HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 281, Issue 14, 9101-9109, April 7, 2006

This Article Full Text Full Text (PDF) All Versions of this Article: 281/14/9101    most recent M511049200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yu, Z. Articles by Kone, B. C. Search for Related Content PubMed PubMed Citation Articles by Yu, Z. Articles by Kone, B. C. Social Bookmarking                      What's this?

Nitric Oxide-dependent Negative Feedback of PARP-1 trans-Activation of the Inducible Nitric-oxide Synthase Gene^*

From the Departments of Internal Medicine and of Integrative Biology and Pharmacology and The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, The University of Texas Health Science Center at Houston, Houston, Texas 77030

Nitric oxide (NO) participates in a variety of physiologic and pathophysiologic processes in diverse tissues, including the kidney. Although mechanisms for cytokine induction of inducible nitric-oxide synthase (iNOS) have been increasingly clarified, the controls for termination of NO production remain unclear. Because excessive NO production can be cytotoxic to host cells, feedback inhibition of iNOS transcription would represent a means of cytoprotection. Many of the cGMP-independent functions of NO are mediated by S-nitrosylation of cysteine thiols of target proteins. We hypothesized that NO-mediated S-nitrosylation of transcription factors might serve to feedback inhibit their trans-activation potential and deactivate iNOS gene transcription. Transient transfection of murine mesangial cells with iNOS promoter deletion-luciferase constructs revealed the region –915 to –849 to be NO sensitive with respect to IL-1-induced promoter activity. In vitro DNase I footprinting identified a footprint at –865/–842 in the absence of NO, but not in the presence of endogenous or exogenously delivered NO. Southwestern blotting using this probe coupled with partial peptide sequencing of the protein bands revealed that poly(ADP-ribose) polymerase isoform 1 (PARP-1) bound the probe in a sequence-specific manner. Gel shift/supershift experiments and chromatin immunoprecipitation assay analysis confirmed this binding in vitro and in vivo. Functionally, mutation of the –859/–850 site to prevent PARP-1 binding or PARP-1 knockdown by RNA interference relieved the inhibitory effects of NO on iNOS promoter activity. Biotin-switch assays and co-immunoprecipitation with an anti-nitrocysteine antibody indicated that PARP-1 was S-nitrosylated. We conclude that NO feedback inhibits iNOS gene transcription by S-nitrosylating the trans-activator PARP-1 and decreasing its binding and/or action at the iNOS promoter.

Received for publication, October 11, 2005 , and in revised form, January 17, 2006.

^* This work was supported by National Institutes of Health Grants RO1 DK50745 and P50 GM38529, a Dept. of Defense "T5" grant, and endowment funds from The James T. and Nancy B. Willerson Chair (to B. C. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Internal Medicine, The University of Texas Medical School at Houston, 6431 Fannin, MSB 1.150, Houston, TX 77030. Tel.: 713-500-6501; Fax: 713-500-6497; E-mail: Bruce.C.Kone{at}uth.tmc.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				A. S. Naura, R. Datta, C. P. Hans, M. Zerfaoui, B. M. Rezk, Y. Errami, M. Oumouna, K. Matrougui, and A. H. Boulares Reciprocal regulation of iNOS and PARP-1 during allergen-induced eosinophilia Eur. Respir. J., February 1, 2009; 33(2): 252 - 262. [Abstract] [Full Text] [PDF]

				J. W. Elrod, J. W. Calvert, S. Gundewar, N. S. Bryan, and D. J. Lefer Nitric oxide promotes distant organ protection: Evidence for an endocrine role of nitric oxide PNAS, August 12, 2008; 105(32): 11430 - 11435. [Abstract] [Full Text] [PDF]

				H. Okada, T. Inoue, T. Kikuta, N. Kato, Y. Kanno, N. Hirosawa, Y. Sakamoto, T. Sugaya, and H. Suzuki Poly(ADP-Ribose) Polymerase-1 Enhances Transcription of the Profibrotic CCN2 Gene J. Am. Soc. Nephrol., May 1, 2008; 19(5): 933 - 942. [Abstract] [Full Text] [PDF]

				Z. T. Kelleher, A. Matsumoto, J. S. Stamler, and H. E. Marshall NOS2 Regulation of NF-{kappa}B by S-Nitrosylation of p65 J. Biol. Chem., October 19, 2007; 282(42): 30667 - 30672. [Abstract] [Full Text] [PDF]

				N. Pottier, M. H. Cheok, W. Yang, M. Assem, L. Tracey, J. C. Obenauer, J. C. Panetta, M. V. Relling, and W. E. Evans Expression of SMARCB1 modulates steroid sensitivity in human lymphoblastoid cells: identification of a promoter snp that alters PARP1 binding and SMARCB1 expression Hum. Mol. Genet., October 1, 2007; 16(19): 2261 - 2271. [Abstract] [Full Text] [PDF]