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

Jonathan D. Finder, Jennifer L. Litz, Michelle A. Blaskovich, Terence F. McGuire, Yimin Qian, Andrew Hamilton, Paul Davies, Saïd M. Sebti

Research output: Contribution to journalArticle

Abstract

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-1β (IL-1β)-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-1β. RPASMC treated with GGTI-298 (10 μM) prior to IL-1β (10 ng/ml) expressed levels of NOS-2 protein five times higher than those exposed to IL-1β 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-1β and 10-fold higher at 1 ng/ml IL-1β. Furthermore, NOS-2 mRNA levels in RPASMC were also increased 6- and 14-fold (at 10 and 1 ng/ml IL-1β, respectively) when the cells were pretreated with GGTI-298. In contrast, treatment of cells with the inhibitor of protein farnesylation, FTI-277 (10 μM), blocked IL-1β-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-1β induction of NOS-2, whereas a geranylgeranylated protein(s) represses this induction.

Original languageEnglish (US)
Pages (from-to)13484-13488
Number of pages5
JournalJournal of Biological Chemistry
Volume272
Issue number21
DOIs
StatePublished - May 23 1997

Fingerprint

Protein Prenylation
Interleukin-1
Vascular Smooth Muscle
Nitric Oxide Synthase
Smooth Muscle Myocytes
Muscle
Cells
Proteins
Rats
Pulmonary Artery
Prenylation
Interleukin-10
Farnesol
Farnesyltranstransferase
Lovastatin
Messenger RNA
Nitrites
Hepatocytes
GGTI 298

ASJC Scopus subject areas

  • Biochemistry

Cite this

Inhibition of protein geranylgeranylation causes a superinduction of nitric-oxide synthase-2 by interleukin-1β in vascular smooth muscle cells. / Finder, Jonathan D.; Litz, Jennifer L.; Blaskovich, Michelle A.; McGuire, Terence F.; Qian, Yimin; Hamilton, Andrew; Davies, Paul; Sebti, Saïd M.

In: Journal of Biological Chemistry, Vol. 272, No. 21, 23.05.1997, p. 13484-13488.

Research output: Contribution to journalArticle

Finder, Jonathan D. ; Litz, Jennifer L. ; Blaskovich, Michelle A. ; McGuire, Terence F. ; Qian, Yimin ; Hamilton, Andrew ; Davies, Paul ; Sebti, Saïd M. / Inhibition of protein geranylgeranylation causes a superinduction of nitric-oxide synthase-2 by interleukin-1β in vascular smooth muscle cells. In: Journal of Biological Chemistry. 1997 ; Vol. 272, No. 21. pp. 13484-13488.
@article{ea344f470b5d42739c220aca1c3dc33e,
title = "Inhibition of protein geranylgeranylation causes a superinduction of nitric-oxide synthase-2 by interleukin-1β in vascular smooth muscle cells",
abstract = "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-1β (IL-1β)-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-1β. RPASMC treated with GGTI-298 (10 μM) prior to IL-1β (10 ng/ml) expressed levels of NOS-2 protein five times higher than those exposed to IL-1β 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-1β and 10-fold higher at 1 ng/ml IL-1β. Furthermore, NOS-2 mRNA levels in RPASMC were also increased 6- and 14-fold (at 10 and 1 ng/ml IL-1β, respectively) when the cells were pretreated with GGTI-298. In contrast, treatment of cells with the inhibitor of protein farnesylation, FTI-277 (10 μM), blocked IL-1β-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-1β induction of NOS-2, whereas a geranylgeranylated protein(s) represses this induction.",
author = "Finder, {Jonathan D.} and Litz, {Jennifer L.} and Blaskovich, {Michelle A.} and McGuire, {Terence F.} and Yimin Qian and Andrew Hamilton and Paul Davies and Sebti, {Sa{\"i}d M.}",
year = "1997",
month = "5",
day = "23",
doi = "10.1074/jbc.272.21.13484",
language = "English (US)",
volume = "272",
pages = "13484--13488",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "21",

}

TY - JOUR

T1 - Inhibition of protein geranylgeranylation causes a superinduction of nitric-oxide synthase-2 by interleukin-1β in vascular smooth muscle cells

AU - Finder, Jonathan D.

AU - Litz, Jennifer L.

AU - Blaskovich, Michelle A.

AU - McGuire, Terence F.

AU - Qian, Yimin

AU - Hamilton, Andrew

AU - Davies, Paul

AU - Sebti, Saïd M.

PY - 1997/5/23

Y1 - 1997/5/23

N2 - 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-1β (IL-1β)-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-1β. RPASMC treated with GGTI-298 (10 μM) prior to IL-1β (10 ng/ml) expressed levels of NOS-2 protein five times higher than those exposed to IL-1β 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-1β and 10-fold higher at 1 ng/ml IL-1β. Furthermore, NOS-2 mRNA levels in RPASMC were also increased 6- and 14-fold (at 10 and 1 ng/ml IL-1β, respectively) when the cells were pretreated with GGTI-298. In contrast, treatment of cells with the inhibitor of protein farnesylation, FTI-277 (10 μM), blocked IL-1β-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-1β induction of NOS-2, whereas a geranylgeranylated protein(s) represses this induction.

AB - 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-1β (IL-1β)-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-1β. RPASMC treated with GGTI-298 (10 μM) prior to IL-1β (10 ng/ml) expressed levels of NOS-2 protein five times higher than those exposed to IL-1β 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-1β and 10-fold higher at 1 ng/ml IL-1β. Furthermore, NOS-2 mRNA levels in RPASMC were also increased 6- and 14-fold (at 10 and 1 ng/ml IL-1β, respectively) when the cells were pretreated with GGTI-298. In contrast, treatment of cells with the inhibitor of protein farnesylation, FTI-277 (10 μM), blocked IL-1β-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-1β induction of NOS-2, whereas a geranylgeranylated protein(s) represses this induction.

UR - http://www.scopus.com/inward/record.url?scp=0030999565&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0030999565&partnerID=8YFLogxK

U2 - 10.1074/jbc.272.21.13484

DO - 10.1074/jbc.272.21.13484

M3 - Article

VL - 272

SP - 13484

EP - 13488

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 21

ER -