Functional impact of sequence variation in the promoter region of TGFB1
Jasmine Healy
Division of Hematology–Oncology, Sainte-Justine Hospital Research Center, Montreal, Quebec, Canada
Jasmine Healy and Joëlle Dionne contributed equally to this work.
Search for more papers by this authorJoëlle Dionne
Division of Hematology–Oncology, Sainte-Justine Hospital Research Center, Montreal, Quebec, Canada
Jasmine Healy and Joëlle Dionne contributed equally to this work.
Search for more papers by this authorHélène Bélanger
Division of Hematology–Oncology, Sainte-Justine Hospital Research Center, Montreal, Quebec, Canada
Search for more papers by this authorMathieu Larivière
Division of Hematology–Oncology, Sainte-Justine Hospital Research Center, Montreal, Quebec, Canada
Search for more papers by this authorPatrick Beaulieu
Division of Hematology–Oncology, Sainte-Justine Hospital Research Center, Montreal, Quebec, Canada
Search for more papers by this authorDamian Labuda
Division of Hematology–Oncology, Sainte-Justine Hospital Research Center, Montreal, Quebec, Canada
Faculty of Medicine, Department of Pediatrics, University of Montreal, Montreal, Quebec, Canada
Search for more papers by this authorCorresponding Author
Daniel Sinnett
Division of Hematology–Oncology, Sainte-Justine Hospital Research Center, Montreal, Quebec, Canada
Faculty of Medicine, Department of Pediatrics, University of Montreal, Montreal, Quebec, Canada
Fax: +514-345-4731.
Division of Hematology–Oncology, Sainte-Justine Hospital Research Center, 3175 chemin de la Côte-Sainte-Catherine, Montreal, Quebec, Canada H3T 1C5Search for more papers by this authorJasmine Healy
Division of Hematology–Oncology, Sainte-Justine Hospital Research Center, Montreal, Quebec, Canada
Jasmine Healy and Joëlle Dionne contributed equally to this work.
Search for more papers by this authorJoëlle Dionne
Division of Hematology–Oncology, Sainte-Justine Hospital Research Center, Montreal, Quebec, Canada
Jasmine Healy and Joëlle Dionne contributed equally to this work.
Search for more papers by this authorHélène Bélanger
Division of Hematology–Oncology, Sainte-Justine Hospital Research Center, Montreal, Quebec, Canada
Search for more papers by this authorMathieu Larivière
Division of Hematology–Oncology, Sainte-Justine Hospital Research Center, Montreal, Quebec, Canada
Search for more papers by this authorPatrick Beaulieu
Division of Hematology–Oncology, Sainte-Justine Hospital Research Center, Montreal, Quebec, Canada
Search for more papers by this authorDamian Labuda
Division of Hematology–Oncology, Sainte-Justine Hospital Research Center, Montreal, Quebec, Canada
Faculty of Medicine, Department of Pediatrics, University of Montreal, Montreal, Quebec, Canada
Search for more papers by this authorCorresponding Author
Daniel Sinnett
Division of Hematology–Oncology, Sainte-Justine Hospital Research Center, Montreal, Quebec, Canada
Faculty of Medicine, Department of Pediatrics, University of Montreal, Montreal, Quebec, Canada
Fax: +514-345-4731.
Division of Hematology–Oncology, Sainte-Justine Hospital Research Center, 3175 chemin de la Côte-Sainte-Catherine, Montreal, Quebec, Canada H3T 1C5Search for more papers by this authorAbstract
Pathological deregulation of the transforming growth factor, beta 1 (TGFB1) pathway has been implicated in the development of several major diseases, including cancers. Regulatory variation in the TGFB1 gene may lead to altered TGFB1 expression and activity, and thus, modulate an individual's susceptibility to disease. Here, we performed a study of the functional relevance of cis-acting regulatory variation in the proximal promoter region of the TGFB1 gene. In a previous study, 9 promoter polymorphisms were identified in the 2kb region upstream of the transcription start site and 9 distinct promoter haplotypes were inferred from a panel of individuals from 5 distinct continental population groups. Following experimental validation, we found that the 2 major haplotypes significantly influenced TGFB1 transcriptional activity in an allele-specific manner and that 3 of the SNPs (−1886G>A, −509C>T and −1550DEL/AGG) altered DNA-protein complexe formation. Though the biological relevance of these findings remains to be verified, our study suggests that polymorphisms in the TGFB1 promoter could indeed influence gene expression and potentially contribute to the pathogenesis of TGFB1 related diseases. © 2009 UICC
References
- 1 Elliott RL,Blobe GC. Role of transforming growth factor Beta in human cancer. J Clin Oncol 2005; 23: 2078–93.
- 2 Glick AB. TGFbeta1, back to the future: revisiting its role as a transforming growth factor. Cancer Biol Ther 2004; 3: 276–83.
- 3 Shirai Y,Kawata S,Ito N,Tamura S,Takaishi K,Kiso S,Tsushima H,Matsuzawa Y. Elevated levels of plasma transforming growth factor-beta in patients with hepatocellular carcinoma. Jpn J Cancer Res 1992; 83: 676–9.
- 4 Grainger DJ,Metcalfe JC. Transforming growth factor-beta: the key to understanding lipoprotein (a)? Curr Opin Lipidol 1995; 6: 81–5.
- 5 Awad MR,El-Gamel A,Hasleton P,Turner DM,Sinnott PJ,Hutchinson IV. Genotypic variation in the transforming growth factor-beta1 gene: association with transforming growth factor-beta1 production, fibrotic lung disease, and graft fibrosis after lung transplantation. Transplantation 1998; 66: 1014–20.
- 6 Long JR,Liu PY,Liu YJ,Lu Y,Xiong DH,Elze L,Recker RR,Deng HW. APOE and TGF-beta1 genes are associated with obesity phenotypes. J Med Genet 2003; 40: 918–24.
- 7 de Caestecker MP,Piek E,Roberts AB. Role of transforming growth factor-beta signaling in cancer. J Natl Cancer Inst 2000; 92: 1388–402.
- 8 Markowitz SD,Roberts AB. Tumor suppressor activity of the TGF-beta pathway in human cancers. Cytokine Growth Factor Rev 1996; 7: 93–102.
- 9 Reiss M. TGF-beta and cancer. Microbes Infect 1999; 1: 1327–47.
- 10 Cox DG,Penney K,Guo Q,Hankinson SE,Hunter DJ. TGFB1 and TGFBR1 polymorphisms and breast cancer risk in the nurses' health study. BMC Cancer 2007; 7: 175.
- 11 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, et al. A transforming growth factorbeta1 signal peptide variant increases secretion in vitro and is associated with increased incidence of invasive breast cancer. Cancer Res 2003; 63: 2610–5.
- 12 Kang HG,Chae MH,Park JM,Kim EJ,Park JH,Kam S,Cha SI,Kim CH,Park RW,Park SH,Kim YL,Kim IS, et al. Polymorphisms in TGF-beta1 gene and the risk of lung cancer. Lung Cancer 2006; 52: 1–7.
- 13 Saltzman BS,Yamamoto JF,Decker R,Yokochi L,Theriault AG,Vogt TM,Le Marchand L. Association of genetic variation in the transforming growth factor beta-1 gene with serum levels and risk of colorectal neoplasia. Cancer Res 2008; 68: 1236–44.
- 14 Chung SJ,Kim JS,Jung HC,Song IS. Transforming growth factor-β1–509T reduces risk of colorectal cancer, but not adenoma in Koreans. Cancer Sci 2007; 98: 401–4.
- 15 Ewart-Toland A,Chan JM,Yuan J,Balmain A,Ma J. A gain of function TGFB1 polymorphism may be associated with late stage prostate cancer. Cancer Epidemiol Biomarkers Prev 2004; 13: 759–64.
- 16 Sinnett D,Beaulieu P,Belanger H,Lefebvre JF,Langlois S,Theberge MC,Drouin S,Zotti C,Hudson TJ,Labuda D. Detection and characterization of DNA variants in the promoter regions of hundreds of human disease candidate genes. Genomics 2006; 87: 704–10.
- 17 Labuda D,Labbe C,Langlois S,Lefebvre JF,Freytag V,Moreau C,Sawicki J,Beaulieu P,Pastinen T,Hudson TJ,Sinnett D. Patterns of variation in DNA segments upstream of transcription start sites. Hum Mutat 2007; 28: 441–50.
- 18 Stephens M,Smith NJ,Donnelly P. A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 2001; 68: 978–89.
- 19 Cartharius K,Frech K,Grote K,Klocke B,Haltmeier M,Klingenhoff A,Frisch M,Bayerlein M,Werner T. MatInspector and beyond: promoter analysis based on transcription factor binding sites. Bioinformatics 2005; 21: 2933–42.
- 20 Belanger H,Beaulieu P,Moreau C,Labuda D,Hudson TJ,Sinnett D. Functional promoter SNPs in cell cycle checkpoint genes. Hum Mol Genet 2005; 14: 2641–8.
- 21 Shah R,Rahaman B,Hurley CK,Posch PE. Allelic diversity in the TGFB1 regulatory region: characterization of novel functional single nucleotide polymorphisms. Hum Genet 2006; 119: 61–74.
- 22 Jung P,Menssen A,Mayr D,Hermeking H. AP4 encodes a c-MYC-inducible repressor of p21. Proc Natl Acad Sci USA 2008; 105: 15046–51.
- 23 Iwata I,Nagafuchi S,Nakashima H,Kondo S,Koga T,Yokogawa Y,Akashi T,Shibuya T,Umeno Y,Okeda T,Shibata S,Kono S, et al. Association of polymorphism in the NeuroD/BETA2 gene with type 1 diabetes in the Japanese. Diabetes 1999; 48: 416–9.
- 24 Harigae H. GATA transcription factors and hematological diseases. Tohoku J Exp Med 2006; 210: 1–9.
- 25 St-Onge L,Sosa-Pineda B,Chowdhury K,Mansouri A,Gruss P. Pax6 is required for differentiation of glucagon-producing alpha-cells in mouse pancreas. Nature 1997; 387: 406–9.
- 26 Bossone SA,Asselin C,Patel AJ,Marcu KB. MAZ, a zinc finger protein, binds to c-MYC and C2 gene sequences regulating transcriptional initiation and termination. Proc Natl Acad Sci USA 1992; 89: 7452–6.
- 27 Yamada K,Ogawa H,Honda S,Harada N,Okazaki T. A GCM motif protein is involved in placenta-specific expression of human aromatase gene. J Biol Chem 1999; 274: 32279–86.
- 28 Kim SJ,Glick A,Sporn MB,Roberts AB. Characterization of the promoter region of the human transforming growth factor-beta 1 gene. J Biol Chem 1989; 264: 402–8.
- 29 Yamada Y,Miyauchi A,Takagi Y,Tanaka M,Mizuno M,Harada A. Association of the C-509–>T polymorphism, alone of in combination with the T869–>C polymorphism, of the transforming growth factor-beta1 gene with bone mineral density and genetic susceptibility to osteoporosis in Japanese women. J Mol Med 2001; 79: 149–56.
- 30 Grainger DJ,Heathcote K,Chiano M,Snieder H,Kemp PR,Metcalfe JC,Carter ND,Spector TD. Genetic control of the circulating concentration of transforming growth factor type beta1. Hum Mol Genet 1999; 8: 93–7.
Citing Literature
