Fischer C, Clendenin C, Leiden JM . (1996). Nature 379: 81–85.

  • Beadling C, Guschin D, Witthuhn BA, Ziemiecki A, Ihle JN, Kerr IM et al. (1994). EMBO J 13: 5605–5615.

  • Belkowski SM, Rubin CS, Prystowsky MB . (1998). J Immunol 161: 659–665.

  • Brennan P, Babbage JW, Burgering BM, Groner B, Reif K, Cantrell DA . (1997). Immunity 7: 679–689.

  • Brennan P, Mehl AM, Jones M, Rowe M . (2002). Oncogene 21: 1263–1271.

  • Brennan P, O'Neill LA . (1996). Biochem Soc Trans 24: 3S.

  • Breslin EM, White PC, Shore AM, Clement M, Brennan P . (2005). Br J Pharmacol 144: 791–800.

  • Brooks AR, Shiffman D, Chan CS, Brooks EE, Milner PG . (1996). J Biol Chem 271: 9090–9099.

  • Delmer A, Ajchenbaum-Cymbalista F, Tang R, Ramond S, Faussat AM, Marie JP, Zittoun R . (1995). Blood 85: 2870–2876.

  • Feuerstein N, Huang D, Prystowsky MB . (1995a). J Biol Chem 270: 9454–9458.

  • Feuerstein N, Huang D, Hinrichs SH, Orten DJ, Aiyar N, Prystowsky MB . (1995b). J Immunol 154: 68–79.

  • Frissora F, Chen HC, Durbin J, Bondada S, Muthusamy N . (2003). Eur J Immunol 33: 907–912.

  • Fruman DA, Ferl GZ, An SS, Donahue AC, Satterthwaite AB, Witte ON . (2002). Proc Natl Acad Sci USA 99: 359–364.

  • Hori T, Uchiyama T, Tsudo M, Umadome H, Ohno H, Fukuhara S et al. (1987). Blood 70: 1069–1072.

  • Huang Y, Ohtani K, Iwanaga R, Matsumura Y, Nakamura M . (2001). Oncogene 20: 1094–1102.

  • Lam EW, Glassford J, Banerji L, Thomas NS, Sicinski P, Klaus GG . (2000). J Biol Chem 275: 3479–3484.

  • Martino A, Holmes JHt, Lord JD, Moon JJ, Nelson BH . (2001). J Immunol 166: 1723–1729.

  • Mayr B, Montminy M . (2001). Nat Rev Mol Cell Biol 2: 599–609.

  • Mehl AM, Floettmann JE, Jones M, Brennan P, Rowe M . (2001). J Biol Chem 276: 984–992.

  • Moriggl R, Sexl V, Piekorz R, Topham D, Ihle JN . (1999). Immunity 11: 225–230.

  • Palmero I, Holder A, Sinclair AJ, Dickson C, Peters G . (1993). Oncogene 8: 1049–1054.

  • Rudolph D, Tafuri A, Gass P, Hammerling GJ, Arnold B, Schutz G . (1998). Proc Natl Acad Sci USA 95: 4481–4486.

  • Sample J, Kieff E . (1990). J Virol 64: 1667–1674.

  • Schmidt M, Fernandez de Mattos S, van der Horst A, Klompmaker R, Kops GJ, Lam EW et al. (2002). Mol Cell Biol 22: 7842–7852.

  • Sherr CJ . (1996). Science 274: 1672–1677.

  • Sinclair AJ, Palmero I, Peters G, Farrell PJ . (1994). EMBO J 13: 3321–3328.

  • Solvason N, Wu WW, Parry D, Mahony D, Lam EW, Glassford J et al. (2000). Int Immunol 12: 631–638.

  • Spender LC, Cornish GH, Rowland B, Kempkes B, Farrell PJ . (2001). J. Virol 75: 3537–3546.

  • Takano Y, Kato Y, Masuda M, Ohshima Y, Okayasu I . (1999). J Pathol 189: 194–200.

  • Teramoto N, Pokrovskaja K, Szekely L, Polack A, Yoshino T, Akagi T et al. (1999). Int J Cancer 81: 543–550.

  • Vlahos CJ, Matter WF, Hui KY, Brown RF . (1994). J Biol Chem 269: 5241–5248.

  • Waltereit R, Weller M . (2003). Mol Neurobiol 27: 99–106.

  • Xie H, Rothstein TL . (1995). J Immunol 154: 1717–1723.

  • Yu CT, Shih HM, Lai MZ . (2001). J Immunol 166: 284–292.

  • Zhang CY, Wu YL, Boxer LM . (2002). J Biol Chem 277: 48359–48365.

Download references

Acknowledgements

This work was supported by the Leukaemia Research Fund, UK and by Tenovus, the Cancer Charity.

Author information

Authors and Affiliations

  1. Medical Biochemistry and Immunology, Henry Wellcome Building, Cardiff University, Heath Park, Cardiff, UK

    P C White, A M Shore, M Clement, J McLaren & P Brennan

  2. Cancer Research UK Labs and Section of Cancer Cell Biology, Imperial College School of Medicine at Hammersmith Hospital, London, UK

    I Soeiro & E W-F Lam

Authors
  1. P C White
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A M Shore
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M Clement
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J McLaren
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. I Soeiro
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. E W-F Lam
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. P Brennan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to P Brennan.

Rights and permissions

Reprints and permissions

About this article

Cite this article

White, P., Shore, A., Clement, M. et al. Regulation of cyclin D2 and the cyclin D2 promoter by protein kinase A and CREB in lymphocytes. Oncogene 25, 2170–2180 (2006). https://doi.org/10.1038/sj.onc.1209255

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1209255

Keywords

This article is cited by

Search

Advanced search

Quick links