Skip to main content
SpringerLink
Log in

A role of both NF-κB pathways in expression and transcription regulation of BAFF-R gene in multiple myeloma cells

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

Abstract

B-lymphocyte stimulator (BAFF) is a recently recognized member of the tumor necrosis factor ligand family (TNF) and a potent cell-survival factor expressed in many hematopoietic cells. BAFF regulates B-cell survival, differentiation, and proliferation by binding to three TNF receptors: TACI, BCMA, and BAFF-R. The mechanism involved in BAFF-R gene expression and regulation remains elusive. In this study, we examined BAFF-R gene expression, function, and regulation in multiple myeloma (KM3) cells. It was found that BAFF–BAFF-R induced cell survival by activating NF-κB1 pathway and NF-κB2 pathway. It was also found that NF-κB was an important transcription factor involved in regulating BAFF-R expression through one NF-κB binding site in the BAFF-R promoter, suggesting that inhibiting NF-κB could decrease the expression of BAFF-R mRNA and protein, and promote activity of BAFF-R gene. Our findings indicate that both NF-κB pathways are involved in the regulation of BAFF-R gene and the NF-κB-binding site of BAFF-R may be a new therapeutic target in this disease.

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
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Moore PA, Belvedere O, Orr A et al (1999) BLyS: member of the tumor necrosis factor family and B lymphocyte stimulator. Science 285:260–263

    Article  PubMed  CAS  Google Scholar 

  2. Shu HB, Hu WH, Johnson H (1999) TALL-1 is a novel member of the TNF family that is down-regulated by mitogens. J Leukoc Biol 65:680–686

    PubMed  CAS  Google Scholar 

  3. Batten M, Fletcher C, Ng LG et al (2004) TNF deficiency fails to protect BAFF transgenic mice against autoimmunity and reveals a predisposition to B cell lymphoma. J Immunol 172:812–822

    PubMed  CAS  Google Scholar 

  4. Thompson JS, Bixler SA, Qian F et al (2001) BAFF-R, a newly identified TNF receptor that specifically interacts with BAFF. Science 293:2108–2111

    Article  PubMed  CAS  Google Scholar 

  5. Khare SD, Sarosi I, Xia XZ et al (2000) Severe B cell hyperplasia and autoimmune disease in TALL-1 transgenic mice. Proc Natl Acad Sci USA 97:3370–3375

    Article  PubMed  CAS  Google Scholar 

  6. Novak AJ, Grote DM, Stenson M et al (2004) Expression of BLyS and its receptors in B-cell non-Hodgkin lymphoma: correlation with disease activity and patient outcome. Blood 104:2247–2253

    Article  PubMed  CAS  Google Scholar 

  7. Fu L, Lin-Lee YC, Pham LV et al (2006) Constitutive NF-kappaB and NFAT activation leads to stimulation of the BLyS survival pathway in aggressive B-cell lymphomas. Blood 107:4540–4548

    Article  PubMed  CAS  Google Scholar 

  8. Ju S, Zhang D, Wang Y et al (2006) Correlation of the expression levels of BLyS and its receptors mRNA in patients with systemic lupus erythematosus. Clin Biochem 39:1131–1137

    Article  PubMed  CAS  Google Scholar 

  9. Wang H, Marsters SA, Baker T et al (2001) TACI-ligand interactions are required for T cell activation and collagen-induced arthritis in mice. Nat Immunol 2:632–637

    Article  PubMed  CAS  Google Scholar 

  10. Kern C, Cornuel JF, Billard C et al (2004) Involvement of BAFF and APRIL in the resistance to apoptosis of B-CLL through an autocrine pathway. Blood 103:679–688

    Article  PubMed  CAS  Google Scholar 

  11. Ghosh S, May MJ, Kopp EB (1998) NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol 16:225–260

    Article  PubMed  CAS  Google Scholar 

  12. Senftleben U, Cao Y, Xiao G et al (2001) Activation by IKKalpha of a second, evolutionary conserved, NF-kappa B signaling pathway. Science 293:1495–1499

    Article  PubMed  CAS  Google Scholar 

  13. Kayagaki N, Yan M, Seshasayee D et al (2002) BAFF/BLyS receptor 3 binds the B cell survival factor BAFF ligand through a discrete surface loop and promotes processing of NF-kappaB2. Immunity 17:515–524

    Article  PubMed  CAS  Google Scholar 

  14. Karin M, Ben-Neriah Y (2000) Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity. Annu Rev Immunol 8:621–663

    Article  Google Scholar 

  15. Aggarwal BB (2004) Nuclear factor-kappaB: the enemy within. Cancer Cell 6:203–208

    Article  PubMed  CAS  Google Scholar 

  16. Baldwin AS (2001) Control of oncogenesis and cancer therapy resistance by the transcription factor NF-kappaB. J Clin Invest 107:241–246

    Article  PubMed  CAS  Google Scholar 

  17. Jiang P, Yueguo W, Huiming H et al (2009) B-Lymphocyte stimulator: a new biomarker for multiple myeloma. Eur J Haematol 82:267–276

    Article  PubMed  Google Scholar 

  18. Wada K, Maeda K, Tajima K et al (2009) Expression of BAFF-R and TACI in reactive lymphoid tissues and B-cell lymphomas. Histopathology 54:221–232

    Article  PubMed  Google Scholar 

  19. Bian M, Yu M, Yang S et al (2008) Expression of Cbl-interacting protein of 85 kDa in MPTP mouse model of Parkinson’s disease and 1-methyl-4-phenyl-pyridinium ion-treated dopaminergic SH-SY5Y cells. Acta Biochim Biophys 40:505–512

    CAS  Google Scholar 

  20. Smirnova IV, Bittel DC, Ravindra R et al (2000) Zinc and cadmium can promote rapid nuclear translocation of metal response element-binding transcription factor-1. J Biol Chem 275:9377–9384

    Article  PubMed  CAS  Google Scholar 

  21. Day ES, Cachero TG, Qian F et al (2005) Selectivity of BAFF/BLyS and APRIL for binding to the TNF family receptors. Biochemistry 44:1919–1931

    Article  PubMed  CAS  Google Scholar 

  22. Khan WN (2009) B cell receptor and BAFF receptor signaling regulation of B cell homeostasis. J Immunol 183:3561–3567

    Article  PubMed  CAS  Google Scholar 

  23. Rauch M, Tussiwand R, Bosco N et al (2009) Crucial role for BAFF–BAFF-R signaling in the survival and maintenance of mature B cells. PLoS One 4:e5456

    Article  PubMed  Google Scholar 

  24. Fu L, Lin-Lee YC, Pham LV et al (2009) BAFF-R promotes cell proliferation and survival through interaction with IKKbeta and NF-kappaB/c-Rel in the nucleus of normal and neoplastic B-lymphoid cells. Blood 113:4627–4636

    Article  PubMed  CAS  Google Scholar 

  25. Shinners NP, Carlesso G, Castro I et al (2007) Bruton’s tyrosine kinase mediates NF-kappa B activation and B cell survival by B cell-activating factor receptor of the TNF-R family. J Immunol 179:3872–3880

    PubMed  CAS  Google Scholar 

  26. Endo T, Nishio M, Enzler T et al (2007) BAFF and APRIL support chronic lymphocytic leukemia B-cell survival through activation of the canonical NF-kappaB pathway. Blood 109:703–710

    Article  PubMed  CAS  Google Scholar 

  27. Gross JA, Johnston J, Mudri S et al (2000) TACI and BCMA are receptors for a TNF homologue implicated in B-cell autoimmune disease. Nature 404:995–999

    Article  PubMed  CAS  Google Scholar 

  28. Litinskiy MB, Nardelli B, Hilbert DM et al (2002) DCs induce CD40-independent immunoglobulin class switching through BLyS and APRIL. Nat Immunol 3:822–829

    Article  PubMed  CAS  Google Scholar 

  29. Hideshima T, Chauhan D, Richardson P et al (2002) NF-kappa B as a therapeutic target in multiple myeloma. J Biol Chem 277:16639–16647

    Article  PubMed  CAS  Google Scholar 

  30. Frelin C, Imbert V, Griessinger E et al (2005) Targeting NF-kappaB activation via pharmacologic inhibition of IKK2-induced apoptosis of human acute myeloid leukemia cells. Blood 105:804–811

    Article  PubMed  CAS  Google Scholar 

  31. Hideshima T, Chauhan D, Richardson P et al (2002) NF-kappa B as a therapeutic target in multiple myeloma. J Biol Chem 77:16639–16647

    Article  Google Scholar 

Download references

Acknowledgments

This study was supported by the Key Subject of Jiangsu Province (XK20070302), the Six Major Human Resources Project of Jiangsu Province, and Jiangsu provincial Government Scholarship.

Author information

Authors and Affiliations

  1. Laboratory Medicine Center, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, 226001, Jiangsu, People’s Republic of China

    Xianjuan Shen, Wencai Zhu, Xia Zhang, Guang Xu & Shaoqing Ju

  2. Surgical Comprehensive Laboratory, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, 226001, Jiangsu, People’s Republic of China

    Shaoqing Ju

  3. Public Health School of Nantong University, Nantong, 226001, Jiangsu, People’s Republic of China

    Shaoqing Ju

Authors
  1. Xianjuan Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wencai Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xia Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Guang Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shaoqing Ju
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shaoqing Ju.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shen, X., Zhu, W., Zhang, X. et al. A role of both NF-κB pathways in expression and transcription regulation of BAFF-R gene in multiple myeloma cells. Mol Cell Biochem 357, 21–30 (2011). https://doi.org/10.1007/s11010-011-0871-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-011-0871-9

Keywords

Search

Navigation