PLoS ONE 2011-01-01

The hedgehog receptor patched is involved in cholesterol transport.

Michel Bidet, Olivier Joubert, Benoit Lacombe, Marine Ciantar, Rony Nehmé, Patrick Mollat, Lionel Brétillon, Hélène Faure, Robert Bittman, Martial Ruat, Isabelle Mus-Veteau

文献索引:PLoS ONE 6 , e23834, (2011)

全文:HTML全文

摘要

Sonic hedgehog (Shh) signaling plays a crucial role in growth and patterning during embryonic development, and also in stem cell maintenance and tissue regeneration in adults. Aberrant Shh pathway activation is involved in the development of many tumors, and one of the most affected Shh signaling steps found in these tumors is the regulation of the signaling receptor Smoothened by the Shh receptor Patched. In the present work, we investigated Patched activity and the mechanism by which Patched inhibits Smoothened.Using the well-known Shh-responding cell line of mouse fibroblasts NIH 3T3, we first observed that enhancement of the intracellular cholesterol concentration induces Smoothened enrichment in the plasma membrane, which is a crucial step for the signaling activation. We found that binding of Shh protein to its receptor Patched, which involves Patched internalization, increases the intracellular concentration of cholesterol and decreases the efflux of a fluorescent cholesterol derivative (BODIPY-cholesterol) from these cells. Treatment of fibroblasts with cyclopamine, an antagonist of Shh signaling, inhibits Patched expression and reduces BODIPY-cholesterol efflux, while treatment with the Shh pathway agonist SAG enhances Patched protein expression and BODIPY-cholesterol efflux. We also show that over-expression of human Patched in the yeast S. cerevisiae results in a significant boost of BODIPY-cholesterol efflux. Furthermore, we demonstrate that purified Patched binds to cholesterol, and that the interaction of Shh with Patched inhibits the binding of Patched to cholesterol.Our results suggest that Patched may contribute to cholesterol efflux from cells, and to modulation of the intracellular cholesterol concentration. This activity is likely responsible for the inhibition of the enrichment of Smoothened in the plasma membrane, which is an important step in Shh pathway activation.


相关化合物

  • 巯基胆固醇

相关文献:

Poly(amidoamine) conjugates with disulfide-linked cholesterol pendants self-assembling into redox-sensitive nanoparticles.

2008-10-01

[Biomacromolecules 9(10) , 2693-704, (2008)]

Effect of the nature of the spacer on gene transfer efficacies of novel thiocholesterol derived gemini lipids in different cell lines: a structure-activity investigation.

2008-04-24

[J. Med. Chem. 51(8) , 2533-40, (2008)]

Thiocholesterol-based lipids for ordered assembly of bioresponsive gene carriers.

2005-03-01

[Mol. Ther. 11(3) , 409-17, (2005)]

Enhanced hepatic uptake and bioactivity of type alpha1(I) collagen gene promoter-specific triplex-forming oligonucleotides after conjugation with cholesterol.

2006-05-01

[J. Pharmacol. Exp. Ther. 317(2) , 797-805, (2006)]

Effective incorporation of 2'-O-methyl-oligoribonucleotides into liposomes and enhanced cell association through modification with thiocholesterol.

1992-02-11

[Nucleic Acids Res. 20(3) , 533-8, (1992)]

更多文献...