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Decreased stability of transforming growth factor beta type II receptor mRNA in RER+ human colon carcinoma cells

W Jiang1, M P Tillekeratne, M G Brattain

  • 1Department of Biochemistry and Molecular Biology, Medical College of Ohio, Toledo 43699, USA.

Biochemistry
|December 24, 1997
PubMed

Insights

Loss of functional transforming growth factor beta type II receptor (RII) in colon cancer cells is due to decreased mRNA stability, not reduced transcription. A frameshift mutation causes premature stop codons, leading to reduced RII mRNA levels.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Genetics

Background:

  • Transforming growth factor beta (TGF-beta) inhibits cell growth and tumor progression.
  • Loss of functional TGF-beta type II receptor (RII) confers TGF-beta resistance.
  • A frameshift mutation in the RII gene is linked to TGF-beta resistance in HCT116 colon cancer cells.

Purpose of the Study:

  • To investigate the mechanism underlying the reduced expression of the mutated TGF-beta type II receptor (RII) in RER+ colon carcinoma cells.
  • To determine if reduced RII expression is due to transcriptional repression or decreased mRNA stability.

Main Methods:

  • RNase protection assays to analyze RII gene expression and mRNA half-life.
  • Nuclear run-on and RII promoter-reporter (CAT) assays to assess transcriptional levels.
  • Transfection experiments with wild-type and mutant RII constructs.

Main Results:

  • RII gene expression was repressed in RER+ cell lines (HCT116, RKO).
  • Transcriptional levels of RII were not reduced, but mRNA half-lives were significantly decreased in RER+ cells.
  • Mutated RII mRNA exhibited shorter half-lives compared to wild-type RII mRNA.

Conclusions:

  • Reduced RII mRNA levels in RER+ colon carcinoma cells are primarily due to decreased mRNA stability.
  • A frameshift mutation causing a premature stop codon in the RII mRNA transcript is responsible for the reduced mRNA stability and expression.
  • These findings elucidate a mechanism for TGF-beta resistance in colon cancer.

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