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Loss of type III transforming growth factor-beta receptor expression is due to methylation silencing of the transcription factor GATA3 in renal cell carcinoma.

Publication ,  Journal Article
Cooper, SJ; Zou, H; Legrand, SN; Marlow, LA; von Roemeling, CA; Radisky, DC; Wu, KJ; Hempel, N; Margulis, V; Tun, HW; Blobe, GC; Wood, CG; Copland, JA
Published in: Oncogene
May 20, 2010

Loss of transforming growth factor-beta receptor III (TbetaRIII) correlates with loss of transforming growth factor-beta (TGF-beta) responsiveness and suggests a role for dysregulated TGF-beta signaling in clear cell renal cell carcinoma (ccRCC) progression and metastasis. Here we identify that for all stages of ccRCC TbetaRIII expression is downregulated in patient-matched tissue samples and cell lines. We find that this loss of expression is not due to methylation of the gene and we define GATA3 as the first transcriptional factor to positively regulate TbetaRIII expression in human cells. We localize GATA3's binding to a 10-bp region of the TbetaRIII proximal promoter. We demonstrate that GATA3 mRNA is downregulated in all stages, of ccRCC, mechanistically show that GATA3 is methylated in ccRCC patient tumor tissues as well as cell lines, and that inhibiting GATA3 expression in normal renal epithelial cells downregulates TbetaRIII mRNA and protein expression. These data support a sequential model whereby loss of GATA3 expression through epigenetic silencing decreases TbetaRIII expression during ccRCC progression.

Duke Scholars

Published In

Oncogene

DOI

EISSN

1476-5594

Publication Date

May 20, 2010

Volume

29

Issue

20

Start / End Page

2905 / 2915

Location

England

Related Subject Headings

  • Transforming Growth Factor beta
  • Transfection
  • Signal Transduction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Receptors, Transforming Growth Factor beta
  • RNA, Messenger
  • Proteoglycans
  • Promoter Regions, Genetic
  • Oncology & Carcinogenesis
  • Oligonucleotide Array Sequence Analysis
 

Citation

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Cooper, S. J., Zou, H., Legrand, S. N., Marlow, L. A., von Roemeling, C. A., Radisky, D. C., … Copland, J. A. (2010). Loss of type III transforming growth factor-beta receptor expression is due to methylation silencing of the transcription factor GATA3 in renal cell carcinoma. Oncogene, 29(20), 2905–2915. https://doi.org/10.1038/onc.2010.64
Cooper, S. J., H. Zou, S. N. Legrand, L. A. Marlow, C. A. von Roemeling, D. C. Radisky, K. J. Wu, et al. “Loss of type III transforming growth factor-beta receptor expression is due to methylation silencing of the transcription factor GATA3 in renal cell carcinoma.Oncogene 29, no. 20 (May 20, 2010): 2905–15. https://doi.org/10.1038/onc.2010.64.
Cooper SJ, Zou H, Legrand SN, Marlow LA, von Roemeling CA, Radisky DC, et al. Loss of type III transforming growth factor-beta receptor expression is due to methylation silencing of the transcription factor GATA3 in renal cell carcinoma. Oncogene. 2010 May 20;29(20):2905–15.
Cooper, S. J., et al. “Loss of type III transforming growth factor-beta receptor expression is due to methylation silencing of the transcription factor GATA3 in renal cell carcinoma.Oncogene, vol. 29, no. 20, May 2010, pp. 2905–15. Pubmed, doi:10.1038/onc.2010.64.
Cooper SJ, Zou H, Legrand SN, Marlow LA, von Roemeling CA, Radisky DC, Wu KJ, Hempel N, Margulis V, Tun HW, Blobe GC, Wood CG, Copland JA. Loss of type III transforming growth factor-beta receptor expression is due to methylation silencing of the transcription factor GATA3 in renal cell carcinoma. Oncogene. 2010 May 20;29(20):2905–2915.

Published In

Oncogene

DOI

EISSN

1476-5594

Publication Date

May 20, 2010

Volume

29

Issue

20

Start / End Page

2905 / 2915

Location

England

Related Subject Headings

  • Transforming Growth Factor beta
  • Transfection
  • Signal Transduction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Receptors, Transforming Growth Factor beta
  • RNA, Messenger
  • Proteoglycans
  • Promoter Regions, Genetic
  • Oncology & Carcinogenesis
  • Oligonucleotide Array Sequence Analysis