       Document 0574
 DOCN  M9640574
 TI    Role of glucocorticoid receptor binding sites in the human
       immunodeficiency virus type 1 long terminal repeat in steroid-mediated
       suppression of HIV gene expression.
 DT    9604
 AU    Mitra D; Sikder SK; Laurence J; Department of Medicine, Cornell
       University Medical College, New; York, New York 10021, USA.
 SO    Virology. 1995 Dec 20;214(2):512-21. Unique Identifier : AIDSLINE
       MED/96130191
 AB    Dexamethasone inhibited human immunodeficiency virus type 1 (HIV-1) long
       terminal repeat (LTR)-directed gene expression in cells of T and B
       lymphoblastoid lineages, but not in monocytic cells. Suppression
       required an intact glucocorticoid receptor (GR), as it was amplified by
       transfection of lymphocytes with a plasmid encoding the human GR and
       blocked by the receptor antagonist RU486. These results were in direct
       contrast to the effects of dexamethasone on a murine leukemia retrovirus
       promoter where, consistent with the findings of others, activation of
       gene expression was obtained. Potential regions of the HIV-1 LTR
       mediating these effects were sought, with sequence homologies predicting
       two new glucocorticoid response element half-sites, GRE-II (nucleotides
       -6 to -1) and GRE-III (+ 15 to + 20), downstream from a previously
       identified GR DNA binding domain, GRE-I (-264 to -259). Mutational
       analyses documented the loss of inhibitory activity attendant on changes
       in GRE-III and the independence of steroid-mediated effects from GRE-I
       and GRE-II. Consistent with these findings, electrophoretic mobility
       shift assays revealed a difference in binding of cellular factors to
       GRE-III in cells of T and B lymphocyte vs. monocytic lineages. Binding
       sites for the cellular transcription factor leader binding protein
       (LBP-1) were found to overlap with GRE-III, and LBP-1 interacted with
       this element in the HIV LTR only in T and B lymphocytic extracts. We
       hypothesize that GRE-III sequence-specific effects, including modulation
       of LBP-GR interactions, underlie the negative regulatory effect of
       glucocorticoids on HIV-1 gene expression, with some specificity for cell
       type.
 DE    Base Sequence  Binding Sites  Cell Line  Dexamethasone/*PHARMACOLOGY
       DNA, Viral/*METABOLISM  Gene Expression Regulation, Viral/*DRUG EFFECTS
       Human  HIV Long Terminal Repeat/*DRUG EFFECTS  HIV-1/*DRUG
       EFFECTS/GENETICS  Mifepristone/PHARMACOLOGY  Molecular Sequence Data
       Receptors, Glucocorticoid/ANTAGONISTS & INHIB/*METABOLISM  Support,
       Non-U.S. Gov't  Support, U.S. Gov't, P.H.S.  Transcription, Genetic
       Tumor Cells, Cultured  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).

