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:

Ski can negatively regulates macrophage differentiation through its interaction with PU.1

An Erratum to this article was published on 21 February 2008

This article has been updated

Abstract

In the hematopoietic cell system, the oncoprotein Ski dramatically affects growth and differentiation programs, in some cases leading to malignant leukemia. However, little is known about the interaction partners or signaling pathways involved in the Ski-mediated block of differentiation in hematopoietic cells. Here we show that Ski interacts with PU.1, a lineage-specific transcription factor essential for terminal myeloid differentiation, and thereby represses PU.1-dependent transcriptional activation. Consistent with this, Ski inhibits the biological function of PU.1 to promote myeloid cells to differentiate into macrophage colony-stimulating factor receptor (M-CSFR)-positive macrophages. Using a Ski mutant deficient in PU.1 binding, we demonstrate that Ski–PU.1 interaction is critical for Ski's ability to repress PU.1-dependent transcription and block macrophage differentiation. Furthermore, we provide evidence that Ski-mediated repression of PU.1 is due to Ski's ability to recruit histone deacetylase 3 to PU.1 bound to DNA. Since inactivation of PU.1 is closely related to the development of myeloid leukemia and Ski strongly inhibits PU.1 function, we propose that aberrant Ski expression in certain types of myeloid cell lineages might contribute to leukemogenesis.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Change history

Abbreviations

ChIP:

chromatin immunoprecipitation

EMSA:

electrophoretic mobility shift assay

HDAC:

histone deacetylase

M-CSFR:

macrophage colony-stimulating factor receptor

TGF-β:

transforming growth factor-β

TPA:

12-O-tetradecanoylphorbol-13-acetate

TSA:

trichostatin A

References

  • Akiyoshi S, Inoue H, Hanai J, Kusanagi K, Nemoto N, Miyazono K et al. (1999). c-Ski acts as a transcriptional co-repressor in transforming growth factor-beta signaling through interaction with Smads. J Biol Chem 274: 35269–35277.

    Article  CAS  PubMed  Google Scholar 

  • Ano S, Pereira R, Pironin M, Lesault I, Milley C, Lebigot I et al. (2004). Erythroblast transformation by FLI-1 depends upon its specific DNA binding and transcriptional activation properties. J Biol Chem 279: 2993–3002.

    Article  CAS  PubMed  Google Scholar 

  • Behre G, Whitmarsh AJ, Coghlan MP, Hoang T, Carpenter CL, Zhang DE et al. (1999). c-Jun is a JNK-independent coactivator of the PU.1 transcription factor. J Biol Chem 274: 4939–4946.

    Article  CAS  PubMed  Google Scholar 

  • Beug H, Dahl R, Steinlein P, Meyer S, Deiner EM, Hayman MJ . (1995). In vitro growth of factor-dependent multipotential hematopoietic cells is induced by the nuclear oncoprotein v-Ski. Oncogene 11: 59–72.

    CAS  PubMed  Google Scholar 

  • Dahl R, Iyer SR, Owens KS, Cuylear DD, Simon MC . (2007). The transcriptional repressor GFI-1 antagonizes PU.1 activity through protein–protein interaction. J Biol Chem 282: 6473–6483.

    Article  CAS  PubMed  Google Scholar 

  • Dahl R, Kieslinger M, Beug H, Hayman MJ . (1998). Transformation of hematopoietic cells by the Ski oncoprotein involves repression of retinoic acid receptor signaling. Proc Natl Acad Sci USA 95: 11187–11192.

    Article  CAS  PubMed  Google Scholar 

  • Dahl R, Simon MC . (2003). The importance of PU.1 concentration in hematopoietic lineage commitment and maturation. Blood Cells Mol Dis 31: 229–233.

    Article  CAS  PubMed  Google Scholar 

  • Fukuchi M, Nakajima M, Fukai Y, Miyazaki T, Masuda N, Sohda M et al. (2004). Increased expression of c-Ski as a co-repressor in transforming growth factor-beta signaling correlates with progression of esophageal squamous cell carcinoma. Int J Cancer 108: 818–824.

    Article  CAS  PubMed  Google Scholar 

  • Jepsen K, Rosenfeld MG . (2002). Biological roles and mechanistic actions of co-repressor complexes. J Cell Sci 115: 689–698.

    CAS  PubMed  Google Scholar 

  • Khan MM, Nomura T, Kim H, Kaul SC, Wadhwa R, Shinagawa T et al. (2001). Role of PML and PML-RARalpha in Mad-mediated transcriptional repression. Mol Cell 7: 1233–1243.

    Article  CAS  PubMed  Google Scholar 

  • Kronenwett R, Butterweck U, Steidl U, Kliszewski S, Neumann F, Bork S et al. (2005). Distinct molecular phenotype of malignant CD34(+) hematopoietic stem and progenitor cells in chronic myelogenous leukemia. Oncogene 24: 5313–5324.

    Article  CAS  PubMed  Google Scholar 

  • Larsen J, Beug H, Hayman MJ . (1992). The v-ski oncogene cooperates with the v-sea oncogene in erythroid transformation by blocking erythroid differentiation. Oncogene 7: 1903–1911.

    CAS  PubMed  Google Scholar 

  • Larsen J, Meyer S, Steinlein P, Beug H, Hayman MJ . (1993). Transformation of chicken bone marrow cells by the v-ski oncogene. Oncogene 8: 3221–3228.

    CAS  PubMed  Google Scholar 

  • Liu X, Sun Y, Weinberg RA, Lodish HF . (2001). Ski/Sno and TGF-beta signaling. Cytokine Growth Factor Rev 12: 1–8.

    Article  CAS  PubMed  Google Scholar 

  • Luo K, Stroschein SL, Wang W, Chen D, Martens E, Zhou S et al. (1999). The Ski oncoprotein interacts with the Smad proteins to repress TGFbeta signaling. Genes Dev 13: 2196–2206.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McKercher SR, Torbett BE, Anderson KL, Henkel GW, Vestal DJ, Baribault H et al. (1996). Targeted disruption of the PU.1 gene results in multiple hematopoietic abnormalities. EMBO J 15: 5647–5658.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Metcalf D, Dakic A, Mifsud S, Di Rago L, Wu L, Nutt S . (2006). Inactivation of PU.1 in adult mice leads to the development of myeloid leukemia. Proc Natl Acad Sci USA 103: 1486–1491.

    Article  CAS  PubMed  Google Scholar 

  • Moreau-Gachelin F, Wendling F, Molina T, Denis N, Titeux M, Grimber G et al. (1996). Spi-1/PU.1 transgenic mice develop multistep erythroleukemias. Mol Cell Biol 16: 2453–2463.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nomura T, Khan MM, Kaul SC, Dong HD, Wadhwa R, Colmenares C et al. (1999). Ski is a component of the histone deacetylase complex required for transcriptional repression by Mad and thyroid hormone receptor. Genes Dev 13: 412–423.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ohneda K, Yamamoto M . (2002). Roles of hematopoietic transcription factors GATA-1 and GATA-2 in the development of red blood cell lineage. Acta Haematol 108: 237–245.

    Article  CAS  PubMed  Google Scholar 

  • Reddy VA, Iwama A, Iotzova G, Schulz M, Elsasser A, Vangala RK et al. (2002). Granulocyte inducer C/EBPalpha inactivates the myeloid master regulator PU.1: possible role in lineage commitment decisions. Blood 100: 483–490.

    Article  CAS  PubMed  Google Scholar 

  • Reed JA, Bales E, Xu W, Okan NA, Bandyopadhyay D, Medrano EE . (2001). Cytoplasmic localization of the oncogenic protein Ski in human cutaneous melanomas in vivo: functional implications for transforming growth factor beta signaling. Cancer Res 61: 8074–8078.

    CAS  PubMed  Google Scholar 

  • Rekhtman N, Radparvar F, Evans T, Skoultchi AI . (1999). Direct interaction of hematopoietic transcription factors PU.1 and GATA-1: functional antagonism in erythroid cells. Genes Dev 13: 1398–1411.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ritter M, Kattmann D, Teichler S, Hartmann O, Samuelsson MK, Burchert A et al. (2006). Inhibition of retinoic acid receptor signaling by Ski in acute myeloid leukemia. Leukemia 20: 437–443.

    Article  CAS  PubMed  Google Scholar 

  • Rosenbauer F, Wagner K, Kutok JL, Iwasaki H, Le Beau MM, Okuno Y et al. (2004). Acute myeloid leukemia induced by graded reduction of a lineage-specific transcription factor, PU.1. Nat Genet 36: 624–630.

    Article  CAS  PubMed  Google Scholar 

  • Scott EW, Simon MC, Anastasi J, Singh H . (1994). Requirement of transcription factor PU.1 in the development of multiple hematopoietic lineages. Science 265: 1573–1577.

    Article  CAS  PubMed  Google Scholar 

  • Simon MC, Olson M, Scott E, Hack A, Su G, Singh H . (1996). Terminal myeloid gene expression and differentiation requires the transcription factor PU.1. Curr Top Microbiol Immunol 211: 113–119.

    CAS  PubMed  Google Scholar 

  • Stavnezer E, Gerhard DS, Binari RC, Balazs I . (1981). Generation of transforming viruses in cultures of chicken fibroblasts infected with an avian leukosis virus. J Virol 39: 920–934.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sun Y, Liu X, Eaton EN, Lane WS, Lodish HF, Weinberg RA . (1999). Interaction of the Ski oncoprotein with Smad3 regulates TGF-beta signaling. Mol Cell 4: 499–509.

    Article  CAS  PubMed  Google Scholar 

  • Suzuki M, Yamada T, Kihara-Negishi F, Sakurai T, Oikawa T . (2003). Direct association between PU.1 and MeCP2 that recruits mSin3A-HDAC complex for PU.1-mediated transcriptional repression. Oncogene 22: 8688–8698.

    Article  CAS  PubMed  Google Scholar 

  • Tokitou F, Nomura T, Khan MM, Kaul SC, Wadhwa R, Yasukawa T et al. (1999). Viral ski inhibits retinoblastoma protein (Rb)-mediated transcriptional repression in a dominant negative fashion. J Biol Chem 274: 4485–4488.

    Article  CAS  PubMed  Google Scholar 

  • Ueki N, Hayman MJ . (2003a). Direct interaction of Ski with either Smad3 or Smad4 is necessary and sufficient for Ski-mediated repression of transforming growth factor-beta signaling. J Biol Chem 278: 32489–32492.

    Article  CAS  PubMed  Google Scholar 

  • Ueki N, Hayman MJ . (2003b). Signal-dependent N-CoR requirement for repression by the Ski oncoprotein. J Biol Chem 278: 24858–24864.

    Article  CAS  PubMed  Google Scholar 

  • Ueki N, Zhang L, Hayman MJ . (2004). Ski negatively regulates erythroid differentiation through its interaction with GATA1. Mol Cell Biol 24: 10118–10125.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vangala RK, Heiss-Neumann MS, Rangatia JS, Singh SM, Schoch C, Tenen DG et al. (2003). The myeloid master regulator transcription factor PU.1 is inactivated by AML1-ETO in t(8;21) myeloid leukemia. Blood 101: 270–277.

    Article  CAS  PubMed  Google Scholar 

  • Xu W, Angelis K, Danielpour D, Haddad MM, Bischof O, Campisi J et al. (2000). Ski acts as a co-repressor with Smad2 and Smad3 to regulate the response to type beta transforming growth factor. Proc Natl Acad Sci USA 97: 5924–5929.

    Article  CAS  PubMed  Google Scholar 

  • Zhang DE, Hetherington CJ, Chen HM, Tenen DG . (1994). The macrophage transcription factor PU.1 directs tissue-specific expression of the macrophage colony-stimulating factor receptor. Mol Cell Biol 14: 373–381.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang P, Behre G, Pan J, Iwama A, Wara-Aswapati N, Radomska HS et al. (1999). Negative cross-talk between hematopoietic regulators: GATA proteins repress PU.1. Proc Natl Acad Sci USA 96: 8705–8710.

    Article  CAS  PubMed  Google Scholar 

  • Zhang P, Zhang X, Iwama A, Yu C, Smith KA, Mueller BU et al. (2000). PU.1 inhibits GATA-1 function and erythroid differentiation by blocking GATA-1 DNA binding. Blood 96: 2641–2648.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank J Ghysdael and R Dahl for valuable reagents; K Donnelly for supporting our research project and the members of the Hayman laboratory for helpful discussions and criticisms on the manuscript. This work was supported by grant CA42573 from the National Institutes of Health (to MJH).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to M J Haymann.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ueki, N., Zhang, L. & Haymann, M. Ski can negatively regulates macrophage differentiation through its interaction with PU.1. Oncogene 27, 300–307 (2008). https://doi.org/10.1038/sj.onc.1210654

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1210654

Keywords

This article is cited by

Search

Quick links