Skip to main content
SpringerLink
Log in

PDGF-induced airway smooth muscle proliferation is associated with Human antigen R activation and could be weakened by AMPK activation

  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

CyclinD1 over-expression is the key pathogenetic event underlying airway smooth muscle (ASM) proliferation. Human antigen R (HuR) is a ubiquitously expressed RNA-binding protein, and is known to regulate the expression of multiple cell cycle regulators. The aim of the study is to investigate whether HuR might also be involved in ASM proliferation. In cultured ASM cells, PDGF treatment induced a significant elevation of HuR expression at both mRNA and protein levels. Immunofluorescence analysis demonstrated PDGF might promote HuR translocation from nucleus to cytoplasma as well. RNA-interference of HuR effectively decreased PDGF-induced cyclinD1 over-expression in ASM cells. Furthermore, AMPK activation by AICAR could effectively decrease PDGF-induced HuR cytoplasmatic translocation, cyclinD1 expression and ASM cells proliferation. In conclusion, altered expression and activity of HuR might participate in PDGF-induced ASM cells cyclinD1 expression and proliferation. The effectiveness of AMPK activation indicated a novel intervention method for airway remodeling.

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

Similar content being viewed by others

Abbreviations

HuR:

Human antigen R

ASM:

Airway smooth muscle

PDGF:

Platelet-derived growth factor

AMPK:

Amp-activated protein kinase

ARE:

Adenosine and uracil (AU) rich element

References

  1. Tliba O, Panettieri RA Jr (2009) Noncontractile functions of airway smooth muscle cells in asthma. Annu Rev Physiol 71:509–535

    Article  PubMed  CAS  Google Scholar 

  2. Benayoun L, Druilhe A, Dombret MC et al (2003) Airway structural alterations selectively associated with severe asthma. Am J Respir Crit Care Med 167:1360–1368

    Article  PubMed  Google Scholar 

  3. Woodruff PG, Dolganov GM, Ferrando RE et al (2004) Hyperplasia of smooth muscle in mild to moderate asthma without changes in cell size or gene expression. Am J Respir Crit Care Med 169:1001–1006

    Article  PubMed  Google Scholar 

  4. Page K, Li J, Corbit KC et al (2002) Regulation of airway smooth muscle cyclinD1 transcription by protein kinase C-delta. Am J Respir Cell Mol Biol 27:204–213

    PubMed  CAS  Google Scholar 

  5. Ravenhall C, Guida E, Harris T et al (2000) The importance of ERK activity in the regulation of cyclinD1 levels and DNA synthesis in human cultured airway smooth muscle. Br J Pharmacol 131(1):17–28

    Article  PubMed  CAS  Google Scholar 

  6. Vlahos R, Lee KS, Guida E et al (2003) Differential inhibition of thrombin- and EGF-stimulated human cultured airway smooth muscle proliferation by glucocorticoids. Pulm Pharmacol Ther 16(3):171–180

    Article  PubMed  CAS  Google Scholar 

  7. Hawker KM, Johnson PR, Hughes JM et al (1998) Interleukin-4 inhibits mitogen-induced proliferation of human airway smooth muscle cells in culture. Am J Physiol 275(3 Pt 1):L469–L477

    PubMed  CAS  Google Scholar 

  8. Xiong W, Pestell RG, Watanabe G et al (1997) CyclinD1 is required for S phase traversal in bovine tracheal myocytes. Am J Physiol 272(6 Pt 1):L1205–L1210

    PubMed  CAS  Google Scholar 

  9. Fernandes DJ, Ravenhall CE, Harris T et al (2004) Contribution of the p38MAPK signalling pathway to proliferation in human cultured airway smooth muscle cells is mitogen-specific. Br J Pharmacol 142(7):1182–1190

    Article  PubMed  CAS  Google Scholar 

  10. Du CL, Xu YJ, Liu XS et al (2010) Up-regulation of cyclinD1 expression in asthma serum-sensitized human airway smooth muscle promotes proliferation via protein kinase C alpha. Exp Lung Res 36(4):201–210

    Article  PubMed  CAS  Google Scholar 

  11. Lee JH, Johnson PR, Roth M et al (2001) ERK activation and mitogenesis in human airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 280(5):L1019–L1029

    PubMed  CAS  Google Scholar 

  12. Hizli AA, Black AR, Pysz MA et al (2006) Protein kinase C alpha signaling inhibits cyclinD1 translation in intestinal epithelial cells. J Biol Chem 281(21):14596–14603

    Article  PubMed  CAS  Google Scholar 

  13. Guo Y, Harwalkar J, Stacey DW et al (2005) Destabilization of cyclinD1 message plays a critical role in cell cycle exit upon mitogen withdrawal. Oncogene 24(6):1032–1042

    Article  PubMed  CAS  Google Scholar 

  14. Dufourny B, van Teeffelen HA, Hamelers IH et al (2000) Stabilization of cyclinD1 mRNA via the phosphatidylinositol 3-kinase pathway in MCF-7 human breast cancer cells. J Endocrinol 166(2):329–338

    Article  PubMed  CAS  Google Scholar 

  15. López de Silanes I, Lal A, Gorospe M (2005) HuR: post-transcriptional paths to malignancy. RNA Biol 2(1):11–13

    Article  PubMed  Google Scholar 

  16. Guo Y, Stacey DW, Hitomi M (2002) Post-transcriptional regulation of cyclinD1 expression during G2 phase. Oncogene 21(49):7545–7556

    Article  PubMed  CAS  Google Scholar 

  17. Hinman MN, Lou H (2008) Diverse molecular functions of Hu proteins. Cell Mol Life Sci 65(20):3168–3181

    Article  PubMed  CAS  Google Scholar 

  18. Lal A, Mazan-Mamczarz K, Kawai T et al (2004) Concurrent versus individual binding of HuR and AUF-1 to common labile target mRNA. EMBO J 23:3092–3102

    Article  PubMed  CAS  Google Scholar 

  19. Eberhardt W, Doller A, Akool el-S et al (2007). Modulation of mRNA stability as a novel therapeutic approach. Pharmacol Ther 114(1):56–73

    Google Scholar 

  20. Pullmann R Jr, Juhaszova M, López de Silanes I et al (2005) Enhanced proliferation of cultured human vascular smooth muscle cells linked to increased function of RNA-binding protein HuR. J Biol Chem 280(24):22819–22826

    Article  PubMed  CAS  Google Scholar 

  21. Wang W, Yang X, Kawai T et al (2004) AMP-activated protein kinase-regulated phosphorylation and acetylation of importin alpha1: involvement in the nuclear import of RNA-binding protein HuR. J Biol Chem 279(46):48376–48388

    Article  PubMed  CAS  Google Scholar 

  22. Rajasingh J, Bord E, Luedemann C et al (2006) IL-10-induced TNF-alpha mRNA destabilization is mediated via IL-10 suppression of p38 MAP kinase activation and inhibition of HuR expression. FASEB J 20(12):2112–2114

    Article  PubMed  CAS  Google Scholar 

  23. Doller A, Akool el-S, Huwiler A et al (2008) Posttranslational modification of the AU-rich element binding protein HuR by protein kinase Cdelta elicits angiotensin II-induced stabilization and nuclear export of cyclooxygenase 2 mRNA. Mol Cell Biol 28(8):2608–2625

    Google Scholar 

  24. Kang MJ, Ryu BK, Lee MG et al (2008) NF-kappaB activates transcription of the RNA-binding factor HuR, via PI3K-AKT signaling, to promote gastric tumorigenesis. Gastroenterology 135(6):2030–2042

    Article  PubMed  CAS  Google Scholar 

  25. Heinonen M, Fagerholm R, Aaltonen K et al (2007) Prognostic role of HuR in hereditary breast cancer. Clin Cancer Res 13(23):6959–6963

    Article  PubMed  CAS  Google Scholar 

  26. Danilin S, Sourbier C, Thomas et al (2006) Role of the RNA-binding protein HuR in human renal cell carcinoma. Carcinogenesis 31(6):1018–1026

    Article  Google Scholar 

  27. Wang W, Caldwell MC, Lin S et al (2000) HuR regulates cyclin A and cyclin B1 mRNA stability during cell proliferation. EMBO J 19:2340–2350

    Article  PubMed  CAS  Google Scholar 

  28. Capaccioli S, Quattrone A, Schiavone N et al (1996) A bcl-2/IgH antisense transcript deregulates bcl-2 gene expression in human follicular lymphoma t(14;18) cell lines. Oncogene 13:105–115

    PubMed  CAS  Google Scholar 

  29. Bollig F, Winzen R, Kracht M et al (2002) Evidence for general stabilization of mRNA in response to UV light. Eur J Biochem 269:5830–5839

    Article  PubMed  CAS  Google Scholar 

  30. Chen CY, Gherzi R, Andersen JS et al (2000) Nucleolin and YB-1 are required for JNK-mediated interleukin-2 mRNA stabilization during T-cell activation. Genes Dev 14:1236–1248

    PubMed  CAS  Google Scholar 

  31. Park JW, Jang MA, Lee YH et al (2001) p53-independent elevation of p21 expression by PMA results from PKC-mediated mRNA stabilization. Biochem Biophys Res Commun 280:244–248

    Article  PubMed  CAS  Google Scholar 

  32. Wang W, Yang X, Lopez de Silanes I et al (2003) Increased AMP:ATP ratio and AMP-activated protein kinase activity during cellular senescence linked to reduced HuR function. J Biol Chem 278:27016–27023

    Article  PubMed  CAS  Google Scholar 

  33. Yun H, Lee M, Kim SS et al (2005) Glucose deprivation increases mRNA stability of vascular endothelial growth factor through activation of AMP-activated protein kinase in DU145 prostate carcinoma. J Biol Chem 280:9963–9972

    Article  PubMed  CAS  Google Scholar 

  34. Martínez-Chantar ML, Vázquez-Chantada M, Garnacho M et al (2006) S-adenosylmethionine regulates cytoplasmic HuR via AMP-activated kinase. Gastroenterology 131(1):223–232

    Article  PubMed  Google Scholar 

  35. Wang W, Fan J, Yang X et al (2002) AMP-activated kinase regulates cytoplasmic HuR. Mol Cell Biol 22:3425–3436

    Article  PubMed  CAS  Google Scholar 

  36. Zhang J, Bowden GT (2008) UVB irradiation regulates Cox-2 mRNA stability through AMPK and HuR in human keratinocytes. Mol Carcinog 47(12):974–983

    Article  PubMed  CAS  Google Scholar 

  37. Liu Y, Wan Q, Guan Q et al (2006) High-fat diet feeding impairs both the expression and activity of AMPKa in rats’ skeletal muscle. Biochem Biophys Res Commun 339(2):701–707

    Article  PubMed  CAS  Google Scholar 

  38. Wang R, Wan Q, Zhang Y et al (2007) Emodin suppresses interleukin-1beta induced mesangial cells proliferation and extracellular matrix production via inhibiting P38 MAPK. Life Sci 80(26):2481–2488

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by Shandong Natural Science Foundation (ZR2009CM043, ZR2009CQ034) and Shandong Doctoral Foundation of China (2006BS03030, BS2009YY020).

Author information

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan, China

    Pengju Zhang

  2. Department of Respiratory Medicine, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China

    Mingfeng Cao, Yi Liu, Qingrui Yang & Huaichen Li

  3. Department of Nephropathy, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China

    Zhimei Lv & Qiang Wan

  4. Department of Pathology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China

    Xiaoyan Lin

Authors
  1. Pengju Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mingfeng Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yi Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zhimei Lv
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Qingrui Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xiaoyan Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Huaichen Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Qiang Wan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Huaichen Li or Qiang Wan.

Additional information

Pengju Zhang and Mingfeng Cao contributed equally to the research.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhang, P., Cao, M., Liu, Y. et al. PDGF-induced airway smooth muscle proliferation is associated with Human antigen R activation and could be weakened by AMPK activation. Mol Biol Rep 39, 5819–5829 (2012). https://doi.org/10.1007/s11033-011-1392-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-011-1392-z

Keywords

Search

Navigation