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

J. Biol. Chem., Vol. 282, Issue 17, 12590-12597, April 27, 2007

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 282/17/12590    most recent M611446200v1 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 McMillan, B. J. Articles by Bradfield, C. A. Search for Related Content PubMed PubMed Citation Articles by McMillan, B. J. Articles by Bradfield, C. A. Social Bookmarking                      What's this?

2,3,7,8-Tetrachlorodibenzo-p-dioxin Induces Premature Activation of the KLF2 Regulon during Thymocyte Development^*

From the McArdle Laboratory for Cancer Research, University of Wisconsin Medical School, Madison, Wisconsin 53706

The environmental pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin) causes numerous and diverse toxic events via activation of the aryl hydrocarbon receptor, including atrophy of the thymus. Exposure to TCDD induces acute thymocyte cell loss, which occurs concomitantly with proliferation arrest and premature emigration of triple negative (TN; CD4^-, CD8^-, CD3^-) T cell progenitors. In this report, we demonstrate that TCDD exposure results in dysregulation of KLF2 (Kruppel-like factor 2) expression in developing thymocytes. The Klf2 gene encodes an Sp1-like zinc finger transcription factor that functions as a central regulator of T lymphocyte proliferation and trafficking. During normal thymocyte development, KLF2 is expressed exclusively in CD4 and CD8 single positive T cells and promotes a nonproliferative, promigratory phenotype. In mice exposed to TCDD, however, the Klf2 gene is prematurely expressed in TN thymocytes. Administration of a 100 µg/kg dose of TCDD results in a 15-fold induction of KLF2 as early as the TN2 (CD44⁺, CD25⁺) stage of development and immediately precedes acute cell loss in the TN3, TN4, and double positive (CD4⁺, CD8⁺) cell stages. Induction of KLF2 occurs within 12 h of TCDD exposure and is fully dependent on expression of the aryl hydrocarbon receptor. In addition, TCDD exposure alters the expression of several factors comprising the KLF2 regulon, including Edg1/S1P₁, ₇ integrin, CD52, Cdkn2d (cyclin-dependent kinase inhibitor 2D), s100a4, and IL10R. These findings indicate that the pollutant TCDD interferes with early thymopoeisis via ectopic expression of the KLF2 regulon.

Received for publication, December 14, 2006

^* This work was supported by National Institutes of Health Grants R37-ES05703, T32-CA009135, and P30-CA014520. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S4.

¹ To whom correspondence should be addressed: McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, 1400 University Ave., Madison, WI 53706-1599. Tel.: 608-262-1209; Fax: 608-262-2824; E-mail: bradfield{at}oncology.wisc.edu.

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

This article has been cited by other articles:

				K. Nohara, K. Ao, Y. Miyamoto, T. Suzuki, S. Imaizumi, Y. Tateishi, S. Omura, C. Tohyama, and T. Kobayashi Arsenite-Induced Thymus Atrophy is Mediated by Cell Cycle Arrest: A Characteristic Downregulation of E2F-Related Genes Revealed by a Microarray Approach Toxicol. Sci., February 1, 2008; 101(2): 226 - 238. [Abstract] [Full Text] [PDF]

				L. Z. Shi, N. G. Faith, Y. Nakayama, M. Suresh, H. Steinberg, and C. J. Czuprynski The Aryl Hydrocarbon Receptor Is Required for Optimal Resistance to Listeria monocytogenes Infection in Mice J. Immunol., November 15, 2007; 179(10): 6952 - 6962. [Abstract] [Full Text] [PDF]