Skip to main content

Advertisement

SpringerLink
Log in

Transcription factor FBI-1 acts as a dual regulator in adipogenesis by coordinated regulation of cyclin-A and E2F-4

  • Original Article
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

Generation of new adipocytes plays a major role in the development of obesity. We previously have shown that transcriptional repressor factor that binds to IST (FBI)-1 exerts a dual effect in the process of adipogenesis by inhibiting proliferation and promoting differentiation of preadipocytes. The aim of the present study was to identify FBI-1 regulated molecular effectors that could account for these effects. Overexpressing FBI-1 in preadipocytes resulted in reduced expression of the cell cycle regulator cyclin A, which may explain FBI-1 induced inhibition of proliferation. Interestingly, FBI-1 repressed cyclin A promoter activity through an indirect mechanisms that did not involve direct binding of FBI-1 to the promoter sequence, but rather FBI-1 inhibition of transcriptional activator Sp1 binding to a regulatory element at −452 to −443. We also show that FBI-1 promotes terminal preadipocyte differentiation through a mechanism involving decreased levels of expression of the PPARγ inhibitor E2F-4. FBI-1 significantly reduced E2F-4 promoter activity. Contrary to cyclin A, we found FBI-1-induced repression of E2F-4 is mediated by a direct mechanism via a FBI-1 regulatory element at −11 to −5. As function of transcriptional repressors normally depends on the presence of regulatory co-factors we also performed expression profiling of potential FBI-1 co-repressors throughout adipogenesis. In these experiments Sin3A and histon deacetylase (HDAC)-1 showed a similar expression pattern compared to FBI-1. Strikingly, co-immunoprecipitation studies revealed that FBI-1 binds Sin3A and HDAC-1 to form a repressor complex. Furthermore, by mutational analysis the amino terminal Poxvirus (POZ) domain of FBI-1 was found to be important for Sin3A and HDAC-1 binding. Taken together, FBI-1 is the first transcriptional repressor shown to act as a dual regulator in adipogenesis exerting repressor activities on target genes by both, direct and indirect mechanisms.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. Kahn BB, Flier JS (2000) Obesity and insulin resistance. J Clin Invest 106:473–481

    Article  PubMed  CAS  Google Scholar 

  2. Tang QQ, Otto TC, Lane MD (2003) CCAAT/enhancer-binding protein beta is required for mitotic clonal expansion during adipogenesis. Proc Natl Acad Sci U S A 100:850–855

    Article  PubMed  CAS  Google Scholar 

  3. Albagli-Curiel O, Dhordain P, Lantoine D, Aurade F, Quief S, Kerckaert JP, Montarras D, Pinset C (1998) Increased expression of the LAZ3 (BCL6) proto-oncogene accompanies murine skeletal myogenesis. Differentiation 64:33–44

    Article  PubMed  CAS  Google Scholar 

  4. Kumagai T, Miki T, Kikuchi M, Fukuda T, Miyasaka N, Kamiyama R, Hirosawa S (1999) The proto-oncogene Bc16 inhibits apoptotic cell death in differentiation-induced mouse myogenic cells. Oncogene 18:467–475

    Article  PubMed  CAS  Google Scholar 

  5. Labbaye C, Quaranta MT, Pagliuca A, Militi S, Licht JD, Testa U, Peschle C (2002) PLZF induces megakaryocytic development, activates Tpo receptor expression and interacts with GATA1 protein. Oncogene 21:6669–6679

    Article  PubMed  CAS  Google Scholar 

  6. Kukita A, Kukita T, Ouchida M, Maeda H, Yatsuki H, Kohashi O (1999) Osteoclast-derived zinc finger (OCZF) protein with POZ domain, a possible transcriptional repressor, is involved in osteoclastogenesis. Blood 94:1987–1997

    PubMed  CAS  Google Scholar 

  7. Davies JM, Hawe N, Kabarowski J, Huang QH, Zhu J, Brand NJ, Leprince D, Dhordain P, Cook M, Morriss-Kay G, Zelent A (1999) Novel BTB/POZ domain zinc-finger protein, LRF, is a potential target of the LAZ-3/BCL-6 oncogene. Oncogene 18:365–75

    Article  PubMed  CAS  Google Scholar 

  8. Pessler F, Pendergrast PS, Hernandez N (1997) Purification and characterization of FBI-1, a cellular factor that binds to the human immunodeficiency virus type 1 inducer of short transcripts. Mol Cell Biol 17:3786–3798

    PubMed  CAS  Google Scholar 

  9. Laudes M, Christodoulides C, Sewter C, Rochford JJ, Considine RV, Sethi JK, Vidal-Puig A, O'Rahilly S (2004) Role of the POZ zinc finger transcription factor FBI-1 in human and murine adipogenesis. J Biol Chem 279:11711–11718

    Article  PubMed  CAS  Google Scholar 

  10. Henglein B, Chenivesse X, Wang J, Eick D, Brechot C (1994) Structure and cell cycle-regulated transcription of the human cyclin A gene. Proc Natl Acad Sci U S A 9:5490–5494

    Article  Google Scholar 

  11. Fajas L, Landsberg RL, Huss-Garcia Y, Sardet C, Lees JA, Auwerx J (2002) E2Fs regulate adipocyte differentiation. Dev Cell 3:39–49

    Article  PubMed  CAS  Google Scholar 

  12. Chauchereau A, Mathieu M, de Saintignon J, Ferreira R, Pritchard LL, Mishal Z, Dejean A, Harel-Bellan A (2004) HDAC4 mediates transcriptional repression by the acute promyelocytic leukaemia-associated protein PLZF. Oncogene 23:8777–8784

    Article  PubMed  CAS  Google Scholar 

  13. Dhordain P, Lin RJ, Quief S, Lantoine D, Kerckaert JP, Evans RM, Albagli O (1998) The LAZ3(BCL-6) oncoprotein recruits a SMRT/mSIN3A/histone deacetylase containing complex to mediate transcriptional repression. Nucleic Acids Res 26:4645–4651

    Article  PubMed  CAS  Google Scholar 

  14. Richon VM, Emiliani S, Verdin E, Webb Y, Breslow R, Rifkind RA, Marks PA (1998) A class of hybrid polar inducers of transformed cell differentiation inhibits histone deacetylases. Proc Natl Acad Sci U S A 95:3003–3007

    Article  PubMed  CAS  Google Scholar 

  15. Pessler F, Hernandez N (2003) Flexible DNA binding of the BTB/POZ-domain protein FBI-1. J Biol Chem 278:29327–29335

    Article  PubMed  CAS  Google Scholar 

  16. Suske G (1999) The Sp-family of transcription factors. Review. Gene 238:291–300

    Article  PubMed  CAS  Google Scholar 

  17. Lee DK, Suh D, Edenberg HJ, Hur MW (2002) POZ domain transcription factor, FBI-1, represses transcription of ADH5/FDH by interacting with the zinc finger and interfering with DNA binding activity of Sp1. J Biol Chem 277:26761–26768

    Article  PubMed  CAS  Google Scholar 

  18. David G, Alland L, Hong SH, Wong CW, DePinho RA, Dejean A (1998) Histone deacetylase associated with mSin3A mediates repression by the acute promyelocytic leukemia-associated PLZF protein. Oncogene 16:2549–2556

    Article  PubMed  CAS  Google Scholar 

  19. Wolffe AP, Guschin D (2000) Chromatin structural features and targets that regulate transcription. Review. J Struct Biol 129:102–122

    Article  PubMed  CAS  Google Scholar 

  20. Fischle W, Kiermer V, Dequiedt F, Verdin E (2001) The emerging role of class II histone deacetylases. Review. Biochem Cell Biol 79:337–348

    Article  PubMed  CAS  Google Scholar 

  21. Hong SH, David G, Wong CW, Dejean A, Privalsky ML (1997) SMRT corepressor interacts with PLZF and with the PML-retinoic acid receptor alpha (RARalpha) and PLZF-RARalpha oncoproteins associated with acute promyelocytic leukemia. Proc Natl Acad Sci U S A 94:9028–9033

    Article  PubMed  CAS  Google Scholar 

  22. Yoo EJ, Chung JJ, Choe SS, Kim KH, Kim JB (2006) Down-regulation of histone deacetylases stimulates adipocyte differentiation. J Biol Chem 281:6608–6615

    Article  PubMed  Google Scholar 

  23. Zhu L, Skoultchi AI (2001) Coordinating cell proliferation and differentiation. Curr Opin Genet Dev 11:91–97

    Article  PubMed  CAS  Google Scholar 

  24. Guo K, Wang J, Andres V, Smith RC, Walsh K (1995) MyoD-induced expression of p21 inhibits cyclin-dependent kinase activity upon myocyte terminal differentiation. Mol Cell Biol 15:3823–3829

    PubMed  CAS  Google Scholar 

  25. Halevy O, Novitch BG, Spicer DB, Skapek SX, Rhee J, Hannon GJ, Beach D, Lassar AB (1995) Correlation of terminal cell cycle arrest of skeletal muscle with induction of p21 by MyoD. Science 267:1018–1021

    Article  PubMed  CAS  Google Scholar 

  26. Yeyati PL, Shaknovich R, Boterashvili S, Li J, Ball HJ, Waxman S, Nason-Burchenal K, Dmitrovsky E, Zelent A, Licht JD (1999) Leukemia translocation protein PLZF inhibits cell growth and expression of cyclin A. Oncogene 18:925–934

    Article  PubMed  CAS  Google Scholar 

  27. Melnick A, Carlile G, Ahmad KF, Kiang CL, Corcoran C, Bardwell V, Prive GG, Licht JD (2002) Critical residues within the BTB domain of PLZF and Bcl-6 modulate interaction with corepressors. Mol Cell Biol 22:1804–1818

    Article  PubMed  CAS  Google Scholar 

  28. Harbour JW, Dean DC (2000) The Rb/E2F pathway: expanding roles and emerging paradigms. Genes Dev 14:2393–2409

    Article  PubMed  CAS  Google Scholar 

  29. Gaubatz S, Lindeman GJ, Ishida S, Jakoi L, Nevins JR, Livingston DM, Rempel RE (2000) E2F4 and E2F5 play an essential role in pocket protein-mediated G1 control. Mol Cell 3:729–735

    Article  Google Scholar 

  30. Schubot FD, Tropea JE, Waugh DS (2006) Structure of the POZ domain of human LRF, a master regulator of oncogenesis. Biochem Biophys Res Commun 351:1–6

    Article  PubMed  Google Scholar 

  31. Stogios PJ, Chen L, Prive GG (2007) Crystal structure of the BTB domain from the LRF/ZBTB7 transcriptional regulator. Protein Sci 16:336–342

    Article  PubMed  Google Scholar 

  32. Liu CJ, Prazak L, Fajardo M, Yu S, Tyagi N, Di Cesare PE (2004) Leukemia/lymphoma-related factor, a POZ domain-containing transcriptional repressor, interacts with histone deacetylase-1 and inhibits cartilage oligomeric matrix protein gene expression and chondrogenesis. J Biol Chem 279:47081–47091

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the Deutsche Forschungsgemeinschaft (DFG), grant: LA1347/3-1. We thank Antonio Vidal-Puig, Robert K. Semple and Justin J. Rochford from the Department of Clinical Biochemistry of the University of Cambridge (UK) for useful advice and discussions.

Author information

Authors and Affiliations

  1. Department of Internal Medicine II and Centre of Molecular Medicine Cologne (CMMC), University of Cologne, Kerpener Strasse 62, 50937, Cologne, Germany

    Matthias Laudes, Roman Bilkovski, Frank Oberhauser, Andrea Droste, Matthias Gomolka, Uschi Leeser, Michael Udelhoven & Wilhelm Krone

Authors
  1. Matthias Laudes
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Roman Bilkovski
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Frank Oberhauser
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Andrea Droste
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Matthias Gomolka
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Uschi Leeser
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Michael Udelhoven
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Wilhelm Krone
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Matthias Laudes.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Laudes, M., Bilkovski, R., Oberhauser, F. et al. Transcription factor FBI-1 acts as a dual regulator in adipogenesis by coordinated regulation of cyclin-A and E2F-4. J Mol Med 86, 597–608 (2008). https://doi.org/10.1007/s00109-008-0326-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-008-0326-2

Keywords

Search

Navigation