Suppression of Latent Transforming Growth Factor (TGF)-beta 1 Restores Growth Inhibitory TGF-beta Signaling through microRNAs

Open access
Date
2011-05Type
- Journal Article
ETH Bibliography
yes
Altmetrics
Abstract
Cancer cells secreting excess latent TGF-β are often resistant to TGF-β induced growth inhibition. We observed that RNAi against TGF-β1 led to apoptotic death in such cell lines with features that were, paradoxically, reminiscent of TGF-β signaling activity and that included transiently enhanced SMAD2 and AKT phosphorylation. A comprehensive search in Hela cells for potential microRNA drivers of this mechanism revealed that RNAi against TGF-β1 led to induction of pro-apoptotic miR-34a and to a globally decreased oncomir expression. The reduced levels of the oncomirs miR-18a and miR-24 accounted for the observed derepression of two TGF-β1 processing factors, thrombospondin-1, and furin, respectively. Our data suggest a novel mechanism in which latent TGF-β1, thrombospondin 1, and furin form a microRNA-mediated regulatory feedback loop. For cells with high levels of latent TGF-β, this provides a potentially widespread mechanism of escape from TGF-β-mediated growth arrest at the earliest point in the signaling pathway, TGF-β processing. Show more
Permanent link
https://doi.org/10.3929/ethz-b-000036222Publication status
publishedExternal links
Journal / series
Journal of Biological ChemistryVolume
Pages / Article No.
Publisher
American Society for Biochemistry and Molecular BiologySubject
Apotosis; MicroRNA; RNA Interference (RNAi); Signal Transduction; Tumor Suppressor; Furin; Laten TGFβ; miR-18a; miR-24; Thrombospondin 1Organisational unit
03760 - Hall, Jonathan / Hall, Jonathan
More
Show all metadata
ETH Bibliography
yes
Altmetrics