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Molecular and Cellular Biology, December 1999, p. 8146-8157, Vol. 19, No. 12
Department of Physiology, Dartmouth Medical
School, Lebanon, New Hampshire 03756,1 and
Laboratory of Receptor Biology and Gene Expression, National
Cancer Institute, Bethesda, Maryland 208922
Received 6 August 1999/Returned for modification 10 September
1999/Accepted 15 September 1999
We utilized the mouse mammary tumor virus (MMTV) long terminal
repeat (LTR) in vivo to understand how the interaction of the glucocorticoid receptor (GR) with a nucleosome-assembled promoter allows access of factors required for the transition from a repressed promoter to a derepressed, transcriptionally competent promoter. A
mutation (C644G) in the ligand binding domain (LBD) of the mouse GR has
provided information regarding the steps required in the derepression/activation process and in the functional significance of
the two major transcriptional activation domains, AF1 and AF2. The
mutant GR activates transcription from a transiently transfected promoter that has a disordered nucleosomal structure, though
significantly less well than the wild-type GR. With an integrated,
replicated promoter, which is assembled in an ordered nucleosomal
array, the mutant GR does not activate transcription, and it fails to induce chromatin remodeling of the MMTV LTR promoter, as indicated by
nuclease accessibility assays. Together, these findings support a
two-step model for the transition of a nucleosome-assembled, repressed
promoter to its transcriptionally active, derepressed form. In
addition, we find that the C-terminal GR mutation is dominant over the
transcription activation function of the N-terminal GR activation
domain. These findings suggest that the primary activation function of
the C-terminal activation domain is different from the function of the
N-terminal activation domain and that it is required for derepression
of the chromatin-repressed MMTV promoter.
0270-7306/99/$04.00+0
A Ligand Binding Domain Mutation in the Mouse Glucocorticoid
Receptor Functionally Links Chromatin Remodeling and
Transcription Initiation
*
Corresponding author. Mailing address: Department of
Physiology, 750W Borwell, 1 Medical Center Dr., Dartmouth Medical
School, Lebanon, NH 03756. Phone: (603) 650-7734. Fax: (603) 650-6130. E-mail: Lynn.A.Sheldon.{at}Dartmouth.edu.
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