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Articles

Tomoshige Kino^*, Alexander Gragerov, Jeffrey B. Kopp, Roland H. Stauber, George N. Pavlakis, and George P. Chrousos^*

From the ^* Section on Pediatric Endocrinology, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, and the Kidney Disease Section, Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892; and the Human Retrovirus Section, ABL Basic Research Program, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, Maryland 21702

The HIV-1 virion-associated accessory protein Vpr affects both viral replication and cellular transcription, proliferation, and differentiation. We report that Vpr enhances the activity of glucocorticoids in lymphoid and muscle-derived cell lines by interacting directly with the glucocorticoid receptor and general transcription factors, acting as a coactivator. Vpr contains the signature motif LXXLL also present in cellular nuclear receptor coactivators, such as steroid receptor coactivator 1 and p300/CREB-binding protein, which mediates their interaction with the glucocorticoid and other nuclear hormone receptors. A mutant Vpr molecule with disruption of this coactivator signature motif lost its ability to influence transcription of glucocorticoid-responsive genes and became a dominant-negative inhibitor of Vpr, possibly by retaining its general transcription factor–binding activities. The glucocorticoid coactivator activity of Vpr may contribute to increased tissue glucocorticoid sensitivity in the absence of hypercortisolism and to the pathogenesis of AIDS.

Key Words: nuclear receptors • AIDS • mouse mammary tumor virus • p300/CBP • steroid receptor coactivator 1

Address correspondence Tomoshige Kino, Section on Pediatric Endocrinology, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bldg. 10, Rm. 10N262, 10 Center Drive MSC 1862, Bethesda, MD 20892-1862. Phone: 301-496-6909; Fax: 301-402-0574; E-mail: kinot{at}cc1.nichd.nih.gov; or Dr. George N. Pavlakis, ABL Basic Research Program, National Cancer Institute-Frederick Cancer Research and Development Center, Bldg. 535, Rm. 210, Frederick, MD 21702. Phone: 301-846-1474; Fax: 301-846-6368; E-mail: pavlakis{at}ncifcrf.gov

Abbreviations used: CAT, chloramphenicol acetyltransferase; CBP, CREB-binding protein; CREB, cAMP-response element binding protein; GFP, green fluorescence protein; GR, glucocorticoid receptor; GRE, glucocorticoid response element; GST, glutathione S-transferase; h, human; MMTV, mouse mammary tumor virus; NF, nuclear factor; PKA, protein kinase A; RSV, Rous sarcoma virus; SRC, steroid receptor coactivator; SV40, simian virus 40.

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