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Caveolin-1 down-regulates inducible nitric oxide synthase via the proteasome pathway in human colon carcinoma cells

E Felley-Bosco1, F C Bender, F Courjault-Gautier

  • 1Institute of Pharmacology and Toxicology, University of Lausanne, Bugnon 27, 1005 Lausanne, Switzerland. emanuela.felley-bosco@ipharm.unil.ch

Proceedings of the National Academy of Sciences of the United States of America
|December 13, 2000
PubMed

Insights

Caveolin-1 (cav-1) reduces inducible nitric oxide synthase (iNOS) levels in intestinal cells by promoting its proteasomal degradation. This study reveals cav-1

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Inducible nitric oxide synthase (iNOS) plays a critical role in cellular functions.
  • Caveolin-1 (cav-1) is involved in various cellular processes, including protein trafficking and degradation.
  • The interaction between cav-1 and iNOS function is not fully understood.

Purpose of the Study:

  • To investigate the role of caveolin-1 (cav-1) in modulating inducible nitric oxide synthase (iNOS) function in human intestinal carcinoma cells.
  • To elucidate the mechanism by which cav-1 affects iNOS levels and activity.

Main Methods:

  • Transfection of HT29 and DLD1 cells with cav-1 cDNA.
  • Cytokine induction of iNOS expression.
  • Assessment of iNOS mRNA and protein levels.
  • Proteasome inhibition studies using N-acetyl-Leu-Leu-Norleucinal and lactacystin.
  • Cofractionation analysis in Triton X-100-insoluble membrane fractions.
  • In vitro binding assays between cav-1 and iNOS.

Main Results:

  • Ectopic expression of cav-1 in intestinal cells led to significantly decreased iNOS activity and protein levels.
  • This decrease was mediated by a posttranscriptional mechanism involving enhanced proteasomal degradation of iNOS protein.
  • iNOS protein levels increased upon proteasome inhibition, confirming the degradation pathway.
  • iNOS was found to cofractionate with cav-1 in detergent-insoluble membrane fractions, where degradation occurred.
  • Direct binding between cav-1 and iNOS was detected in vitro.

Conclusions:

  • Caveolin-1 (cav-1) promotes the presence of inducible nitric oxide synthase (iNOS) in detergent-insoluble membrane fractions.
  • Cav-1 facilitates iNOS degradation via the proteasome pathway.
  • These findings suggest a novel regulatory mechanism for iNOS function involving cav-1.

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