Document Detail


Geranylgeranyl transferase 1 modulates autophagy and apoptosis in human airway smooth muscle.
MedLine Citation:
PMID:  22160308     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Saeid Ghavami; Mark M Mutawe; Dedmer Schaafsma; Behzad Yeganeh; Helmut Unruh; Thomas Klonisch; Andrew J Halayko
Related Documents :
22199288 - Novel cytotoxic isolated from jamaican hyptis verticillata jacq induces apoptosis and o...
19265458 - The effect of 17 estradiol on the immunocompetence of japanese sea bass lateolabrax jap...
12213578 - Cell-specific regulation of apoptosis by glucocorticoids: implication to their anti-inf...
11165008 - Crucial role of cytokines in sex steroid formation in normal and tumoral tissues.
17640998 - Microarray analysis of cytokine activation of apoptosis pathways in the thyroid.
24155988 - Atopic dermatitis and the stratum corneum: part 1: the role of filaggrin in the stratum...
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    
Affiliation:
Department of Physiology, University of Manitoba, Winnipeg, Canada.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Alkyl and Aryl Transferases / antagonists & inhibitors,  genetics,  metabolism*
Apoptosis*
Autophagy*
Benzamides / pharmacology
Benzothiazoles / pharmacology
Bronchi / cytology*
Cell Survival
Cells, Cultured
Farnesyltranstransferase / antagonists & inhibitors,  genetics,  metabolism*
Humans
Myocytes, Smooth Muscle / enzymology*,  physiology
Primary Cell Culture
Signal Transduction
Toluene / analogs & derivatives,  pharmacology
Tumor Suppressor Protein p53 / antagonists & inhibitors,  genetics,  metabolism
Grant Support
ID/Acronym/Agency:
//Canadian Institutes of Health Research
Chemical
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 2.5.1.29/Farnesyltranstransferase

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


Previous Document:  Lung heparan sulfates modulate K(fc) during increased vascular pressure: evidence for glycocalyx-med...
Next Document:  TLR4-dependent GM-CSF protects against lung injury in Gram-negative bacterial pneumonia.