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J. Biol. Chem., Vol. 283, Issue 24, 16299-16308, June 13, 2008

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Human T-cell Leukemia Virus Type 1 Oncoprotein Tax Represses ZNF268 Expression through the cAMP-responsive Element-binding Protein/Activating Transcription Factor Pathway^*

Di Wang¹, Ming-Xiong Guo¹, Hai-Ming Hu, Zhou-Zhou Zhao, Hong-Ling Qiu, Huan-Jie Shao, Chen-Gang Zhu, Lu Xue, Yun-Bo Shi, and Wen-Xin Li²

From the State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China and Section on Molecular Morphogenesis, Laboratory of Gene Regulation and Development, NICHD, National Institutes of Health, Bethesda, Maryland 20892

Expression of the human T-cell leukemia virus type 1 (HTLV-1) oncoprotein Tax is correlated with cellular transformation, contributing to the development of adult T-cell leukemia. In this study, we investigated the role of Tax in the regulation of the ZNF268 gene, which plays a role in the differentiation of blood cells and the pathogenesis of leukemia. We demonstrated that ZNF268 mRNA was repressed in HTLV-1-infected cells. We also showed that stable and transient expression of HTLV-1 Tax led to repression of ZNF268. In addition, by using reporter constructs that bear the human ZNF268 promoter and its mutants, we showed that Tax repressed ZNF268 promoter in a process dependent on a functional cAMP-responsive element. By using Tax, cAMP-responsive element-binding protein (CREB)-1, CREB-2, and their mutants, we further showed that Tax repressed ZNF268 through the CREB/activating transcription factor pathway. Electrophoretic mobility shift assays and chromatin immunoprecipitation demonstrated the formation of the complex of Tax·CREB-1 directly at the cAMP-responsive element both in vitro and in vivo. These findings suggest a role for ZNF268 in aberrant T-cell proliferation observed in HTLV-1-associated diseases.

Received for publication, August 3, 2007 , and in revised form, March 27, 2008.

^* This work was supported, in whole or in part, by the National Institutes of Health Intramural Research Program (NICHD). This research was also supported by National High Technology Research and Development Program of China (863 Program) Grant 2006AA02A306, Programme of Introducing Talents of Discipline to Universities Grant B06018 [GenBank] , Key Project of the Ministry of Science and Technology of China (973 Program) Grant 2005CB522903, and National Natural Science Foundation of China Grant 30500266. 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 Both authors contributed equally to this work.

² To whom correspondence should be addressed: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China. Tel.: 86-27-68752831; Fax: 86-27-68752146; E-mail: liwxlab{at}whu.edu.cn.

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