Regulation of MCP-1 gene transcription by Smads and HIV-1 Tat in human glial cells

被引:42
|
作者
Abraham, S
Sawaya, BE
Safak, M
Batuman, O
Khalili, K
Amini, S
机构
[1] Temple Univ, Coll Sci & Technol, Ctr Neurovirol & Canc Biol, Philadelphia, PA 19122 USA
[2] SUNY Hlth Sci Ctr, Brooklyn, NY 11203 USA
关键词
D O I
10.1016/S0042-6822(03)00112-0
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
Expression of several cytokines involved in signal transduction such as TGFbeta-1 and the inflammatory chemokines including MCP-1 is elevated during the course of AIDS progression. The enhancement of these cellular proteins in astrocytic cells is mediated, at least in part, by HIV-1 Tat protein. Here, we investigate the possible regulation of MCP-1 transcription by Tat and the Smad family of transcription factors whose activities are induced by the TGFbeta-1 pathway. Results from transfection studies revealed that Smad-3 stimulates basal and Tat-mediated transcription of MCP-1 in human astrocytic cells. Smad-4, on the other hand, had no effect on the basal activity of the MCP-1 promoter, but showed the ability to decrease both Smad-3 and Tat-induced transcription of the MCP promoter. Results from protein-binding studies revealed the ability of both Smad-3 and Smad-4 to associate with the region of Tat spanning residues 1-40. Examination of the transcriptional activity of the various domains of Smad including MH1, at the N-terminus, and MH2, at the C-terminus of the protein indicated that neither MH1 or MH2 alone positively cooperate with Tat in modulating MCP-1 transcription. However, ectopic expression of MH1 and, more notably, MH2 severely suppressed transcriptional activation of MCP-1 by Tat in astrocytic cells. Binding studies revealed that similar to the full-length Smad protein, both MH1 and MH2 associate with Tat protein and that the residues between I and 40 of Tat are important for their interaction. These observations reveal a novel mechanism for Tat-mediated transcriptional activation via TGFbeta signaling pathway and provide evidence for regulation of MCP-1 gene transcription by this signaling pathway in human astrocytic cells. (C) 2003 Elsevier Science (USA). All rights reserved.
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页码:196 / 202
页数:7
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