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 Paper
  • Published:

Activation of FoxO transcription factors contributes to the antiproliferative effect of cAMP

Oncogene volume 24, pages 2087–2095 (2005)Cite this article

Abstract

cAMP is a potent inhibitor of cell proliferation in a variety of cell lines. Downregulation of cyclin D1 and upregulation of the cell cycle inhibitor p27Kip1 are two mechanisms by which cAMP may induce a G1-arrest. Here we show that cAMP inhibits proliferation of cells that constitutively express cyclin D1 or are deficient for Rb, demonstrating that changes in these cell cycle regulators do not account for the cAMP-induced growth effects in mouse embryo fibroblasts (MEFs). Interestingly, the antiproliferative effect of cAMP mimics the effect previously observed for FoxO transcription factors. These transcription factors are under negative control of protein kinase B (PKB). We show that in MEFs cAMP strongly induces transcriptional activation of FoxO4 through the inhibition of PKB. Accordingly, not only p27Kip1 but also the FoxO target MnSOD is upregulated by cAMP. Importantly, introduction of dominant-negative FoxO partially rescues cAMP-induced inhibition of proliferation. From these results we conclude that inhibition of PKB and subsequent activation of FoxO transcription factors mediates an antiproliferative effect of cAMP.

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

Similar content being viewed by others

References

  • Agrawal D, Hauser P, McPherson F, Dong F, Garcia A and Pledger WJ . (1996). Mol. Cell. Biol., 16, 4327–4336.

  • Aktas H, Cai H and Cooper GM . (1997). Mol. Cell. Biol., 17, 3850–3857.

  • Balmanno K, Millar T, McMahon M and Cook SJ . (2003). Mol. Cell. Biol., 23, 9303–9317.

  • Boehm M, Yoshimoto T, Crook MF, Nallamshetty S, True A, Nabel GJ and Nabel EG . (2002). EMBO J., 21, 3390–3401.

  • Boucher MJ, Duchesne C, Laine J, Morisset J and Rivard N . (2001). Biochem. Biophys. Res. Commun., 285, 207–216.

  • Brownawell AM, Kops GJ, Macara IG and Burgering BM . (2001). Mol. Cell. Biol., 21, 3534–3546.

  • Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J and Greenberg ME . (1999). Cell, 96, 857–868.

  • Burgering BM and Coffer PJ . (1995). Nature, 376, 599–602.

  • Burgering BM, Pronk GJ, van Weeren PC, Chardin P and Bos JL . (1993). EMBO J., 12, 4211–4220.

  • Cook SJ and McCormick F . (1993). Science, 262, 1069–1072.

  • Dannenberg JH, van Rossum A, Schuijff L and te Riele H . (2000). Genes Dev., 14, 3051–3064.

  • de Vries-Smits AM, Burgering BM, Leevers SJ, Marshall CJ and Bos JL . (1992). Nature, 357, 602–604.

  • Delmas C, Aragou N, Poussard S, Cottin P, Darbon JM and Manenti S . (2003). J. Biol. Chem., 278, 12443–12451. Epub 2003 Jan 14.

  • Diehl JA, Cheng M, Roussel MF and Sherr CJ . (1998). Genes Dev., 12, 3499–3511.

  • Dumaz N, Light Y and Marais R . (2002). Mol. Cell. Biol., 22, 3717–3728.

  • Durocher Y, Perret S and Kamen A . (2002). Nucleic Acids Res., 30, E9.

  • Fujita N, Sato S, Katayama K and Tsuruo T . (2002). J. Biol. Chem., 277, 28706–28713.

  • Furuyama T, Nakazawa T, Nakano I and Mori N . (2000). Biochem. J., 349, 629–634.

  • Hafner S, Adler HS, Mischak H, Janosch P, Heidecker G, Wolfman A, Pippig S, Lohse M, Ueffing M and Kolch W . (1994). Mol. Cell. Biol., 14, 6696–6703.

  • Hengst L and Reed SI . (1996). Science, 271, 1861–1864.

  • Kato JY, Matsuoka M, Polyak K, Massague J and Sherr CJ . (1994). Cell, 79, 487–496.

  • Kim S, Jee K, Kim D, Koh H and Chung J . (2001a). J. Biol. Chem., 276, 12864–12870. Epub 2001 Jan 26.

  • Kim TY, Kim WI, Smith RE and Kay ED . (2001b). Invest. Ophthalmol. Vis. Sci., 42, 3142–3149.

  • Kops GJ, Dansen TB, Polderman PE, Saarloos I, Wirtz KW, Coffer PJ, Huang TT, Bos JL, Medema RH and Burgering BM . (2002). Nature, 419, 316–321.

  • Kops GJ, de Ruiter ND, De Vries-Smits AM, Powell DR, Bos JL and Burgering BM . (1999). Nature, 398, 630–634.

  • Kwon TK, Nagel JE, Buchholz MA and Nordin AA . (1996). Gene, 180, 113–120.

  • L'Allemain G, Lavoie JN, Rivard N, Baldin V and Pouyssegur J . (1997). Oncogene, 14, 1981–1990.

  • Lavoie JN, L'Allemain G, Brunet A, Muller R and Pouyssegur J . (1996). J. Biol. Chem., 271, 20608–20616.

  • Lee HT and Kay EP . (2003). Invest. Ophthalmol. Vis. Sci., 44, 3816–3825.

  • Lee RJ, Albanese C, Stenger RJ, Watanabe G, Inghirami G, Haines III GK, Webster M, Muller WJ, Brugge JS, Davis RJ and Pestell RG . (1999). J. Biol. Chem., 274, 7341–7350.

  • Lee TH, Chuang LY and Hung WC . (2000). Oncogene, 19, 3766–3773.

  • Li J, Yang S and Billiar TR . (2000). J. Biol. Chem., 275, 13026–13034.

  • Liang J, Zubovitz J, Petrocelli T, Kotchetkov R, Connor MK, Han K, Lee JH, Ciarallo S, Catzavelos C, Beniston R, Franssen E and Slingerland JM . (2002). Nat. Med., 8, 1153–1160.

  • Loubat A, Rochet N, Turchi L, Rezzonico R, Far DF, Auberger P, Rossi B and Ponzio G . (1999). Oncogene, 18, 3324–3333.

  • Malek NP, Sundberg H, McGrew S, Nakayama K, Kyriakides TR, Roberts JM and Kyriakidis TR . (2001). Nature, 413, 323–327.

  • McKenzie FR and Pouyssegur J . (1996). J. Biol. Chem., 271, 13476–13483.

  • Medema RH, Kops GJ, Bos JL and Burgering BM . (2000). Nature, 404, 782–787.

  • Mischak H, Seitz T, Janosch P, Eulitz M, Steen H, Schellerer M, Philipp A and Kolch W . (1996). Mol. Cell. Biol., 16, 5409–5418.

  • Muise-Helmericks RC, Grimes HL, Bellacosa A, Malstrom SE, Tsichlis PN and Rosen N . (1998). J. Biol. Chem., 273, 29864–29872.

  • Muller D, Bouchard C, Rudolph B, Steiner P, Stuckmann I, Saffrich R, Ansorge W, Huttner W and Eilers M . (1997). Oncogene, 15, 2561–2576.

  • Nakamura N, Ramaswamy S, Vazquez F, Signoretti S, Loda M and Sellers WR . (2000). Mol. Cell. Biol., 20, 8969–8982.

  • Pagano M, Tam SW, Theodoras AM, Beer-Romero P, Del Sal G, Chau V, Yew PR, Draetta GF and Rolfe M . (1995). Science, 269, 682–685.

  • Parvathenani LK, Buescher ES, Chacon-Cruz E and Beebe SJ . (1998). J. Biol. Chem., 273, 6736–6743.

  • Ramaswamy S, Nakamura N, Sansal I, Bergeron L and Sellers WR . (2002). Cancer Cell, 2, 81–91.

  • Rao S, Gray-Bablin J, Herliczek TW and Keyomarsi K . (1999). Exp. Cell Res., 252, 211–223.

  • Schmidt M, Fernandez de Mattos S, van der Horst A, Klompmaker R, Kops GJ, Lam EW, Burgering BM and Medema RH . (2002). Mol. Cell. Biol., 22, 7842–7852.

  • Seoane J, Le HV, Shen L, Anderson SA and Massague J . (2004). Cell, 117, 211–223.

  • Sewing A, Burger C, Brusselbach S, Schalk C, Lucibello FC and Muller R . (1993). J. Cell Sci., 104, 545–555.

  • Sherr CJ and Roberts JM . (1999). Genes Dev., 13, 1501–1512.

  • Shin I, Yakes FM, Rojo F, Shin NY, Bakin AV, Baselga J and Arteaga CL . (2002). Nat. Med., 8, 1145–1152.

  • Takuwa N, Fukui Y and Takuwa Y . (1999). Mol. Cell. Biol., 19, 1346–1358.

  • Tomoda K, Kubota Y and Kato J . (1999). Nature, 398, 160–165.

  • Vadiveloo PK, Filonzi EL, Stanton HR and Hamilton JA . (1997). Atherosclerosis, 133, 61–69.

  • van Oirschot BA, Stahl M, Lens SM and Medema RH . (2001). J. Biol. Chem., 276, 33854–33860.

  • Viglietto G, Motti ML, Bruni P, Melillo RM, D'Alessio A, Califano D, Vinci F, Chiappetta G, Tsichlis P, Bellacosa A, Fusco A and Santoro M . (2002). Nat. Med., 8, 1136–1144.

  • Vlach J, Hennecke S and Amati B . (1997). EMBO J., 16, 5334–5344.

  • Williamson EA, Burgess GS, Eder P, Litz-Jackson S and Boswell HS . (1997). Leukemia, 11, 73–85.

  • Wu J, Dent P, Jelinek T, Wolfman A, Weber MJ and Sturgill TW . (1993). Science, 262, 1065–1069.

Download references

Acknowledgements

We thank Joost Das for technical assistance and other members of our lab for support and continuous discussions. This project was supported by grants from the Dutch Cancer Foundation (KWF), the Council of Earth and Life Sciences of the Dutch Organisation for Scientific Research (NWO-ALW) and from the Centre of Biomedical Genetics (CBG).

Author information

Authors and Affiliations

  1. Department of Physiological Chemistry and Centre for Biomedical Genetics, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG, Utrecht, The Netherlands

    H Bea Kuiperij, Armando van der Horst, Judith Raaijmakers, Sanne Weijzen, Johannes L Bos, Boudewijn M T Burgering & Fried J T Zwartkruis

  2. Division of Molecular Biology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

    Rene H Medema

Authors
  1. H Bea Kuiperij
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Armando van der Horst
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Judith Raaijmakers
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sanne Weijzen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Rene H Medema
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Johannes L Bos
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Boudewijn M T Burgering
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Fried J T Zwartkruis
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Fried J T Zwartkruis.

Additional information

Supplementary Information accompanies the paper on Oncogene website (http://www.nature.com/onc)

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kuiperij, H., van der Horst, A., Raaijmakers, J. et al. Activation of FoxO transcription factors contributes to the antiproliferative effect of cAMP. Oncogene 24, 2087–2095 (2005). https://doi.org/10.1038/sj.onc.1208450

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1208450

Keywords

This article is cited by

Search

Advanced search

Quick links