Synergistic Enhansons Located within an Acute Phase Responsive Enhancer Modulate Glucocorticoid Induction of Angiotensinogen Gene Transcription (original) (raw)
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1Laboratory of Molecular Endocrinology, Massachusetts General Hospital and Howard Hughes Medical Institute, Harvard Medical School Boston, Massachusetts 02114
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1Laboratory of Molecular Endocrinology, Massachusetts General Hospital and Howard Hughes Medical Institute, Harvard Medical School Boston, Massachusetts 02114
Search for other works by this author on:
,
1Laboratory of Molecular Endocrinology, Massachusetts General Hospital and Howard Hughes Medical Institute, Harvard Medical School Boston, Massachusetts 02114
Search for other works by this author on:
1Laboratory of Molecular Endocrinology, Massachusetts General Hospital and Howard Hughes Medical Institute, Harvard Medical School Boston, Massachusetts 02114
Search for other works by this author on:
This work was supported in part by NIH Grant DK-30834.
Revision received:
07 September 1990
Accepted:
13 September 1990
Published:
01 December 1990
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Allan R. Brasier, David Ron, James E. Tate, Joel F. Habener, Synergistic Enhansons Located within an Acute Phase Responsive Enhancer Modulate Glucocorticoid Induction of Angiotensinogen Gene Transcription, Molecular Endocrinology, Volume 4, Issue 12, 1 December 1990, Pages 1921–1933, https://doi.org/10.1210/mend-4-12-1921
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Abstract
The hepatic transcription of the angiotensinogen gene is regulated by both glucocorticoids and cytokines generated as products of the acute phase reaction. We have identified a multimodular enhancer in the 5′-flanking region of the rat angiotensinogen gene that mediates these responses and consists of an acute phase response element (APRE) flanked on both sides by adjacent glucocorticoid response element consensus motifs (GREs). Induction of transcription by the cytokine interleukin-1 (IL-1) is glucocorticoid dependent and mediated through the APRE. The APRE binds in a mutually exclusive manner a cytokine/phorbol ester-inducible protein (BPi), indistinguishable from nuclear factor kB, and a family of constitutive liver proteins (BPcs) related to the heat-stable transcription factor C/EBP. Using mutated 5′-flanking sequences of the angiotensinogen gene fused to a firefly luciferase reporter gene transfected into hepatoblastoma (HepG2) cells, we have mapped enhanson sequences required for the transcriptional response to glucocorticoids. Two functionally distinct GREs are identified by deletion and site-directed mutagenesis, both of which mediate glucocorticoid-stimulated transcription in vivo. Glucocorticoid-induced transcription mediated by the angiotensinogen gene enhancer is, furthermore, dependent on the occupancy of the APRE by either the BPi or a member of the BPc family because a mutant APRE that binds neither BPi nor BPc exhibits an attenuated glucocorticoid responsiveness. Mutant APREs that permit exclusive binding of either BPi or BPc synergistically transmit the glucocorticoid response mediated by one or the other of the adjacent GREs. Thus, the induction of angiotensinogen gene transcription involves interaction between the glucocorticoid receptor and either one of the APRE-binding proteins: either the cytokine-inducible NFkB or the constitutive family of C/EBP-like proteins, bound to adjacent enhansons in a mutually synergistic enhancer complex.
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Author notes
This work was supported in part by NIH Grant DK-30834.
Copyright © 1990 by The Endocrine Society
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