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Published online before print November 10, 2005

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(Journal of Leukocyte Biology. 2006;79:192-201.)
© 2006 by Society for Leukocyte Biology

HIV-1 TAT represses transcription of the bone morphogenic protein receptor-2 in U937 monocytic cells

Robert L. Caldwell^*,,1, Radhika Gadipatti, Kirk B. Lane and Virginia L. Shepherd^*,,2

Departments of
^* Pathology and
Medicine, Vanderbilt University School of Medicine, and
Department of Veterans Affairs Medical Center, Nashville, Tennessee

² Correspondence: VA Medical Center/Research Service, 1310 24th Ave., South, Nashville, TN 37212. E-mail: Virginia.l.shepherd{at}vanderbilt.edu

The bone morphogenetic protein receptor-2 (BMPR2) is a member of the transforming growth factor-ß receptor family and is expressed on the surface of several cell types including endothelial cells and macrophages. Recently, a cause for familial primary pulmonary hypertension (FPPH) has been identified as mutations in the gene encoding BMPR2. Three forms of pulmonary hypertension (PH) exist, including PPH, FPPH, and PH secondary to other etiologies (sporadic PH) such as drug abuse and human immunodeficiency virus (HIV) infection. It is interesting that these subtypes are histologically indistinguishable. The macrophage is a key target cell for HIV-1, significantly altering macrophage cell function upon infection. HIV-1 trans-activator of transcription (Tat), an immediate-early product of the HIV-1 lifecycle, plays an important role in mediating HIV-induced modulation of host cell function. Our laboratory has previously shown that Tat represses mannose receptor transcription in macrophages. In the current study, we examined activity from the BMPR2 promoter in the macrophage cell line U937 and potential regulation by Tat. Transfection of U937 cells with BMPR2 promoter-reporter constructs revealed dose-dependent repression of BMPR2 promoter activity in the presence of Tat. Experiments using truncations of the BMPR2 promoter localized Tat-mediated repression to the first 208 bases of the promoter. Decreased BMPR2 transcription resulted in altered downstream signaling. Similar to mothers against decapentaplegics (SMAD) phosphorylation and SMAD6 expression, in response to BMP2 treatment, were down-regulated after Tat treatment. Finally, HIV-1 infection and treatment with Tat protein of the U937 human monocytic cell line resulted in a decreased, endogenous BMPR2 transcript copy number.

Key Words: monocytes/macrophages • AIDS • cell-surface molecules • gene regulation • lung

This article has been cited by other articles:

				C. F. Barnett, P. Y. Hsue, and R. F. Machado Pulmonary Hypertension: An Increasingly Recognized Complication of Hereditary Hemolytic Anemias and HIV Infection JAMA, January 23, 2008; 299(3): 324 - 331. [Abstract] [Full Text] [PDF]

				N. W. Morrell Pulmonary Hypertension Due to BMPR2 Mutation: A New Paradigm for Tissue Remodeling? Proceedings of the ATS, November 1, 2006; 3(8): 680 - 686. [Abstract] [Full Text] [PDF]