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

J. Biol. Chem., Vol. 282, Issue 2, 1003-1009, January 12, 2007

This Article Full Text Full Text (PDF) All Versions of this Article: 282/2/1003    most recent M607609200v1 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 Zhang, J. Articles by Danner, R. L. Search for Related Content PubMed PubMed Citation Articles by Zhang, J. Articles by Danner, R. L. Social Bookmarking                      What's this?

Nitric Oxide Down-regulates Polo-like Kinase 1 through a Proximal Promoter Cell Cycle Gene Homology Region^*

From the Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland 20892

Polo-like kinase 1 (PLK1) is an evolutionarily conserved serine/threonine kinase essential for cell mitosis. As a master cell cycle regulator, p21/Waf1 plays a critical role in cell cycle progression. Nitric oxide (NO·) has been shown to down-regulate PLK1 and up-regulate p21/Waf1 independent of cGMP. Here, the respective roles of p38 MAPK and p21/Waf1 in NO·-mediated PLK1 repression were investigated using differentiated U937 cells that lack soluble guanylate cyclase. NO· was shown to down-regulate both PLK1 mRNA and protein. Nuclear run-on assays and mRNA stability studies demonstrated that the effect of NO· on PLK1 expression was associated with decreased transcription without changes in transcript stability. SB202190, a p38 MAPK inhibitor, prevented transcriptional repression of PLK1 by NO·. Transfection with dominant-negative p38 MAPK mutant eliminated the NO· effect on both p21/Waf1 and PLK1 gene expression. Knockdown of p21/Waf1 with siRNA also substantially reduced the regulatory effect of NO· on PLK1. Reporter gene experiments showed that NO· decreased activity of the PLK1 proximal promoter, an effect that was blocked by p38 MAPK inhibitor. Deletion or mutation of the CDE/CHR promoter site, an element regulated by p21/Waf1, increased base-line promoter activity and abolished NO· repression of the PLK1 promoter. Likewise, electrophoretic mobility shift assays with CDE/CHR probe revealed a NO·-mediated change in protein-probe complex formation. Competition with various unlabeled CDE/CHR mutant sequences showed that NO· increased nuclear protein binding to intact CHR. These results demonstrate that a NO·-p38 MAPK-p21/Waf1 signal transduction pathway represses PLK1 through a canonical CDE/CHR promoter element.

Received for publication, August 9, 2006 , and in revised form, November 8, 2006.

^* This work was supported by intramural National Institutes of Health funds. 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 These authors contributed equally to this work and are joint first authors.

² To whom correspondence to: Critical Care Medicine Dept., Clinical Center, Bldg. 10, Rm. 2C145, National Institutes of Health, Bethesda, MD 20892. Tel.: 301-496-9320; Fax: 301-402-1213; E-mail: rdanner{at}nih.gov.

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

This article has been cited by other articles:

				S. Wang, J. Zhang, Y. Zhang, S. Kern, and R. L. Danner Nitric oxide-p38 MAPK signaling stabilizes mRNA through AU-rich element-dependent and -independent mechanisms J. Leukoc. Biol., April 1, 2008; 83(4): 982 - 990. [Abstract] [Full Text] [PDF]

				M. A. Retamal, N. Froger, N. Palacios-Prado, P. Ezan, P. J. Saez, J. C. Saez, and C. Giaume Cx43 Hemichannels and Gap Junction Channels in Astrocytes Are Regulated Oppositely by Proinflammatory Cytokines Released from Activated Microglia J. Neurosci., December 12, 2007; 27(50): 13781 - 13792. [Abstract] [Full Text] [PDF]