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:

Phosphorylation of forkhead transcription factors by erythropoietin and stem cell factor prevents acetylation and their interaction with coactivator p300 in erythroid progenitor cells

Oncogene volume 21, pages 1556–1562 (2002)Cite this article

Abstract

The mammalian forkhead transcription factors, FOXO3a (FKHRL1), FOXO1a (FKHR) and FOXO4 (AFX) are negatively regulated by PKB/Akt kinase. In the present study we examined the engagement of forkhead family of transcription factors in erythropoietin (Epo)- and stem cell factor (SCF)-mediated signal transduction. Our data show that all three forkhead family members, FOXO3a, FOXO1a and FOXO4 are phosphorylated in human primary erythroid progenitors. Experiments performed to determine various upstream signaling pathways contributing to phosphorylation of forkhead family members show that only PI-3-kinase pathway is required for inactivation of FOXO3a. Our data also demonstrate that during Epo deprivation FOXO3a interacts with the transcriptional coactivator p300 and such interaction is disrupted by stimulation of cells with Epo. To determine the domains in FOXO3a, mediating its interaction with p300, we performed GST pull-down assays and found that the N-terminus region containing the first 52 amino acids was sufficient for binding p300. Finally, our data demonstrate that FOXO3a and FOXO1a are acetylated during growth factor deprivation and such acetylation is reversed by stimulation with Epo. Thus mammalian forkhead transcription factors are involved in Epo and SCF signaling in primary erythroid progenitors and may play a role in the induction of apoptotic and mitogenic signals.

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

Abbreviations

FH:

forkhead transcription factor

CBP:

CREB-binding protein

HAT:

histone acetyl transferase

PAGE:

polyacrylamide gel electrophoresis

GST:

glutathione S-transferase

CFU-E:

colony forming unit-erythroid

GSK:

glucocorticoid-inducible kinase

ASK1:

apoptosis signal-regulating kinase

References

  • Avantaggiati ML, Ogryzko V, Gardner K, Giordano A, Levine AS, Kelly K . 1997 Cell 89: 1175–1184

  • Bao H, Jacobs-Helber SM, Lawson AE, Penta K, Wickrema A, Sawyer ST . 1999 Blood 93: 3757–3773

  • Biggs WH, Meisenhelder J, Hunter T, Cavenee WK, Arden KC . 1999 Proc. Natl. Acad. Sci. USA 96: 7421–7426

  • Blobel GA . 2000 Blood 95: 745–755

  • Blobel GA, Nakajima T, Eckner R, Montominy M, Orkin SH . 1998 Proc. Natl. Acad. Sci. USA 95: 2061–2066

  • Boyes J, Byfield P, Nakatani Y, Ogryzko V . 1998 Nature 396: 594–598

  • Brunet A, Bonni A, Zigmond M, Lin M, Juo P, Hu L, Anderson M, Arden K, Blenis J, Greenberg M . 1999 Cell 96: 857–868

  • Cardone MH, Roy N, Stennicke HR, Salvesen GS, Franke TF, Stanbridge E, Frisch S, Reed JC . 1998 Science 282: 1318–1321

  • Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg ME . 1997 Cell 91: 231–241

  • Dijkers PF, Medema RH, Pals C, Banerji L, Thomas NSB, Lam EWF, Burgering BMT, Raaijmakers JAM, Lammers JWJ, Koenderman L, Coffer PJ . 2000 Mol. Cell. Biol. 20: 9138–9148

  • Gu W, Roeder RG . 1997 Cell 90: 595–606

  • Guo S, Cichy SB, He X, Yang Q, Ragland M, Ghosh AK, Jonson PF, Unterman TG . 2001 J. Biol. Chem. 276: 8516–8523

  • Huang S, Qiu Y, Stein RW, Brandt SJ . 1999 Oncogene 18: 4958–4967

  • Hung H-L, Lau J, Kim AY, Weiss MJ, Blobel GA . 1999 Mol. Cell. Biol. 19: 3496–3505

  • Kaestner KH, Knochel W, Martinez DE . 2001 Genes Dev. 14: 142–146

  • Kashii Y, Uchida M, Kirito K, Tanaka M, Nishijima K, Toshima M, Ando T, Koizumi K, Endoh T, Sawada K, Momoi M, Miura Y, Ozawa K, Komatsu N . 2000 Blood 96: 941–949

  • Kim AH, Khursigara G, Sun X, Franke TF, Chao MV . 2001 Mol. Cell. Biol. 21: 893–901

  • Koury MJ, Bondurant MC . 1990 Science 248: 378–381

  • Krantz SB . 1991 Blood 77: 419–434

  • Lee JS, See RH, Deng T, Shi Y . 1996 Mol. Cell. Biol. 16: 4312–4326

  • Medema RH, Kops GJPL, Bos JL, Burgering BMT . 2000 Nature 404: 782–787

  • Miura O, D'Andrea A, Kabat D, Ihle JW . 1991 Mol. Cell Biol. 11: 4895–4902

  • Muta K, Krantz SB, Bondurant MC, Wickrema A . 1994 J. Clin. Invest. 94: 34–43

  • Nakae J, Park BC, Accili D . 1999 J. Biol. Chem. 274: 15982–15985

  • Nasrin N, Ogg S, Cahill CM, Biggs W, Nui S, Dore J, Calvo D, Shi Y, Ruvkun G, Alexander-Bridges MC . 2000 Proc. Natl. Acad. Sci USA 97: 10412–10417

  • Ogg S, Gottlieb S, Paradis S, Patterson GI, Lee L, Tissenbaum HA, Ruvkin G . 1997 Nature 389: 994–999

  • Paradis S, Ruvkun C . 1998 Genes Dev. 12: 2488–2498

  • Park J, Leong ML, Buse P, Maiyar AC, Firestone GL, Hemmings BA . 1999 EMBO J. 18: 3024–3033

  • Rena G, Guo S, Cichy S, Unterman T, Cohen P . 1999 J. Biol. Chem. 274: 17179–17183

  • Tanaka M, Kirito K, Kashii V, Uchida M, Watanabe T, Endo H, Endoh T, Sawada K, Ozawa K, Komatsu N . 2001 J. Biol. Chem. 276: 15082–15089

  • Uddin S, Kottegoda S, Stigger D, Platanias LC, Wickrema A . 2000 Biochem. Biophys. Res. Com. 275: 16–19

  • Wickrema A, Uddin S, Sharma A, Chen F, Alsayed Y, Ahmad S, Sawyer ST, Krystal G, Yi T, Nishada K, Hibi M, Hirano T, Platanias LC . 1999 J. Biol. Chem. 274: 24469–24474

  • Zeng X, Li X, Miller A, Yuan Z, Yuan W, Kwok RPS, Goodman R, Lu H . 2000 Mol. Cell. Biol. 20: 1299–1310

Download references

Acknowledgements

We thank Michael Greenberg for FKHRL1 plasmid constructs, Jing Lee for phospho specific FKHRL1/FkHR antibodies and Stephen Sawyer for HCD57 cell line. We also wish to thank Toni Clark for her technical assistance. This work was supported in part by an American Cancer Society Grants to A Wickrema and S Uddin and the Wendy Will Case Cancer Fund to A Wickrema.

Author information

Authors and Affiliations

  1. Section of Hematology/Oncology, University of Chicago, Chicago, Illinois, USA

    Shahab Uddin & Amittha Wickrema

  2. The University of Illinois Medical Center, Chicago, Illinois, USA

    Dolores L Mahmud, Maaza G-Amlak, Dilip K Deb & Leonidas C Platanias

Authors
  1. Dolores L Mahmud
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maaza G-Amlak
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dilip K Deb
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Leonidas C Platanias
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shahab Uddin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Amittha Wickrema
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Amittha Wickrema.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mahmud, D., G-Amlak, M., Deb, D. et al. Phosphorylation of forkhead transcription factors by erythropoietin and stem cell factor prevents acetylation and their interaction with coactivator p300 in erythroid progenitor cells. Oncogene 21, 1556–1562 (2002). https://doi.org/10.1038/sj.onc.1205230

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1205230

Keywords

This article is cited by

Search

Advanced search

Quick links