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Journal of Virology, November 2002, p. 11159-11165, Vol. 76, No. 21
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.21.11159-11165.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Evidence for Regulation of Long Terminal Repeat Transcription by Wnt Transcription Factor TCF-4 in Human Astrocytic Cells

Bethany Wortman, Nune Darbinian, Bassel E. Sawaya, Kamel Khalili, and Shohreh Amini*

Center for Neurovirology and Cancer Biology, College of Science and Technology, Temple University, Philadelphia, Pennsylvania 19122

Received 9 October 2001/ Accepted 10 July 2002

The Wnt signaling pathway plays an important role in neural cell development and function. The key components of this pathway, ß-catenin and its partner TCF-4/LEF-1, exert their effects on transcription by entering the nuclei, where they associate with the TCF-4/LEF-1 DNA motif positioned in the promoters of several important genes. Here we examined the role of TCF-4 upon transcription of the human immunodeficiency virus type 1 (HIV-1) promoter in human astrocytic cells. Our results showed that expression of TCF-4 in human astrocytic cells (U-87MG cells) decreased the basal and Tat-mediated transcription of the HIV-1 long terminal repeat (LTR). Results from promoter deletion studies revealed that the promoter sequence of the LTR with no classical binding motif for TCF-4/LEF-1, which spans positions -80 to +80 of the LTR, remained responsive to down-regulation by TCF-4. Noticeably, removal of the sequences between positions -80 and -68 decreased the negative effect of TCF-4 on viral gene transcription. A mutant variant of TCF-4 with no binding site for ß-catenin was able to down-regulate LTR transcription, suggesting that ß-catenin may not be directly involved in the observed regulatory events. Results from the glutathione S-transferase pull-down assay as well as the combined immunoprecipitation and Western blot analysis of protein extract from U-87MG cells revealed an interaction of Tat with TCF-4. Subcellular examination of TCF-4 and Tat in cells expressing either protein alone showed a predominantly nuclear accumulation of these proteins. However, in cells which coexpressed both TCF-4 and Tat, significant levels of these proteins were found in the cytoplasm. All together, these observations provide evidence for the cooperative interaction of TCF-4, the important transcription factor of the Wnt pathway, with Tat; this interaction may determine the level of viral gene transcription in human astrocytic cells.

* Corresponding author. Mailing address: Center for Neurovirology and Cancer Biology, College of Science and Technology, Temple University, 1900 N. 12th St., 015-96, Room 203, Philadelphia, PA 19122. Phone: (215) 204-0604. Fax: (215) 204-0679. E-mail: ashohreh{at}astro.temple.edu.

Journal of Virology, November 2002, p. 11159-11165, Vol. 76, No. 21
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.21.11159-11165.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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