RGD Reference Report - Inhibition of protein geranylgeranylation causes a superinduction of nitric-oxide synthase-2 by interleukin-1beta in vascular smooth muscle cells. - Rat Genome Database

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Inhibition of protein geranylgeranylation causes a superinduction of nitric-oxide synthase-2 by interleukin-1beta in vascular smooth muscle cells.

Authors: Finder, JD  Litz, JL  Blaskovich, MA  McGuire, TF  Qian, Y  Hamilton, AD  Davies, P  Sebti, SM 
Citation: Finder JD, etal., J Biol Chem. 1997 May 23;272(21):13484-8.
RGD ID: 2302974
Pubmed: (View Article at PubMed) PMID:9153192

Recently, we have designed farnesyltransferase and geranylgeranyltransferase I inhibitors (FTI-277 and GGTI-298) that selectively block protein farnesylation and geranylgeranylation, respectively. In this study, we describe the opposing effects of these inhibitors on interleukin-1beta (IL-1beta)-stimulated induction of nitric-oxide synthase-2 (NOS-2) in rat pulmonary artery smooth muscle cells (RPASMC) and rat hepatocytes. Pretreatment of cells with GGTI-298 caused a superinduction of NOS-2 by IL-1beta. RPASMC treated with GGTI-298 (10 microM) prior to IL-1beta (10 ng/ml) expressed levels of NOS-2 protein five times higher than those exposed to IL-1beta alone. This superinduction of NOS-2 protein by pretreatment with GGTI-298 resulted in nitrite concentrations in the medium that were 5-fold higher at 10 ng/ml IL-1beta and 10-fold higher at 1 ng/ml IL-1beta. Furthermore, NOS-2 mRNA levels in RPASMC were also increased 6- and 14-fold (at 10 and 1 ng/ml IL-1beta, respectively) when the cells were pretreated with GGTI-298. In contrast, treatment of cells with the inhibitor of protein farnesylation, FTI-277 (10 microM), blocked IL-1beta-induced NOS-2 expression at mRNA and protein levels. Pretreatment with lovastatin, an inhibitor of protein prenylation, resulted in superinduction of NOS-2. This superinduction was reversed by geranylgeraniol, but not by farnesol, further confirming that inhibition of geranylgeranylation, not farnesylation, is responsible for enhanced NOS-2 expression. The results demonstrate that a farnesylated protein(s) mediates IL-1beta induction of NOS-2, whereas a geranylgeranylated protein(s) represses this induction.



Gene Ontology Annotations    

Objects Annotated

Genes (Rattus norvegicus)
Fnta  (farnesyltransferase, CAAX box, alpha)
Fntb  (farnesyltransferase, CAAX box, beta)
Pggt1b  (protein geranylgeranyltransferase type I subunit beta)


Additional Information