Synergistic activation of the human orphan nuclear receptor SHP gene promoter by basic helix-loop-helix protein E2A and orphan nuclear receptor SF-1

Abstract Small heterodimer partner (SHP; NR0B2) is an atypical orphan nuclear receptor that lacks a conventional DNA binding domain (DBD) and represses the transcriptional activity of various nuclear receptors. In this study, we examined the novel cross talk between SHP and BETA2/NeuroD, a basic helix-loop-helix transcription factor. In vitro and in vivo protein interaction studies showed that SHP physically interacts with BETA2/NeuroD, but not its heterodimer partner E47. Moreover, confocal microscopic study and immunostaining results demonstrated that SHP colocalized with BETA2 in islets of mouse pancreas. SHP inhibited BETA2/NeuroD-dependent transactivation of an E-box reporter, whereas SHP was unable to repress the E47-mediated transactivation and the E-box mutant reporter activity. In addition, SHP repressed the BETA2-dependent activity of glucokinase and cyclin-dependent kinase inhibitor p21 gene promoters. Gel shift and in vitro protein competition assays indicated that SHP inhibits neither dimerization nor DNA binding of BETA2 and E47. Rather, SHP directly repressed BETA2 transcriptional activity and p300-enhanced BETA2/NeuroD transcriptional activity by inhibiting interaction between BETA2 and coactivator p300. We also showed that C-terminal repression domain within SHP is also required for BETA2 repression. However, inhibition of BETA2 activity was not observed by naturally occurring human SHP mutants that cannot interact with BETA2/NeuroD. Taken together, these results suggest that SHP acts as a novel corepressor for basic helix-loop-helix transcription factor BETA2/NeuroD by competing with coactivator p300 for binding to BETA2/NeuroD and by its direct transcriptional repression function.

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Hxt encodes a basic helix-loop-helix transcription factor that regulates trophoblast cell development

Development ◽

10.1242/dev.121.8.2513 ◽

1995 ◽

Vol 121 (8) ◽

pp. 2513-2523 ◽

Cited By ~ 15

Author(s):

J.C. Cross ◽

M.L. Flannery ◽

M.A. Blanar ◽

E. Steingrimsson ◽

N.A. Jenkins ◽

...

Keyword(s):

Transcription Factor ◽

Gene Promoter ◽

Giant Cells ◽

Placental Lactogen ◽

Specific Gene ◽

Bhlh Transcription Factor ◽

Trophoblast Cells ◽

Positive Role ◽

Basic Helix Loop Helix ◽

Helix Loop Helix

Trophoblast cells are the first lineage to form in the mammalian conceptus and mediate the process of implantation. We report the cloning of a basic helix-loop-helix (bHLH) transcription factor gene, Hxt, that is expressed in early trophoblast and in differentiated giant cells. A separate gene, Hed, encodes a related protein that is expressed in maternal deciduum surrounding the implantation site. Overexpression of Hxt in mouse blastomeres directed their development into trophoblast cells in blastocysts. In addition, overexpression of Hxt induced the differentiation of rat trophoblast (Rcho-1) stem cells as assayed by changes in cell adhesion and by activation of the placental lactogen-I gene promoter, a trophoblast giant cell-specific gene. In contrast, the negative HLH regulator, Id-1, inhibited Rcho-1 differentiation and placental lactogen-I transcription. These data demonstrate a role for HLH factors in regulating trophoblast development and indicate a positive role for Hxt in promoting the formation of trophoblast giant cells.

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Deregulation of NR2E3, an orphan nuclear receptor, by benzo(a)pyrene-induced oxidative stress is associated with histone modification status change of the estrogen receptor gene promoter

Toxicology Letters ◽

10.1016/j.toxlet.2015.06.1708 ◽

2015 ◽

Vol 237 (3) ◽

pp. 228-236 ◽

Cited By ~ 7

Author(s):

Tilak Khanal ◽

Dasom Kim ◽

Abby Johnson ◽

Divaker Choubey ◽

Kyounghyun Kim

Keyword(s):

Oxidative Stress ◽

Estrogen Receptor ◽

Histone Modification ◽

Nuclear Receptor ◽

Receptor Gene ◽

Gene Promoter ◽

Orphan Nuclear Receptor ◽

Status Change ◽

Estrogen Receptor Gene

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Activation of the thyroid hormone receptor α gene promoter by the orphan nuclear receptor ERRα

Oncogene ◽

10.1038/sj.onc.1202167 ◽

1998 ◽

Vol 17 (19) ◽

pp. 2429-2435 ◽

Cited By ~ 48

Author(s):

Jean-Marc Vanacker ◽

Edith Bonnelye ◽

Cateline Delmarre ◽

Vincent Laudet

Keyword(s):

Thyroid Hormone ◽

Nuclear Receptor ◽

Hormone Receptor ◽

Thyroid Hormone Receptor ◽

Gene Promoter ◽

Orphan Nuclear Receptor ◽

Thyroid Hormone Receptor Α

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Synergistic activation of the insulin gene by a LIM-homeo domain protein and a basic helix-loop-helix protein: building a functional insulin minienhancer complex.

Genes & Development ◽

10.1101/gad.6.11.2165 ◽

1992 ◽

Vol 6 (11) ◽

pp. 2165-2176 ◽

Cited By ~ 256

Author(s):

M S German ◽

J Wang ◽

R B Chadwick ◽

W J Rutter

Keyword(s):

Insulin Gene ◽

Basic Helix Loop Helix ◽

Helix Loop Helix ◽

Synergistic Activation ◽

Domain Protein

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Basic helix-loop-helix transcription factor Tcfl5 interacts with the Calmegin gene promoter in mouse spermatogenesis

Nucleic Acids Research ◽

10.1093/nar/gkh979 ◽

2004 ◽

Vol 32 (21) ◽

pp. 6425-6436 ◽

Cited By ~ 20

Author(s):

M. Siep

Keyword(s):

Transcription Factor ◽

Gene Promoter ◽

Basic Helix Loop Helix ◽

Helix Loop Helix

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The Orphan Nuclear Receptor Rev-erbα Recruits the N-CoR/Histone Deacetylase 3 Corepressor to Regulate the Circadian Bmal1 Gene

Molecular Endocrinology ◽

10.1210/me.2005-0057 ◽

2005 ◽

Vol 19 (6) ◽

pp. 1452-1459 ◽

Cited By ~ 164

Author(s):

Lei Yin ◽

Mitchell A. Lazar

Keyword(s):

Circadian Rhythm ◽

Histone Deacetylase ◽

Nuclear Receptor ◽

Mrna Level ◽

Gene Promoter ◽

Circadian Oscillation ◽

Orphan Nuclear Receptor ◽

Histone Deacetylase 3 ◽

Clock Gene Expression ◽

Expression Of Genes

Abstract Transcriptional regulation plays a fundamental role in controlling circadian oscillation of clock gene expression. The orphan nuclear receptor Rev-erbα has recently been implicated as a major regulator of the circadian clock. Expression of Bmal1, the master regulator of circadian rhythm in mammals, is negatively correlated with Rev-erbα mRNA level, but the molecular mechanism underlying this regulation is largely unknown. Here we show that Rev-erbα dramatically represses the basal activity of the mouse Bmal1 gene promoter via two monomeric binding sites, both of which are required for repression and are conserved between mouse and human. Rev-erbα directly binds to the mouse Bmal1 promoter and recruits the endogenous nuclear receptor corepressor (N-CoR)/histone deacetylase 3 (HDAC3) complex, in association with a decrease in histone acetylation. The endogenous N-CoR/HDAC3 complex is also associated with the endogenous Bmal1 promoter in human HepG2 liver cells, where a reduction in cellular HDAC3 level markedly increases the expression of Bmal1 mRNA. These data demonstrate a new function for the N-CoR/HDAC3 complex in regulating the expression of genes involved in circadian rhythm by functioning as corepressor for Rev-erbα.

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Novel Transcriptional Potentiation of BETA2/NeuroD on the Secretin Gene Promoter by the DNA-Binding Protein Finb/RREB-1

Molecular and Cellular Biology ◽

10.1128/mcb.23.1.259-271.2003 ◽

2003 ◽

Vol 23 (1) ◽

pp. 259-271 ◽

Cited By ~ 35

Author(s):

Subir K. Ray ◽

Junko Nishitani ◽

Mary W. Petry ◽

Michael Y. Fessing ◽

Andrew B. Leiter

Keyword(s):

Dna Binding ◽

Zinc Finger Protein ◽

Mutational Analysis ◽

Gene Promoter ◽

Expression Cloning ◽

Physical Interaction ◽

Activation Domain ◽

Basic Helix Loop Helix ◽

Helix Loop Helix ◽

Distinct Category

ABSTRACT The basic helix-loop-helix protein BETA2/NeuroD activates transcription of the secretin gene and is essential for terminal differentiation of secretin-producing enteroendocrine cells. However, in heterodimeric complexes with its partner basic helix-loop-helix proteins, BETA2 does not appear to be a strong activator of transcription by itself. Mutational analysis of a proximal enhancer in the secretin gene identified several cis-acting elements in addition to the E-box binding site for BETA2. We identified by expression cloning the zinc finger protein RREB-1, also known to exist as a longer form, Finb, as the protein binding to one of the mutationally sensitive elements. Finb/RREB-1 lacks an intrinsic activation domain and by itself did not activate secretin gene transcription. Here we show that Finb/RREB-1 can associate with BETA2 to enhance its transcription-activating function. Both DNA binding and physical interaction of Finb/RREB-1 with BETA2 are required to potentiate transcription. Thus, Finb/RREB-1 does not function as a classical activator of transcription that recruits an activation domain to a DNA-protein complex. Finb/RREB-1 may be distinguished from coactivators, which increase transcription without sequence-specific DNA binding. We suggest that Finb/RREB-1 should be considered a potentiator of transcription, representing a distinct category of transcription-regulating proteins.

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