Skip to main content
SpringerLink
Log in

Macrophage migration inhibitory factor does not modulate co-activation of androgen receptor by Jab1/CSN5

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Macrophage migration inhibitory factor (MIF) is a pro-inflammatory immune modulator that plays an important role in the regulation of innate and adaptive immune responses. MIF signaling involves CD74/CD44 membrane receptor complexes, the chemokine receptors CXCR2 and 4 as well as uptake by non-receptor mediated endocytosis. Endocytosed or endogenous MIF interacts with Jun activation domain-binding protein 1 (Jab1), originally described as transcriptional co-activator for the transcription factor AP-1, that is also known as subunit 5 of the COP9 signalosome (CSN5). Since Jab1/CSN5 also functions as a co-activator for a number of steroid hormone receptors (SHRs), it had been speculated that MIF could modulate Jab1/CSN5–SHR interactions. Here we show (i) that fluorescently labeled MIF is internalized by NIH 3T3 cells within minutes, (ii) compromises the induction of phospho-c-Jun levels by TNFα and PMA and, hence, is biologically active, but (iii) is not able to interfere with co-activation by Jab1/CSN5 of the androgen receptor.

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.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

References

  1. Bozza M, Satoskar AR, Lin G, Lu B, Humbles AA, Gerard C, David JR (1999) Targeted disruption of migration inhibitory factor gene reveals its critical role in sepsis. J Exp Med 189:341–346

    Article  PubMed  CAS  Google Scholar 

  2. Mikulowska A, Metz CN, Bucala R, Holmdahl R (1997) Macrophage migration inhibitory factor is involved in the pathogenesis of collagen type II-induced arthritis in mice. J Immunol 158:5514–5517

    PubMed  CAS  Google Scholar 

  3. Donnelly SC, Haslett C, Reid PT, Grant IS, Wallace WA, Metz CN, Bruce LJ, Bucala R (1997) Regulatory role for macrophage migration inhibitory factor in acute respiratory distress syndrome. Nat Med 3:320–323

    Article  PubMed  CAS  Google Scholar 

  4. Lan HY, Bacher M, Yang N, Mu W, Nikolic-Paterson DJ, Metz C, Meinhardt A, Bucala R, Atkins RC (1997) The pathogenic role of macrophage migration inhibitory factor in immunologically induced kidney disease in the rat. J Exp Med 185:1455–1465

    Article  PubMed  CAS  Google Scholar 

  5. Chesney J, Metz C, Bacher M, Peng T, Meinhardt A, Bucala R (1999) An essential role for macrophage migration inhibitory factor (MIF) in angiogenesis and the growth of a murine lymphoma. Mol Med 5:181–191

    PubMed  CAS  Google Scholar 

  6. Leng L, Metz CN, Fang Y, Xu J, Donnelly S, Baugh J, Delohery T, Chen Y, Mitchell RA, Bucala R (2003) MIF signal transduction initiated by binding to CD74. J Exp Med 197:1467–1476

    Article  PubMed  CAS  Google Scholar 

  7. Shi X, Leng L, Wang T, Wang W, Du X, Li J, McDonald C, Chen Z, Murphy JW, Lolis E, Noble P, Knudson W, Bucala R (2006) CD44 is the signaling component of the macrophage migration inhibitory factor-CD74 receptor complex. Immunity 25:595–606

    Article  PubMed  CAS  Google Scholar 

  8. Bernhagen J, Krohn R, Lue H, Gregory JL, Zernecke A, Koenen RR, Dewor M, Georgiev I, Schober A, Leng L, Kooistra T, Fingerle-Rowson G, Ghezzi P, Kleemann R, McColl SR, Bucala R, Hickey MJ, Weber C (2007) MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment. Nat Med 13:587–596

    Article  PubMed  CAS  Google Scholar 

  9. Kleemann R, Grell M, Mischke R, Zimmermann G, Bernhagen J (2002) Receptor binding and cellular uptake studies of macrophage migration inhibitory factor (MIF): use of biologically active labeled MIF derivatives. J Interferon Cytokine Res 22:351–363

    Article  PubMed  CAS  Google Scholar 

  10. Rosengren E, Bucala R, Aman P, Jacobsson L, Odh G, Metz CN, Rorsman H (1996) The immunoregulatory mediator macrophage migration inhibitory factor (MIF) catalyzes a tautomerization reaction. Mol Med 2:143–149

    PubMed  CAS  Google Scholar 

  11. Kleemann R, Kapurniotu A, Frank RW, Gessner A, Mischke R, Flieger O, Juttner S, Brunner H, Bernhagen J (1998) Disulfide analysis reveals a role for macrophage migration inhibitory factor (MIF) as thiol-protein oxidoreductase. J Mol Biol 280:85–102

    Article  PubMed  CAS  Google Scholar 

  12. Kleemann R, Hausser A, Geiger G, Mischke R, Burger-Kentischer A, Flieger O, Johannes FJ, Roger T, Calandra T, Kapurniotu A, Grell M, Finkelmeier D, Brunner H, Bernhagen J (2000) Intracellular action of the cytokine MIF to modulate AP-1 activity and the cell cycle through Jab1. Nature 408:211–216

    Article  PubMed  CAS  Google Scholar 

  13. Claret FX, Hibi M, Dhut S, Toda T, Karin M (1996) A new group of conserved coactivators that increase the specificity of AP-1 transcription factors. Nature 383:453–457

    Article  PubMed  CAS  Google Scholar 

  14. Chauchereau A, Georgiakaki M, Perrin-Wolff M, Milgrom E, Loosfelt H (2000) JAB1 interacts with both the progesterone receptor and SRC-1. J Biol Chem 275:8540–8548

    Article  PubMed  CAS  Google Scholar 

  15. Gioeli D, Black BE, Gordon V, Spencer A, Kesler CT, Eblen ST, Paschal BM, Weber MJ (2006) Stress kinase signaling regulates androgen receptor phosphorylation, transcription, and localization. Mol Endocrinol 20:503–515

    Article  PubMed  CAS  Google Scholar 

  16. Da Silva JA (1999) Sex hormones and glucocorticoids: interactions with the immune system. Ann NY Acad Sci 876:102–17; discussion 117–8

    Article  PubMed  CAS  Google Scholar 

  17. Keller ET, Chang C, Ershler WB (1996) Inhibition of NFkappaB activity through maintenance of IkappaBalpha levels contributes to dihydrotestosterone-mediated repression of the interleukin-6 promoter. J Biol Chem 271:26267–26275

    Article  PubMed  CAS  Google Scholar 

  18. Sambrook J, Russell DW (2001) Molecular cloning: a laboratory manual. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York

    Google Scholar 

  19. Alen P, Claessens F, Schoenmakers E, Swinnen JV, Verhoeven G, Rombauts W, Peeters B (1999) Interaction of the putative androgen receptor-specific coactivator ARA70/ELE1alpha with multiple steroid receptors and identification of an internally deleted ELE1beta isoform. Mol Endocrinol 13:117–128

    Article  PubMed  CAS  Google Scholar 

  20. Cleutjens CB, Steketee K, van Eekelen CC, van der Korput JA, Brinkmann AO, Trapman J (1997) Both androgen receptor and glucocorticoid receptor are able to induce prostate-specific antigen expression, but differ in their growth-stimulating properties of LNCaP cells. Endocrinology 138:5293–5300

    Article  PubMed  CAS  Google Scholar 

  21. Eustice DC, Feldman PA, Colberg-Poley AM, Buckery RM and Neubauer RH (1991) A sensitive method for the detection of beta-galactosidase in transfected mammalian cells. Biotechniques 11:739–40, 742–743

    Google Scholar 

  22. Flieger O, Engling A, Bucala R, Lue H, Nickel W, Bernhagen J (2003) Regulated secretion of macrophage migration inhibitory factor is mediated by a non-classical pathway involving an ABC transporter. FEBS Lett 551:78–86

    Article  PubMed  CAS  Google Scholar 

  23. Cleutjens KB, van der Korput HA, van Eekelen CC, van Rooij HC, Faber PW, Trapman J (1997) An androgen response element in a far upstream enhancer region is essential for high, androgen-regulated activity of the prostate-specific antigen promoter. Mol Endocrinol 11:148–161

    Article  PubMed  CAS  Google Scholar 

  24. Dotzlaw H, Moehren U, Mink S, Cato AC, Iniguez Lluhi JA, Baniahmad A (2002) The amino terminus of the human AR is target for corepressor action and antihormone agonism. Mol Endocrinol 16:661–673

    Article  PubMed  CAS  Google Scholar 

  25. Deng XW, Dubiel W, Wei N, Hofmann K, Mundt K, Colicelli J, Kato J, Naumann M, Segal D, Seeger M, Carr A, Glickman M, Chamovitz DA (2000) Unified nomenclature for the COP9 signalosome and its subunits: an essential regulator of development. Trends Genet 16:202–203

    Article  PubMed  CAS  Google Scholar 

  26. Kwok SF, Solano R, Tsuge T, Chamovitz DA, Ecker JR, Matsui M, Deng XW (1998) Arabidopsis homologs of a c-Jun coactivator are present both in monomeric form and in the COP9 complex, and their abundance is differentially affected by the pleiotropic cop/det/fus mutations. Plant Cell 10:1779–1790

    Article  PubMed  CAS  Google Scholar 

  27. Seeger M, Kraft R, Ferrell K, Bech-Otschir D, Dumdey R, Schade R, Gordon C, Naumann M, Dubiel W (1998) A novel protein complex involved in signal transduction possessing similarities to 26S proteasome subunits. FASEB J 12:469–478

    PubMed  CAS  Google Scholar 

  28. Bech-Otschir D, Seeger M, Dubiel W (2002) The COP9 signalosome: at the interface between signal transduction and ubiquitin-dependent proteolysis. J Cell Sci 115:467–473

    PubMed  CAS  Google Scholar 

  29. Schweitzer K, Bozko PM, Dubiel W, Naumann M (2007) CSN controls NF-kappaB by deubiquitinylation of IkappaBalpha. Embo J 26:1532–1541

    Article  PubMed  CAS  Google Scholar 

  30. Minden A, Karin M (1997) Regulation and function of the JNK subgroup of MAP kinases. Biochim Biophys Acta 1333:F85–F104

    PubMed  CAS  Google Scholar 

  31. Wilson MP, Sun Y, Cao L, Majerus PW (2001) Inositol 1,3,4-trisphosphate 5/6-kinase is a protein kinase that phosphorylates the transcription factors c-Jun and ATF-2. J Biol Chem 276:40998–41004

    Article  PubMed  CAS  Google Scholar 

  32. Uhle S, Medalia O, Waldron R, Dumdey R, Henklein P, Bech-Otschir D, Huang X, Berse M, Sperling J, Schade R, Dubiel W (2003) Protein kinase CK2 and protein kinase D are associated with the COP9 signalosome. Embo J 22:1302–1312

    Article  PubMed  CAS  Google Scholar 

  33. Faus H, Haendler B (2006) Post-translational modifications of steroid receptors. Biomed Pharmacother 60:520–528

    Article  PubMed  CAS  Google Scholar 

  34. Chen S, Xu Y, Yuan X, Bubley GJ, Balk SP (2006) Androgen receptor phosphorylation and stabilization in prostate cancer by cyclin-dependent kinase 1. Proc Natl Acad Sci USA 103:15969–15974

    Article  PubMed  CAS  Google Scholar 

  35. Guo Z, Dai B, Jiang T, Xu K, Xie Y, Kim O, Nesheiwat I, Kong X, Melamed J, Handratta VD, Njar VC, Brodie AM, Yu LR, Veenstra TD, Chen H, Qiu Y (2006) Regulation of androgen receptor activity by tyrosine phosphorylation. Cancer Cell 10:309–319

    Article  PubMed  CAS  Google Scholar 

  36. Lin HK, Yeh S, Kang HY, Chang C (2001) Akt suppresses androgen-induced apoptosis by phosphorylating and inhibiting androgen receptor. Proc Natl Acad Sci U S A 98:7200–7205

    Article  PubMed  CAS  Google Scholar 

  37. Lue H, Thiele M, Franz J, Dahl E, Speckgens S, Leng L, Fingerle-Rowson G, Bucala R, Lüscher B, Bernhagen J (2007) Macrophage migration inhibitory factor (MIF) promotes cell survival by activation of the Akt pathway and role for CSN5/JAB1 in the control of autocrine MIF activity. Oncogene doi: 10.1038/sj.onc.1210318

  38. Lin HK, Hu YC, Yang L, Altuwaijri S, Chen YT, Kang HY, Chang C (2003) Suppression versus induction of androgen receptor functions by the phosphatidylinositol 3-kinase/Akt pathway in prostate cancer LNCaP cells with different passage numbers. J Biol Chem 278:50902–50907

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We thank Suada Fröhlich, Tamara Henke and Eva Schneider for expert technical assistance; Jürgen Bernhagen for providing pCI-neoJab1 and fruitful discussions; Aria Baniahmad for pSG5-hAR; Jan Trapman for pPSA6.1-Luc; and the Schering AG, Berlin, for generous support. K.B. received a scholarship from the Graduiertenkolleg 533 “Cell-Cell-Interaction in Reproduction”.

Author information

Authors and Affiliations

  1. Institut für Anatomie und Zellbiologie, Justus-Liebig-Universität Giessen, Aulweg 123, 35385, Giessen, Germany

    Kersten Berndt, Marcus Kim, Andreas Meinhardt & Jörg Klug

Authors
  1. Kersten Berndt
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marcus Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andreas Meinhardt
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jörg Klug
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jörg Klug.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Berndt, K., Kim, M., Meinhardt, A. et al. Macrophage migration inhibitory factor does not modulate co-activation of androgen receptor by Jab1/CSN5. Mol Cell Biochem 307, 265–271 (2008). https://doi.org/10.1007/s11010-007-9578-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-007-9578-3

Keywords

Search

Navigation