Advertisement

Tumor Biology

, Volume 34, Issue 6, pp 3619–3625 | Cite as

Transcription factor AP1 binds the functional region of the promoter and regulates gene expression of human PPARdelta in LoVo cell

  • Xiaogang Jiang
  • Xudong Yang
  • Yan Han
  • Shemin Lu
Research Article

Abstract

Peroxisome proliferator-activated receptor δ gene (PPARδ) is correlated with carcinogenesis of colorectal cancer, but the regulation of its gene transcription remains unclear. We herein report that AP1 binds the promoter and regulates PPARδ gene expression. With a luciferase reporter system, we identified a functional promoter region of 30 bp of PPARδ gene by deletion and electrophoretic mobility shift assays (EMSA). Using site-directed mutagenesis and decoy analyses, we demonstrated that AP1 bound the functional transcriptional factor binding site in a region extending from −176 to −73 of the PPARδ promoter, which was confirmed using EMSA and supershift assays. Consequently, inhibition of the AP1 binding site led to decreased PPARδ mRNA. Our study demonstrated that AP1 is the transcriptional factor that contributes to PPARδ expression in LoVo cells.

Keywords

Peroxisome proliferator-activated receptor (PPAR) AP1 (nuclear transcription factor activator protein-1) Electrophoresis mobility shift analysis (EMSA) Supershift Chip LoVo cells 

Notes

Conflicts of interest

None

References

  1. 1.
    Michalik L, Wahli W. Involvement of PPAR nuclear receptors in tissue injury and wound repair. J Clin Invest. 2006;116:598–606.PubMedCrossRefGoogle Scholar
  2. 2.
    Desvergne B, Wahli W. Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocr Rev. 1999;20:649–88.PubMedCrossRefGoogle Scholar
  3. 3.
    Schoonjans K, Staels B, Auwerx J. The peroxisome proliferator activated receptors (PPARs) and their effects on lipid metabolism and adipocyte differentiation. Biochim Biophys Acta. 1996;1302:93–109.PubMedCrossRefGoogle Scholar
  4. 4.
    Willson TM, Brown PJ, Sternbach DD, Henke BR. The PPARs: from orphan receptors to drug discovery. J Med Chem. 2000;43:527–50.PubMedCrossRefGoogle Scholar
  5. 5.
    Hansen MK, Connolly TM. Nuclear receptors as drug targets in obesity, dyslipidemia and atherosclerosis. Curr Opin Investig Drugs. 2008;9:247–55.PubMedGoogle Scholar
  6. 6.
    Torra IP, Chinetti G, Duval C, Fruchart JC, Staels B. Peroxisome proliferator-activated receptors: from transcriptional control to clinical practice. Curr Opin Lipidol. 2001;12:245–54.PubMedCrossRefGoogle Scholar
  7. 7.
    Wang N. PPAR-delta in vascular pathophysiology. PPAR Res. 2008;2008:164163.PubMedGoogle Scholar
  8. 8.
    Meissner M, Hrgovic I, Doll M, Kaufmann R. PPARδ agonists suppress angiogenesis in a VEGFR2-dependent manner. Arch Dermatol Res. 2011;303:41–7.PubMedCrossRefGoogle Scholar
  9. 9.
    Kostadinova R, Montagner A, Gouranton E, Fleury S, Guillou H, et al. GW501516-activated PPARβ/δ promotes liver fibrosis via p38-JNK MAPK-induced hepatic stellate cell proliferation. Cell Biosci. 2012;2:34.PubMedCrossRefGoogle Scholar
  10. 10.
    Kliewer SA, Lehmann JM, Milburn MV, Willson TM. The PPARs and PXRs: nuclear xenobiotic receptors that define novel hormone signaling pathways. Recent Prog Horm Res. 2000;54:345–67.Google Scholar
  11. 11.
    Spiegelman BM. PPAR-gamma: adipogenic regulator and thiazolidinedione receptor. Diabetes. 1998;47:507–14.PubMedCrossRefGoogle Scholar
  12. 12.
    He TC, Chan TA, Vogelstein B, Kinzler KW. PPARd is an APC regulated target of nonsteroidal anti-inflammatory drugs. Cell. 1999;99:335–45.PubMedCrossRefGoogle Scholar
  13. 13.
    Takayama O, Yamamoto H, Damdinsuren B, Sugita Y, Ngan CY, et al. Expression of PPARd in multistage carcinogenesis of the colorectum: implications of malignant cancer morphology. Br J Cancer. 2006;95:889–95.PubMedCrossRefGoogle Scholar
  14. 14.
    Harman FS, Nicol CJ, Marin HE, Ward JM, Gonzalez FJ, et al. Peroxisome proliferator-activated receptor-d attenuates colon carcinogenesis. Nat Med. 2004;10:481–3.PubMedCrossRefGoogle Scholar
  15. 15.
    Reed KR, Sansom OJ, Hayes AJ, Gescher AJ, Winton DJ, et al. PPAR delta status and Apc-mediated tumorigenesis in the mouse intestine. Oncogene. 2004;23:8992–6.PubMedCrossRefGoogle Scholar
  16. 16.
    Park BH, Vogelstein B, Kinzler KW. Genetic disruption of PPARd decreases the tumorigenicity of human colon cancer cells. Proc Natl Acad Sci USA. 2001;98:2598–603.PubMedCrossRefGoogle Scholar
  17. 17.
    Gupta RA, Wang D, Katkuri S, Wang H, Dey SK, et al. Activation of nuclear hormone receptor peroxisome proliferator activated recaptured accelerates intestinal adenoma growth. Nat Med. 2004;10:245–7.PubMedCrossRefGoogle Scholar
  18. 18.
    Zuo X, Peng Z, Moussalli MJ, Morris JS, Broaddus RR, et al. Targeted genetic disruption of peroxisome proliferator-activated receptor-delta and colonic tumorigenesis. J Natl Cancer Inst. 2009;101:762–7.PubMedCrossRefGoogle Scholar
  19. 19.
    Gupta RA, Tan J, Krause WF, Geraci MW, Willson TM, et al. Prostacyclin-mediated activation of peroxisome proliferator-activated receptor δ in colorectal cancer. Proc Natl Acad Sci USA. 2000;97:13275–80.PubMedCrossRefGoogle Scholar
  20. 20.
    Shao J, Sheng H, DuBois RN. Peroxisome proliferator-activated receptors modulate K-Ras-mediated transformation of intestinal epithelial cells. Cancer Res. 2002;62:3282–8.PubMedGoogle Scholar
  21. 21.
    Di-Poï N, Tan NS, Michalik L, Wahli W, Desvergne B. Antiapoptotic role of PPARβ in keratinocytes via transcriptional control of the Akt1 signaling pathway. Mol Cell. 2002;10:721–33.PubMedCrossRefGoogle Scholar
  22. 22.
    Wang D, Wang H, Guo Y, Ning W, Katkuri S, et al. Crosstalk between peroxisome proliferator-activated receptor δ and VEGF stimulates cancer progression. Proc Natl Acad Sci U S A. 2006;103:19069–74.PubMedCrossRefGoogle Scholar
  23. 23.
    Kwak H, Hwang I, Kim JH, Kim MY, Yang JS, et al. Modulation of transcription by the peroxisome proliferator-activated receptor δ-binding RNA aptamer in colon cancer cells. Mol Cancer Ther. 2009;8:2664–73.PubMedCrossRefGoogle Scholar
  24. 24.
    Yang L, Olsson B, Pfeifer D, Jönsson JI, Zhou ZG, et al. Knockdown of peroxisome proliferator-activated receptor-β induces less differentiation and enhances cell-fibronectin adhesion of colon cancer cells. Oncogene. 2010;29:516–26.PubMedCrossRefGoogle Scholar
  25. 25.
    Malnou CE, Brockly F, Favard C, Moquet-Torcy G, Piechaczyk M, et al. Heterodimerization with different Jun proteins controls c-Fos intranuclear dynamics and distribution. J Biol Chem. 2010;285:6552–62.PubMedCrossRefGoogle Scholar
  26. 26.
    Chen W, Bowden GT. Activation of p38 MAP kinase and ERK are required for ultraviolet-B induced c-fos gene expression in human keratinocytes. Oncogene. 1999;18:7469–76.PubMedCrossRefGoogle Scholar
  27. 27.
    Jochum W, Passegue E, Wagner EF. AP-1 in mouse development and tumorigenesis. Oncogene. 2001;20:2401–12.PubMedCrossRefGoogle Scholar
  28. 28.
    Borner C. The Bcl-2 protein family: sensors and checkpoints for life-or-death decisions. Mol Immunol. 2003;39:615–47.PubMedCrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2013

Authors and Affiliations

  • Xiaogang Jiang
    • 1
  • Xudong Yang
    • 1
  • Yan Han
    • 1
  • Shemin Lu
    • 1
  1. 1.Department of Genetics and Molecular BiologyXi’an Jiaotong University College of MedicineXi’anPeople’s Republic of China

Personalised recommendations