Document Detail

Geranylgeranyl transferase 1 modulates autophagy and apoptosis in human airway smooth muscle.
MedLine Citation:
PMID:  22160308     Owner:  NLM     Status:  MEDLINE    
Geranylgeranyl transferase 1 (GGT1) is involved in the posttranslational prenylation of signaling proteins, such as small GTPases. We have shown that blocking the formation of isoprenoids with statins regulates survival of human lung mesenchymal cells; thus, we tested the hypothesis that GGT1 may specifically modulate programmed cell death pathways in these cells. To this end, human airway smooth muscle (HASM) cells were treated with the selective GGT1 inhibitor GGTi-298. Apoptosis was seen using assays for cellular DNA content and caspase activation. Induction of autophagy was observed using transmission electron microscopy, immunoblotting for LC3 lipidation and Atg5-12 complex content, and confocal microscopy to detect formation of lysosome-localized LC3 punctae. Notably, GGT1 inhibition induced expression of p53-dependent proteins, p53 upregulated modulator of apoptosis (Noxa), and damage-regulated autophagy modulator (DRAM), this was inhibited by the p53 transcriptional activation inhibitor cyclic-pifithrin-α. Inhibition of autophagy with bafilomycin-A1 or short-hairpin RNA silencing of Atg7 substantially augmented GGTi-298-induced apoptosis. Overall, we demonstrate for the first time that pharmacological inhibition of GGT1 induces simultaneous p53-dependent apoptosis and autophagy in HASM. Moreover, autophagy regulates apoptosis induction. Thus, our findings identify GGT1 as a key regulator of HASM cell viability.
Saeid Ghavami; Mark M Mutawe; Dedmer Schaafsma; Behzad Yeganeh; Helmut Unruh; Thomas Klonisch; Andrew J Halayko
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2011-12-09
Journal Detail:
Title:  American journal of physiology. Lung cellular and molecular physiology     Volume:  302     ISSN:  1522-1504     ISO Abbreviation:  Am. J. Physiol. Lung Cell Mol. Physiol.     Publication Date:  2012 Feb 
Date Detail:
Created Date:  2012-02-13     Completed Date:  2012-03-27     Revised Date:  2012-08-30    
Medline Journal Info:
Nlm Unique ID:  100901229     Medline TA:  Am J Physiol Lung Cell Mol Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  L420-8     Citation Subset:  IM    
Department of Physiology, University of Manitoba, Winnipeg, Canada.
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MeSH Terms
Alkyl and Aryl Transferases / antagonists & inhibitors,  genetics,  metabolism*
Benzamides / pharmacology
Benzothiazoles / pharmacology
Bronchi / cytology*
Cell Survival
Cells, Cultured
Farnesyltranstransferase / antagonists & inhibitors,  genetics,  metabolism*
Myocytes, Smooth Muscle / enzymology*,  physiology
Primary Cell Culture
Signal Transduction
Toluene / analogs & derivatives,  pharmacology
Tumor Suppressor Protein p53 / antagonists & inhibitors,  genetics,  metabolism
Grant Support
//Canadian Institutes of Health Research
Reg. No./Substance:
0/Benzamides; 0/Benzothiazoles; 0/GGTI 298; 0/TP53 protein, human; 0/Tumor Suppressor Protein p53; 0/pifithrin; 108-88-3/Toluene; EC 2.5.-/Alkyl and Aryl Transferases; EC 2.5.1.-/geranylgeranyltransferase type-I; EC

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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