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

J. Biol. Chem., Vol. 280, Issue 42, 35713-35722, October 21, 2005

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 280/42/35713    most recent M504848200v1 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 Kwon, H. Articles by Greene, W. C. Search for Related Content PubMed PubMed Citation Articles by Kwon, H. Articles by Greene, W. C. Social Bookmarking                      What's this?

Lethal Cutaneous Disease in Transgenic Mice Conditionally Expressing Type I Human T Cell Leukemia Virus Tax^*

Hakju Kwon, Louise Ogle, Bobby Benitez, Jan Bohuslav, Mauricio Montano, Dean W. Felsher, and Warner C. Greene¶1

From the Gladstone Institute of Virology and Immunology, San Francisco, California 94158, the ^¶Departments of Medicine and of Microbiology and Immunology, University of California, San Francisco, California 94143, and the Division of Oncology, Department of Medicine, Stanford University, Stanford, California 94305

Type I human T cell leukemia virus (HTLV-I) is etiologically linked with adult T cell leukemia, an aggressive and usually fatal expansion of activated CD4⁺ T lymphocytes that frequently traffic to skin. T cell transformation induced by HTLV-I involves the action of the 40-kDa viral Tax transactivator protein. Tax both stimulates the HTLV-I long terminal repeat and deregulates the expression of select cellular genes by altering the activity of specific host transcription factors, including cyclic AMP-responsive element-binding protein (CREB)/activating transcription factor, NF-B/Rel, and serum response factor. To study initiating events involved in HTLV-I Tax-induced T cell transformation, we generated "Tet-off" transgenic mice conditionally expressing in a lymphocyte-restricted manner (EµSR promoter-enhancer) either wild-type Tax or mutant forms of Tax that selectively compromise the NF-B (M22) or CREB/activating transcription factor (M47) activation pathways. Wild-type Tax and M47 Tax-expressing mice, but not M22-Tax expressing mice, developed progressive alopecia, hyperkeratosis, and skin lesions containing profuse activated CD4 T cell infiltrates with evidence of deregulated inflammatory cytokine production. In addition, these animals displayed systemic lymphadenopathy and splenomegaly. These findings suggest that Tax-mediated activation of NF-B plays a key role in the development of this aggressive skin disease that shares several features in common with the skin disease occurring during the preleukemic stage in HTLV-I-infected patients. Of note, this skin disease completely resolved when Tax transgene expression was suppressed by administration of doxycycline, emphasizing the key role played by this viral oncoprotein in the observed pathology.

Received for publication, May 3, 2005 , and in revised form, August 16, 2005.

^* This work was supported by NCI, National Institutes of Health Grant R01CA89001 (to W. C. G.) and a Canadian Institutes of Health Research postdoctoral fellowship (to H. 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.

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

¹ To whom correspondence should be addressed: Gladstone Institute of Virology and Immunology, 1650 Owens St., San Francisco, CA 94158. Tel.: 415-734-4805; Fax: 415-355-0153; E-mail: wgreene{at}gladstone.ucsf.edu.

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

This article has been cited by other articles:

				P. Yan, J. Fu, Z. Qu, S. Li, T. Tanaka, M. J. Grusby, and G. Xiao PDLIM2 suppresses human T-cell leukemia virus type I Tax-mediated tumorigenesis by targeting Tax into the nuclear matrix for proteasomal degradation Blood, April 30, 2009; 113(18): 4370 - 4380. [Abstract] [Full Text] [PDF]

				D. Rauch, S. Gross, J. Harding, S. Niewiesk, M. Lairmore, D. Piwnica-Worms, and L. Ratner Imaging spontaneous tumorigenesis: inflammation precedes development of peripheral NK tumors Blood, February 12, 2009; 113(7): 1493 - 1500. [Abstract] [Full Text] [PDF]