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Role of Smad3 in the regulation of rat telomerase reverse transcriptase by TGFbeta

B Hu1, D C Tack, T Liu

  • 1Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109-0602, USA.

Oncogene
|October 6, 2005
PubMed

Insights

Transforming growth factor beta (TGFbeta) represses lung fibroblast telomerase reverse transcriptase (TERT) gene transcription. This repression is mediated by Smad3, which directly interacts with the TERT promoter, impacting cell repair mechanisms.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Telomerase is crucial for cellular repair and is upregulated in pathological conditions like cancer and tissue injury.
  • Transforming growth factor beta (TGFbeta) is known to inhibit telomerase induction in injured lung fibroblasts through incompletely understood pathways.

Purpose of the Study:

  • To investigate the specific role of Smad3 in TGFbeta-mediated repression of telomerase reverse transcriptase (TERT) gene transcription.
  • To elucidate the molecular mechanisms by which TGFbeta regulates TERT expression in lung fibroblasts.

Main Methods:

  • Cloning and functional analysis of the rat TERT (rTERT) gene promoter fused to a luciferase reporter.
  • Investigating promoter activity in fibroblasts isolated from bleomycin-injured lungs.
  • Utilizing Smad3 expressing and antisense constructs for cotransfection experiments.
  • Employing site-directed mutagenesis of the rTERT promoter, including an E-box and a Smad binding element.

Main Results:

  • TGFbeta treatment inhibited rTERT transcription and c-myc expression while increasing Smad3 expression.
  • Overexpression of Smad3 further repressed rTERT and c-myc, whereas Smad3 knockdown reversed this effect.
  • Mutation of the E-box reduced promoter activity, further inhibited by TGFbeta.
  • Mutation of the Smad binding element increased promoter activity and impaired TGFbeta-mediated inhibition.

Conclusions:

  • TGFbeta directly inhibits rTERT gene expression in lung fibroblasts via Smad3, acting through a Smad binding element in the promoter.
  • Smad3 is a key mediator of TGFbeta's suppressive effect on telomerase activity during lung injury and repair.
  • c-myc appears to be regulated independently, influencing constitutive or induced expression of TERT.

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