JBC

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Originally published In Press as doi:10.1074/jbc.M100725200 on April 18, 2001

J. Biol. Chem., Vol. 276, Issue 26, 24268-24273, June 29, 2001
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
276/26/24268    most recent
M100725200v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Musial, A.
Right arrow Articles by Eissa, N. T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Musial, A.
Right arrow Articles by Eissa, N. T.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

Inducible Nitric-oxide Synthase Is Regulated by the Proteasome Degradation Pathway*

Aleksandra Musial and N. Tony EissaDagger

From the Department of Medicine, Baylor College of Medicine, Houston, Texas 77030

Inducible nitric-oxide synthase (iNOS) is responsible for nitric oxide (NO) synthesis from L-arginine in response to inflammatory mediators. To determine the degradation pathway of iNOS, human epithelial kidney HEK293 cells with stable expression of human iNOS were incubated in the presence of various degradation pathway inhibitors. Treatment with the proteasomal inhibitors lactacystin, MG132, and N-acetyl-L-leucinyl-L-leucinyl-L-norleucinal resulted in the accumulation of iNOS, indicating that these inhibitors blocked its degradation. Moreover, proteasomal inhibition blocked iNOS degradation in a dose- and time-dependent manner as well as when NO synthesis was inhibited by Nomega -nitro-L-arginine methyl ester. Furthermore, proteasomal inhibition blocked the degradation of an iNOS splice variant that lacked the capacity to dimerize and of an iNOS mutant that lacks L-arginine binding ability, suggesting that iNOS is targeted by proteasomes, notwithstanding its capacity to produce NO, dimerize, or bind the substrate. In contrast to proteasomal inhibitors, the calpain inhibitor calpastatin and the lysosomal inhibitors trans-epoxysuccinyl-L-leucylamido-4-guanidino butane, leupeptin, pepstatin-A, chloroquine, and NH4Cl did not lead to significant accumulation of iNOS. Interestingly, when cytokines were used to induce iNOS in RT4 human epithelial cells, the effect of proteasomal inhibition was dichotomous. Lactacystin added prior to cytokine stimulation prevented iNOS induction by blocking the degradation of the NF-kappa B inhibitor Ikappa B-alpha , thus preventing activation of NF-kappa B. In contrast, lactacystin added 48 h after iNOS induction led to the accumulation of iNOS. Similarly, in murine macrophage cell line RAW 264.7, lactacystin blocked iNOS degradation when added 48 h after iNOS induction by lipopolysaccharide. These data identify the proteasome as the primary degradation pathway for iNOS.

* This work was supported by the American Lung Association, the Caroline Wiess Law Fund for Molecular Medicine, the Methodist Foundation, and a T. T. Chao scholar award.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed: Baylor College of Medicine, One Baylor Plaza, FBRN-B567, Houston, TX 77030. Tel.: 713-790-5310; Fax: 713-793-1445; E-mail: teissa@bcm.tmc.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?


This article has been cited by other articles:


Home page
 Am. J. Physiol. Renal Physiol.Home page
N. V. Broadbelt, P. J. Stahl, J. Chen, M. Mizrahi, A. Lal, A. Bozkurt, D. P. Poppas, and D. Felsen
Early upregulation of iNOS mRNA expression and increase in NO metabolites in pressurized renal epithelial cells
Am J Physiol Renal Physiol, December 1, 2007; 293(6): F1877 - F1888.
[Abstract] [Full Text] [PDF]

Home page
 Infect. Immun.Home page
R. Chaturvedi, M. Asim, N. D. Lewis, H. M. S. Algood, T. L. Cover, P. Y. Kim, and K. T. Wilson
L-Arginine Availability Regulates Inducible Nitric Oxide Synthase-Dependent Host Defense against Helicobacter pylori
Infect. Immun., September 1, 2007; 75(9): 4305 - 4315.
[Abstract] [Full Text] [PDF]

Home page
 J. Am. Soc. Nephrol.Home page
T. Quaschning, F. Voss, K. Relle, P. Kalk, N. Vignon-Zellweger, T. Pfab, C. Bauer, F. Theilig, S. Bachmann, A. Kraemer-Guth, et al.
Lack of Endothelial Nitric Oxide Synthase Promotes Endothelin-Induced Hypertension: Lessons from Endothelin-1 Transgenic/Endothelial Nitric Oxide Synthase Knockout Mice
J. Am. Soc. Nephrol., March 1, 2007; 18(3): 730 - 740.
[Abstract] [Full Text] [PDF]

Home page
 Reproductive SciencesHome page
C. E. Wood and D. Giroux
Expression of Nitric Oxide Synthase Isoforms in the Ovine Fetal Brain: Alteration by Hormonal and Hemodynamic Stimuli
Reproductive Sciences, July 1, 2006; 13(5): 329 - 337.
[Abstract] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
K. E. Kolodziejska, A. R. Burns, R. H. Moore, D. L. Stenoien, and N. T. Eissa
Regulation of inducible nitric oxide synthase by aggresome formation
PNAS, March 29, 2005; 102(13): 4854 - 4859.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
T. Mazumdar and N. T. Eissa
Preferential Recognition of Undisruptable Dimers of Inducible Nitric Oxide Synthase by a Monoclonal Antibody Directed against an N-Terminal Epitope
J. Immunol., February 15, 2005; 174(4): 2314 - 2317.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
P. J. Kolodziejski, J.-S. Koo, and N. T. Eissa
Regulation of inducible nitric oxide synthase by rapid cellular turnover and cotranslational down-regulation by dimerization inhibitors
PNAS, December 28, 2004; 101(52): 18141 - 18146.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
B.-C. Chen, C.-C. Yu, H.-C. Lei, M.-S. Chang, M.-J. Hsu, C.-L. Huang, M.-C. Chen, J.-R. Sheu, T.-F. Chen, T.-L. Chen, et al.
Bradykinin B2 Receptor Mediates NF-{kappa}B Activation and Cyclooxygenase-2 Expression via the Ras/Raf-1/ERK Pathway in Human Airway Epithelial Cells
J. Immunol., October 15, 2004; 173(8): 5219 - 5228.
[Abstract] [Full Text] [PDF]

Home page
 J Antimicrob ChemotherHome page
A. G. Tempone, D. Perez, S. Rath, A. L. Vilarinho, R. A. Mortara, and H. F. de Andrade Jr
Targeting Leishmania (L.) chagasi amastigotes through macrophage scavenger receptors: the use of drugs entrapped in liposomes containing phosphatidylserine
J. Antimicrob. Chemother., July 1, 2004; 54(1): 60 - 68.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
B.-C. Chen, Y.-S. Chang, J.-C. Kang, M.-J. Hsu, J.-R. Sheu, T.-L. Chen, C.-M. Teng, and C.-H. Lin
Peptidoglycan Induces Nuclear Factor-{kappa}B Activation and Cyclooxygenase-2 Expression via Ras, Raf-1, and ERK in RAW 264.7 Macrophages
J. Biol. Chem., May 14, 2004; 279(20): 20889 - 20897.
[Abstract] [Full Text] [PDF]

Home page
 J. Cell Sci.Home page
I. Navarro-Lerida, M. T. Portoles, A. A. Barrientos, F. Gavilanes, L. Bosca, and I. Rodriguez-Crespo
Induction of nitric oxide synthase-2 proceeds with the concomitant downregulation of the endogenous caveolin levels
J. Cell Sci., May 1, 2004; 117(9): 1687 - 1697.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
H. Huang, D. C. Muddiman, and D. J. Tindall
Androgens Negatively Regulate Forkhead Transcription Factor FKHR (FOXO1) through a Proteolytic Mechanism in Prostate Cancer Cells
J. Biol. Chem., April 2, 2004; 279(14): 13866 - 13877.
[Abstract] [Full Text] [PDF]

Home page
 Alcohol AlcoholHome page
M. L. V. Dizon, L. A. Brown, and S. M. Black
BRAIN NITRIC OXIDE SYNTHASE LEVELS INCREASE IN RESPONSE TO ANTENATAL ETHANOL EXPOSURE
Alcohol Alcohol., March 1, 2004; 39(2): 101 - 105.
[Abstract] [Full Text] [PDF]

Home page
 J. Med. Genet.Home page
P J Lockhart, S Lincoln, M Hulihan, J Kachergus, K Wilkes, G Bisceglio, D C Mash, and M J Farrer
DJ-1 mutations are a rare cause of recessively inherited early onset parkinsonism mediated by loss of protein function
J. Med. Genet., March 1, 2004; 41(3): e22 - 22.
[Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
P. J. Kolodziejski, M. B. Rashid, and N. T. Eissa
Intracellular formation of "undisruptable" dimers of inducible nitric oxide synthase
PNAS, November 25, 2003; 100(24): 14263 - 14268.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
S. El-Gayar, H. Thuring-Nahler, J. Pfeilschifter, M. Rollinghoff, and C. Bogdan
Translational Control of Inducible Nitric Oxide Synthase by IL-13 and Arginine Availability in Inflammatory Macrophages
J. Immunol., November 1, 2003; 171(9): 4561 - 4568.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
Y. Osawa, E. R. Lowe, A. C. Everett, A. Y. Dunbar, and S. S. Billecke
Proteolytic Degradation of Nitric Oxide Synthase: Effect of Inhibitors and Role of hsp90-Based Chaperones
J. Pharmacol. Exp. Ther., February 1, 2003; 304(2): 493 - 497.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
P. J. Kolodziejski, A. Musial, J.-S. Koo, and N. T. Eissa
Ubiquitination of inducible nitric oxide synthase is required for its degradation
PNAS, September 17, 2002; 99(19): 12315 - 12320.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
E. Blasko, C. B. Glaser, J. J. Devlin, W. Xia, R. I. Feldman, M. A. Polokoff, G. B. Phillips, M. Whitlow, D. S. Auld, K. McMillan, et al.
Mechanistic Studies with Potent and Selective Inducible Nitric-oxide Synthase Dimerization Inhibitors
J. Biol. Chem., January 4, 2002; 277(1): 295 - 302.
[Abstract] [Full Text]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
 All ASBMB Journals   Molecular and Cellular Proteomics 
 Journal of Lipid Research   ASBMB Today 
Copyright © 2001 by the American Society for Biochemistry and Molecular Biology.