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J. Biol. Chem., Vol. 282, Issue 26, 18750-18757, June 29, 2007

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Molecular Characterization of the Tax-containing HTLV-1 Enhancer Complex Reveals a Prominent Role for CREB Phosphorylation in Tax Transactivation^*

From the Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, Colorado 80523-1870

Transcriptional activation of human T-cell leukemia virus type 1 (HTLV-1) is mediated by the viral oncoprotein Tax, which utilizes cellular transcriptional machinery to perform this function. The viral promoter carries three cyclic AMP-response elements (CREs), which are recognized by the cellular transcription factor cAMP-response element-binding protein (CREB). Tax binds to GC-rich sequences that immediately flank the CREs. The coactivator CREB-binding protein (CBP)/p300 binds to this promoter-bound ternary complex, which promotes the initiation of HTLV-1 transcription. Protein kinase A phosphorylation of CREB at serine 133 facilitates transcription from cellular CREs by recruiting CBP/p300 via its KIX domain. However, it remains controversial whether CREB phosphorylation plays a role in Tax transactivation. In this study, we biochemically characterized the quaternary complex formed by Tax, CREB, KIX, and the viral CRE by examining the individual molecular interactions that contribute to Tax stabilization in the complex. Our data show KIX, Ser¹³³-phosphorylated CREB, and vCRE DNA are all required for stable Tax incorporation into the complex in vitro. Consonant with a fundamental role for CREB phosphorylation in Tax recruitment to the complex, we found that CREB is highly phosphorylated in a panel of HTLV-1-infected human T-cell lines. Significantly, we show that Tax is directly responsible for promoting elevated levels of CREB phosphorylation. Together, these data support a model in which Tax promotes CREB phosphorylation in vivo to ensure availability for Tax transactivation. Because pCREB has been implicated in leukemogenesis, enhancement of CREB phosphorylation by the virus may play a role in the etiology of adult T-cell leukemia.

Received for publication, January 16, 2007 , and in revised form, April 2, 2007.

^* This work was supported by National Institutes of Health Grant CA55035 (to J. K. N.) and by the W. M. Keck Foundation. 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 Supported by a minority supplement (CA55035-S1).

³ To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, Colorado State University, Campus Box 1870, Fort Collins, CO 80523-1870. Tel.: 970-491-0420; Fax: 970-491-0494; E-mail: Jennifer.Nyborg{at}ColoState.edu.

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				T. R. Geiger, N. Sharma, Y.-M. Kim, and J. K. Nyborg The Human T-Cell Leukemia Virus Type 1 Tax Protein Confers CBP/p300 Recruitment and Transcriptional Activation Properties to Phosphorylated CREB Mol. Cell. Biol., February 15, 2008; 28(4): 1383 - 1392. [Abstract] [Full Text] [PDF]