Human Genetics

, Volume 120, Issue 4, pp 461–469 | Cite as

A molecular mechanism for the differential regulation of TGF-β1 expression due to the common SNP −509C-T (c. −1347C > T)

  • Riddhish Shah
  • Carolyn K. Hurley
  • Phillip E. Posch
Original Investigation

Abstract

Transforming growth factor β1 (TGF-β1) levels influence many cellular, immunologic and pathologic processes. Activator protein 1 (AP1) and hypoxia are key regulators of TGF-β1 expression levels. The common TGFB1 promoter SNP c.−1347C > T (−509C-T, rs1800469) has been linked to a nearly twofold difference in plasma levels among individuals and with risk, progression, and outcome of numerous diseases. We demonstrate exclusive in vitro and in vivo recruitment of AP1 containing JunD to −1347C. This study also is the first to demonstrate hypoxia inducible factor 1 (HIF-1) binding to the TGFB1 promoter. HIF-1 was found to associate with both −1347C and −1347T and compete with AP1 for binding to −1347C. Reporter constructs demonstrate that expression differences between −1347C and −1347T are due to selective AP1 recruitment to the TGFB1 promoter. As AP1 is known to down-regulate transcription of other genes, we suggest that the molecular mechanism for the difference in TGF-β1 plasma levels linked to −1347 is due to transcriptional suppression by AP1 binding to −1347C. These data should aid in our understanding of the association of the −1347 SNP with the pathogenesis of certain TGF-β1-related diseases.

Abbreviations

SNP

Single nucleotide polymorphism

IHWS

International Histocompatibility Workshop

YY1

Yin-yang 1

References

  1. Awad MR, El Gamel A, Hasleton P, Turner DM, Sinnott PJ, Hutchinson IV (1998) Genotypic variation in the transforming growth factor-(beta)1 gene: association with transforming growth factor-(beta)1 production, fibrotic lung disease, and graft fibrosis after lung transplantation. Transplantation 66:1014–1020PubMedCrossRefGoogle Scholar
  2. Blobe GC, Schiemann WP, Lodish HF (2000) Role of transforming growth factor beta in human disease. N Engl J Med 342:1350–1358PubMedCrossRefGoogle Scholar
  3. Dery MA, Michaud MD, Richard DE (2005) Hypoxia-inducible factor 1: regulation by hypoxic and non-hypoxic activators. Int J Biochem Cell Biol 37:535–540PubMedCrossRefGoogle Scholar
  4. Drumm ML, Konstan MW, Schluchter MD, Handler A, Pace R, Zou F, Zariwala M, Fargo D, Xu A, Dunn JM, Darrah RJ, Dorfman R, Sandford AJ, Corey M, Zielenski J, Durie P, Goddard K, Yankaskas JR, Wright FA, Knowles MR (2005) Genetic modifiers of lung disease in cystic fibrosis. N Engl J Med 353:1443–1453PubMedCrossRefGoogle Scholar
  5. Dunning AM, Ellis PD, McBride S, Kirschenlohr HL, Healey CS, Kemp PR, Luben RN, Chang-Claude J, Mannermaa A, Kataja V, Pharoah PD, Easton DF, Ponder BA, Metcalfe JC (2003) A transforming growth factor beta1 signal peptide variant increases secretion in vitro and is associated with increased incidence of invasive breast cancer. Cancer Res 63:2610–2615PubMedGoogle Scholar
  6. Grainger DJ, Heathcote K, Chiano M, Snieder H, Kemp PR, Metcalfe JC, Carter ND, Spector TD (1999) Genetic control of the circulating concentration of transforming growth factor type beta1. Hum Mol Genet 8:93–97PubMedCrossRefGoogle Scholar
  7. Haukim N, Bidwell JL, Smith AJ, Keen LJ, Gallagher G, Kimberly R, Huizinga T, McDermott MF, Oksenberg J, McNicholl J, Pociot F, Hardt C, D’Alfonso S (2002) Cytokine gene polymorphism in human disease: on-line databases, supplement 2. Genes Immun 3:313–330PubMedCrossRefGoogle Scholar
  8. Jessen BA, Qin Q, Rice RH (2000) Functional AP1 and CRE response elements in the human keratinocyte transglutaminase promoter mediating Whn suppression. Gene 254:77–85PubMedCrossRefGoogle Scholar
  9. Kim SJ, Angel P, Lafyatis R, Hattori K, Kim KY, Sporn MB, Karin M, Roberts AB (1990) Autoinduction of transforming growth factor beta 1 is mediated by the AP-1 complex. Mol Cell Biol 10:1492–1497PubMedGoogle Scholar
  10. Kim SJ, Denhez F, Kim KY, Holt JT, Sporn MB, Roberts AB (1989a) Activation of the second promoter of the transforming growth factor-beta 1 gene by transforming growth factor-beta 1 and phorbol ester occurs through the same target sequences. J Biol Chem 264:19373–19378Google Scholar
  11. Kim SJ, Glick A, Sporn MB, Roberts AB (1989b) Characterization of the promoter region of the human transforming growth factor-(beta)1 gene. J Biol Chem 264:402–408Google Scholar
  12. Kim SJ, Glick A, Sporn MB, Roberts AB (1989c) Characterization of the promoter region of the human transforming growth factor-(beta)1 gene. J Biol Chem 264:402–408Google Scholar
  13. Kim YJ, Lee HS, Im JP, Min BH, Kim HD, Jeong JB, Yoon JH, Kim CY, Kim MS, Kim JY, Jung JH, Kim LH, Park BL, Shin HD (2003) Association of transforming growth factor-beta1 gene polymorphisms with a hepatocellular carcinoma risk in patients with chronic hepatitis B virus infection. Exp Mol Med 35:196–202PubMedGoogle Scholar
  14. Kim SY, Han SW, Kim GW, Lee JM, Kang YM (2004) TGF-beta1 polymorphism determines the progression of joint damage in rheumatoid arthritis. Scand J Rheumatol 33:389–394PubMedCrossRefGoogle Scholar
  15. Letterio JJ, Roberts AB (1998) Regulation of immune responses by TGF-beta. Annu Rev Immunol 16:137–161PubMedCrossRefGoogle Scholar
  16. Luedecking EK, DeKosky ST, Mehdi H, Ganguli M, Kamboh MI (2000) Analysis of genetic polymorphisms in the transforming growth factor-beta1 gene and the risk of Alzheimer’s disease. Hum Genet 106:565–569PubMedCrossRefGoogle Scholar
  17. Nishi H, Nakada T, Hokamura M, Osakabe Y, Itokazu O, Huang LE, Isaka K (2004) Hypoxia-inducible factor-1 transactivates transforming growth factor-beta3 in trophoblast. Endocrinology 145:4113–4118PubMedCrossRefGoogle Scholar
  18. Posch PE, Cruz I, Bradshaw D, Medhekar BA (2003) Novel polymorphisms and the definition of promoter ‘alleles’ of the tumor necrosis factor and lymphotoxin alpha loci: inclusion in HLA haplotypes. Genes Immun 4:547–558PubMedCrossRefGoogle Scholar
  19. Pulleyn LJ, Newton R, Adcock IM, Barnes PJ (2001) TGFbeta1 allele association with asthma severity. Hum Genet 109:623–627PubMedCrossRefGoogle Scholar
  20. Quarmby S, Fakhoury H, Levine E, Barber J, Wylie J, Hajeer AH, West C, Stewart A, Magee B, Kumar S (2003) Association of transforming growth factor beta-1 single nucleotide polymorphisms with radiation-induced damage to normal tissues in breast cancer patients. Int J Radiat Biol 79:137–143PubMedGoogle Scholar
  21. Saha A, Gupta V, Bairwa NK, Malhotra D, Bamezai R (2004) Transforming growth factor-beta1 genotype in sporadic breast cancer patients from India: status of enhancer, promoter, 5′-untranslated-region and exon-1 polymorphisms. Eur J Immunogenet 31:37–42PubMedCrossRefGoogle Scholar
  22. Shah R, Rahaman B, Hurley CK, Posch PE (2006) Allelic diversity in the TGFB1 regulatory region: characterization of novel functional single nucleotide polymorphisms. Hum Genet 119:61–74PubMedCrossRefGoogle Scholar
  23. Sheares KK, Jeffery TK, Long L, Yang X, Morrell NW (2004) Differential effects of TGF-beta1 and BMP-4 on the hypoxic induction of cyclooxygenase-2 in human pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 287:L919–L927PubMedCrossRefGoogle Scholar
  24. Silverman ES, Palmer LJ, Subramaniam V, Hallock A, Mathew S, Vallone J, Faffe DS, Shikanai T, Raby BA, Weiss ST, Shore SA (2004) Transforming growth factor-beta(1) promoter polymorphism C-509T is associated with asthma. Am J Respir Crit Care Med 169:214–219PubMedCrossRefGoogle Scholar
  25. Smart DE, Vincent KJ, Arthur MJ, Eickelberg O, Castellazzi M, Mann J, Mann DA (2001) JunD regulates transcription of the tissue inhibitor of metalloproteinases-1 and interleukin-6 genes in activated hepatic stellate cells. J Biol Chem 276:24414–24421PubMedCrossRefGoogle Scholar
  26. de Souza AP, Trevilatto PC, Scarel-Caminaga RM, de Brito RB, Line SR (2003) Analysis of the TGF-beta1 promoter polymorphism (C-509T) in patients with chronic periodontitis. J Clin Periodontol 30:519–523PubMedCrossRefGoogle Scholar
  27. Weigert C, Sauer U, Brodbeck K, Pfeiffer A, Haring HU, Schleicher ED (2000) AP-1 proteins mediate hyperglycemia-induced activation of the human TGF-beta1 promoter in mesangial cells. J Am Soc Nephrol 11:2007–2016PubMedGoogle Scholar
  28. Weitzman JB, Fiette L, Matsuo K, Yaniv M (2000) JunD protects cells from p53-dependent senescence and apoptosis. Mol Cell 6:1109–1119PubMedCrossRefGoogle Scholar
  29. Zhang H, Akman HO, Smith EL, Zhao J, Murphy-Ullrich JE, Batuman OA (2003) Cellular response to hypoxia involves signaling via Smad proteins. Blood 101:2253–2260PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Riddhish Shah
    • 1
  • Carolyn K. Hurley
    • 1
  • Phillip E. Posch
    • 2
  1. 1.Department of Oncology Georgetown University Medical CenterWashingtonUSA
  2. 2.Department of Microbiology and Immunology, E408 New Research BuildingGeorgetown University Medical CenterWashingtonUSA

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