scholarly journals Modulation of Runx2 Activity by Estrogen Receptor-α: Implications for Osteoporosis and Breast Cancer

Endocrinology ◽  
2008 ◽  
Vol 149 (12) ◽  
pp. 5984-5995 ◽  
Author(s):  
Omar Khalid ◽  
Sanjeev K. Baniwal ◽  
Daniel J. Purcell ◽  
Nathalie Leclerc ◽  
Yankel Gabet ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Dna Binding ◽  
Transcriptional Activation ◽  
Target Genes ◽  
Estrogen Receptor Α ◽  
Binding Domain ◽  
Breast Epithelial Cell ◽  
Dependent Manner ◽  
Dna Binding Domain

The transcription factors Runx2 and estrogen receptor-α (ERα) are involved in numerous normal and disease processes, including postmenopausal osteoporosis and breast cancer. Using indirect immunofluorescence microscopy and pull-down techniques, we found them to colocalize and form complexes in a ligand-dependent manner. Estradiol-bound ERα strongly interacted with Runx2 directly through its DNA-binding domain and only indirectly through its N-terminal and ligand-binding domains. Runx2’s amino acids 417–514, encompassing activation domain 3 and the nuclear matrix targeting sequence, were sufficient for interaction with ERα’s DNA-binding domain. As a consequence of the interaction, Runx2’s transcriptional activation activity was strongly repressed, as shown by reporter assays in COS7 cells, breast cancer cells, and late-stage MC3T3-E1 osteoblast cultures. Metaanalysis of gene expression in 779 breast cancer biopsies indicated negative correlation between the expression of ERα and Runx2 target genes. Selective ER modulators (SERM) induced ERα-Runx2 interactions but led to various functional outcomes. The regulation of Runx2 by ERα may play key roles in osteoblast and breast epithelial cell growth and differentiation; hence, modulation of Runx2 by native and synthetic ERα ligands offers new avenues in selective ER modulator evaluation and development.

scholarly journals Phosphorylation of Human Estrogen Receptor α by Protein Kinase A Regulates Dimerization

1999 ◽  
Vol 19 (2) ◽  
pp. 1002-1015 ◽  
Author(s):  
Dongsheng Chen ◽  
Paul E. Pace ◽  
R. Charles Coombes ◽  
Simak Ali
Keyword(s):  
Estrogen Receptor ◽  
Protein Kinase ◽  
Dna Binding ◽  
Ligand Binding ◽  
Protein Kinase A ◽  
Estrogen Receptor Α ◽  
Binding Domain ◽  
Dna Binding Domain ◽  
Ici 182,780 ◽  
Kinase A

ABSTRACT Phosphorylation provides an important mechanism by which transcription factor activity is regulated. Estrogen receptor α (ERα) is phosphorylated on multiple sites, and stimulation of a number of growth factor receptors and/or protein kinases leads to ligand-independent and/or synergistic increase in transcriptional activation by ERα in the presence of estrogen. Here we show that ERα is phosphorylated by protein kinase A (PKA) on serine-236 within the DNA binding domain. Mutation of serine-236 to glutamic acid prevents DNA binding by inhibiting dimerization by ERα, whereas mutation to alanine has little effect on DNA binding or dimerization. Furthermore, PKA overexpression or activation of endogenous PKA inhibits dimerization in the absence of ligand. This inhibition is overcome by the addition of 17β-estradiol or the partial agonist 4-hydroxy tamoxifen. Interestingly, treatment with the complete antagonist ICI 182,780 does not overcome the inhibitory effect of PKA activation. Our results indicate that in the absence of ligand ERα forms dimers through interaction between DNA binding domains and that dimerization mediated by the ligand binding domain only occurs upon ligand binding but that the complete antagonist ICI 182,780 prevents dimerization through the ligand-binding domain. Heterodimer formation between ERα and ERβ is similarly affected by PKA phosphorylation of serine 236 of ERα. However, 4-hydroxytamoxifen is unable to overcome inhibition of dimerization by PKA. Thus, phosphorylation of ERα in the DNA binding domain provides a mechanism by which dimerization and thereby DNA binding by the estrogen receptor is regulated.

The DNA Binding Domain of Estrogen Receptor α Is Required for High-Affinity Nuclear Interaction Induced by Estradiol†

Biochemistry ◽  
2007 ◽  
Vol 46 (31) ◽  
pp. 8933-8942 ◽  
Author(s):  
Amy L. Weinberg ◽  
Damien Carter ◽  
Minna Ahonen ◽  
Elaine T. Alarid ◽  
Fern E. Murdoch ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Dna Binding ◽  
Nuclear Interaction ◽  
Estrogen Receptor Α ◽  
Binding Domain ◽  
Dna Binding Domain ◽  
High Affinity

scholarly journals The Role of the C-terminal Extension (CTE) of the Estrogen Receptor α and β DNA Binding Domain in DNA Binding and Interaction with HMGB

2004 ◽  
Vol 279 (15) ◽  
pp. 14763-14771 ◽  
Author(s):  
Vida Senkus Melvin ◽  
Chuck Harrell ◽  
James S. Adelman ◽  
W. Lee Kraus ◽  
Mair Churchill ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Dna Binding ◽  
Estrogen Receptor Α ◽  
Binding Domain ◽  
Dna Binding Domain

scholarly journals The POU domain of SCIP/Tst-1/Oct-6 is sufficient for activation of an acetylcholine receptor promoter.

1996 ◽  
Vol 16 (9) ◽  
pp. 5004-5014 ◽  
Author(s):  
D Fyodorov ◽  
E Deneris
Keyword(s):  
Dna Binding ◽  
Acetylcholine Receptor ◽  
Transcriptional Activation ◽  
Binding Domain ◽  
Dependent Manner ◽  
Dna Binding Domain ◽  
Wild Type ◽  
Amino Terminal ◽  
Pou Domain ◽  
Synergistic Activation

In the PC12 neuroendocrine line, the neuronal nicotinic acetylcholine receptor alpha3 gene promoter is activated by SCIP/Tst-1/Oct-6, a POU domain transcription factor proposed to be important for regulating the development of specific neural cell populations. In this study, we have investigated the SCIP polypeptide domains involved in alpha3 promoter activation. The characteristics of activation by a chimeric effector in which the GAL4 DNA binding domain was substituted for the SCIP POU domain were dramatically different from those of wild-type SCIP. At low effector masses, the chimeric polypeptide weakly activated alpha3 in a GAL4 binding-site-dependent manner but then squelched transcription at higher masses. In contrast, wild-type SCIP activation was not modulated by the presence of multimerized SCIP binding sites, and squelching was not observed. Analysis of wild-type SCIP truncations revealed that deletion of the previously characterized SCIP amino-terminal activation domain did not destroy activity of the factor. Surprisingly, a truncation expressing nothing more than the POU domain was nearly as active as wild-type SCIP. Moreover, cotransfection of a GAL4-VP16 effector with an effector expressing just the SCIP POU domain resulted in synergistic activation of the promoter. Synergistic activation did not depend on an Sp1 motif that is the only functional alpha3 cis element outside the transcription start site region. Our results show that the DNA binding domain of a POU factor is capable of transcriptional activation probably through protein-protein interactions with components of the basal transcription complex.

scholarly journals PARP7 and Mono-ADP-Ribosylation Negatively Regulate Estrogen Receptor α Signaling in Human Breast Cancer Cells

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 623
Author(s):  
Marit Rasmussen ◽  
Susanna Tan ◽  
Venkata S. Somisetty ◽  
David Hutin ◽  
Ninni Elise Olafsen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Protein Modification ◽  
Target Genes ◽  
Estrogen Receptor Α ◽  
Transactivation Domain ◽  
Adp Ribosylation ◽  
Protein Levels ◽  
17Β Estradiol ◽  
Mcf 7

ADP-ribosylation is a post-translational protein modification catalyzed by a family of proteins known as poly-ADP-ribose polymerases. PARP7 (TIPARP; ARTD14) is a mono-ADP-ribosyltransferase involved in several cellular processes, including responses to hypoxia, innate immunity and regulation of nuclear receptors. Since previous studies suggested that PARP7 was regulated by 17β-estradiol, we investigated whether PARP7 regulates estrogen receptor α signaling. We confirmed the 17β-estradiol-dependent increases of PARP7 mRNA and protein levels in MCF-7 cells, and observed recruitment of estrogen receptor α to the promoter of PARP7. Overexpression of PARP7 decreased ligand-dependent estrogen receptor α signaling, while treatment of PARP7 knockout MCF-7 cells with 17β-estradiol resulted in increased expression of and recruitment to estrogen receptor α target genes, in addition to increased proliferation. Co-immunoprecipitation assays revealed that PARP7 mono-ADP-ribosylated estrogen receptor α, and mass spectrometry mapped the modified peptides to the receptor’s ligand-independent transactivation domain. Co-immunoprecipitation with truncated estrogen receptor α variants identified that the hinge region of the receptor is required for PARP7-dependent mono-ADP-ribosylation. These results imply that PARP7-mediated mono-ADP-ribosylation may play an important role in estrogen receptor positive breast cancer.

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