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Transforming growth factor-beta inhibits telomerase through SMAD3 and E2F transcription factors

Annie Lacerte1, Juliana Korah, Mélanie Roy

  • 1Hormones and Cancer Research Unit, Department of Medicine, Royal Victoria Hospital, McGill University, 687 Pine Avenue West, H3A 1A1, Montreal, Quebec, Canada.

Cellular Signalling
|September 21, 2007
PubMed

Insights

Transforming growth factor-beta (TGFbeta) represses human telomerase reverse transcriptase (hTERT) expression in normal and cancer cells. This regulation involves Smad3 and E2F-1 transcription factors, crucial for TGFbeta

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cellular Regulation

Background:

  • Cancer cells exhibit constitutive telomerase activity, contributing to cellular immortality.
  • Human telomerase reverse transcriptase (hTERT) expression is elevated in most cancers.
  • Transforming growth factor-beta (TGFbeta) is a known tumor suppressor with regulatory roles in gene expression.

Purpose of the Study:

  • To investigate the mechanism by which TGFbeta regulates hTERT expression.
  • To identify key molecular mediators involved in TGFbeta-induced repression of telomerase.
  • To elucidate the role of transcription factors in TGFbeta's effect on hTERT.

Main Methods:

  • Analysis of hTERT expression in response to TGFbeta in normal and cancer cells.
  • Investigation of signaling pathways including Smad3, Erk1/2, and p38 kinase.
  • Chromatin immunoprecipitation and reporter assays to identify transcription factor binding sites (E2F) in the hTERT promoter.
  • Utilizing E2F-1 knockout models to assess its role in TGFbeta signaling.

Main Results:

  • TGFbeta effectively represses hTERT expression in both normal and cancer cells.
  • TGFbeta-mediated repression requires Smad3, Erk1/2, p38 kinase, and histone deacetylase activity.
  • Four critical E2F transcription factor binding sites in the hTERT promoter mediate the TGFbeta response.
  • Loss of E2F-1 in knockout models abrogates TGFbeta's inhibitory effect on telomerase expression.

Conclusions:

  • TGFbeta plays a significant role in controlling telomerase expression.
  • Smad3 and E2F-1 are identified as critical mediators of TGFbeta's tumor-suppressive effects on telomerase.
  • Understanding this pathway offers insights into potential therapeutic strategies targeting cancer immortality.

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