Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1 Pt 1
pubmed:dateCreated
1998-8-25
pubmed:abstractText
The activity of small GTP-binding proteins is regulated by a critical step in posttranslational processing, namely, the addition of isoprenoid lipids farnesyl and geranylgeranyl, mediated by the enzymes farnesyltransferase (FTase) and geranylgeranyltransferase I (GGTase I), respectively. We have developed compounds that inhibit these enzymes specifically and in this study sought to determine their effects on smooth muscle cells (SMC) from the pulmonary microvasculature. We found that the GGTase I inhibitor GGTI-298 suppressed protein geranylgeranylation and blocked serum-dependent growth as measured by thymidine uptake and cell counts. In the absence of serum, however, GGTI-298 induced apoptosis in these cells as measured by both DNA staining and flow cytometry. The FTase inhibitor FTI-277 selectively inhibited protein farnesylation but had a minor effect on growth and no effect on apoptosis. To further investigate the role of geranylgeranylated proteins in apoptosis, we added the cholesterol synthesis inhibitor lovastatin, which inhibits the biosynthesis of farnesyl and geranylgeranyl pyrophosphates. This also induced apoptosis, but when geranylgeraniol was added to replenish cellular pools of geranylgeranyl pyrophosphate, apoptosis was reduced to baseline. In contrast, farnesol achieved only partial rescue of the cells. These results imply that geranylgeranylated proteins are required for growth and protect SMC against apoptosis. GGTase I inhibitors may be useful in preventing hyperplastic remodeling and may have the potential to induce the apoptotic regression of established vascular lesions.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
http://linkedlifedata.com/resource/pubmed/chemical/Alkyl and Aryl Transferases, http://linkedlifedata.com/resource/pubmed/chemical/Benzamides, http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors, http://linkedlifedata.com/resource/pubmed/chemical/FTI 277, http://linkedlifedata.com/resource/pubmed/chemical/Farnesyltranstransferase, http://linkedlifedata.com/resource/pubmed/chemical/GGTI 298, http://linkedlifedata.com/resource/pubmed/chemical/GTP-Binding Proteins, http://linkedlifedata.com/resource/pubmed/chemical/Lovastatin, http://linkedlifedata.com/resource/pubmed/chemical/Methionine, http://linkedlifedata.com/resource/pubmed/chemical/Transcription Factors, http://linkedlifedata.com/resource/pubmed/chemical/geranylgeranyltransferase type-I, http://linkedlifedata.com/resource/pubmed/chemical/rap GTP-Binding Proteins, http://linkedlifedata.com/resource/pubmed/chemical/ras Proteins
pubmed:status
MEDLINE
pubmed:month
Jul
pubmed:issn
0002-9513
pubmed:author
pubmed:issnType
Print
pubmed:volume
275
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
L55-63
pubmed:dateRevised
2007-11-15
pubmed:meshHeading
pubmed-meshheading:9688935-Alkyl and Aryl Transferases, pubmed-meshheading:9688935-Animals, pubmed-meshheading:9688935-Apoptosis, pubmed-meshheading:9688935-Benzamides, pubmed-meshheading:9688935-Cell Division, pubmed-meshheading:9688935-Cells, Cultured, pubmed-meshheading:9688935-Enzyme Inhibitors, pubmed-meshheading:9688935-Farnesyltranstransferase, pubmed-meshheading:9688935-Flow Cytometry, pubmed-meshheading:9688935-GTP-Binding Proteins, pubmed-meshheading:9688935-Kinetics, pubmed-meshheading:9688935-Lovastatin, pubmed-meshheading:9688935-Methionine, pubmed-meshheading:9688935-Microcirculation, pubmed-meshheading:9688935-Muscle, Smooth, Vascular, pubmed-meshheading:9688935-Protein Prenylation, pubmed-meshheading:9688935-Pulmonary Artery, pubmed-meshheading:9688935-Rats, pubmed-meshheading:9688935-Transcription Factors, pubmed-meshheading:9688935-rap GTP-Binding Proteins, pubmed-meshheading:9688935-ras Proteins
pubmed:year
1998
pubmed:articleTitle
Inhibiting geranylgeranylation blocks growth and promotes apoptosis in pulmonary vascular smooth muscle cells.
pubmed:affiliation
Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't