Ligand-dependent Interaction of Estrogen Receptor-α with Members of the Forkhead Transcription Factor Family

Foxl2 is a forkhead transcription factor required for ovary development and ovarian follicle maturation. In this report, we identified and characterized a functional relationship between Foxl2 expression and estrogen receptor (ER)-α signaling. We show that Foxl2 has no effect on classical ERα-mediated transcription, which occurs through canonical estrogen response elements. However, Foxl2 suppresses ERα signaling through nonclassical tethered transcriptional pathways. Specifically, the selective ER modulator tamoxifen stimulates activator protein-1 (AP1)-dependent transcription via the ERα, and this enhancement is blocked by Foxl2. Two lines of evidence suggest that Foxl2 suppression is mediated by physical interactions with ERα rather than direct action at AP1 binding sites. First, ERα is coimmunoprecipitated with Foxl2. Second, activation of a upstream activating sequence (UAS) reporter by Gal4-cJun in the presence of ERα and tamoxifen was blocked by Foxl2, demonstrating suppression in the absence of an AP1 site. Cyclooxygenase-2 (COX2), which is required for ovulation, was identified through expression profiling as a candidate physiological target for nonclassical ERα signaling and thus modulation by ERα/Foxl2 interactions. This possibility was confirmed by two sets of experiments. COX2 protein levels were induced by ERα in the presence of tamoxifen, and protein expression was suppressed by Foxl2. In addition, ERα stimulation of the COX2 promoter was repressed by Foxl2. We conclude that ERα and Foxl2 interact and that Foxl2 selectively suppresses ERα-mediated transcription of AP1-regulated genes. These data provide a potential point of convergence for ERα and Foxl2 to regulate ovarian development and function.

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Expression of the Forkhead Transcription Factor FOXP1 Is Associated with Estrogen Receptor α and Improved Survival in Primary Human Breast Carcinomas

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-03-0461 ◽

2004 ◽

Vol 10 (10) ◽

pp. 3521-3527 ◽

Cited By ~ 68

Author(s):

Stephen B. Fox ◽

Philip Brown ◽

Cheng Han ◽

Sally Ashe ◽

Russel D. Leek ◽

...

Keyword(s):

Estrogen Receptor ◽

Transcription Factor ◽

Estrogen Receptor Α ◽

Breast Carcinomas ◽

Human Breast ◽

Forkhead Transcription Factor ◽

Human Breast Carcinomas ◽

Primary Human Breast

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The Phosphorylated Estrogen Receptor α (ER) Cistrome Identifies a Subset of Active Enhancers Enriched for Direct ER-DNA Binding and the Transcription Factor GRHL2

Molecular and Cellular Biology ◽

10.1128/mcb.00417-18 ◽

2018 ◽

Vol 39 (3) ◽

Cited By ~ 5

Author(s):

Kyle T. Helzer ◽

Mary Szatkowski Ozers ◽

Mark B. Meyer ◽

Nancy A. Benkusky ◽

Natalia Solodin ◽

...

Keyword(s):

Estrogen Receptor ◽

Transcription Factor ◽

Dna Binding ◽

Protein Interactions ◽

Posttranslational Modifications ◽

Binding Sites ◽

Protein Function ◽

Estrogen Receptor Α ◽

Binding Activity

ABSTRACT Posttranslational modifications are key regulators of protein function, providing cues that can alter protein interactions and cellular location. Phosphorylation of estrogen receptor α (ER) at serine 118 (pS118-ER) occurs in response to multiple stimuli and is involved in modulating ER-dependent gene transcription. While the cistrome of ER is well established, surprisingly little is understood about how phosphorylation impacts ER-DNA binding activity. To define the pS118-ER cistrome, chromatin immunoprecipitation sequencing was performed on pS118-ER and ER in MCF-7 cells treated with estrogen. pS118-ER occupied a subset of ER binding sites which were associated with an active enhancer mark, acetylated H3K27. Unlike ER, pS118-ER sites were enriched in GRHL2 DNA binding motifs, and estrogen treatment increased GRHL2 recruitment to sites occupied by pS118-ER. Additionally, pS118-ER occupancy sites showed greater enrichment of full-length estrogen response elements relative to ER sites. In an in vitro DNA binding array of genomic binding sites, pS118-ER was more commonly associated with direct DNA binding events than indirect binding events. These results indicate that phosphorylation of ER at serine 118 promotes direct DNA binding at active enhancers and is a distinguishing mark for associated transcription factor complexes on chromatin.

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Mitochondrial Localization of the Yeast Forkhead Factor Hcm1

International Journal of Molecular Sciences ◽

10.3390/ijms21249574 ◽

2020 ◽

Vol 21 (24) ◽

pp. 9574

Author(s):

María José Rodríguez Colman ◽

Joaquim Ros ◽

Elisa Cabiscol

Keyword(s):

Transcription Factor ◽

Transcriptional Activity ◽

Spindle Pole ◽

Respiratory Metabolism ◽

Mitochondrial Localization ◽

Transcription Factor Family ◽

Forkhead Transcription Factor ◽

Mitochondrial Transcription Factor ◽

Gradient Density

Hcm1 is a member of the forkhead transcription factor family involved in segregation, spindle pole dynamics, and budding in Saccharomyces cerevisiae. Our group described the role of Hcm1 in mitochondrial biogenesis and stress resistance, and in the cellular adaptation to mitochondrial respiratory metabolism when nutrients decrease. Regulation of Hcm1 activity occurs at the protein level, subcellular localization, and transcriptional activity. Here we report that the amount of protein increased in the G1/S transition phase when the factor accumulated in the nucleus. In the G2/M phases, the Hcm1 amount decreased, and it was translocated outside the nucleus with a network-like localization. Preparation of highly purified mitochondria by a sucrose gradient density demonstrated that Hcm1 colocalized with mitochondrial markers, inducing expression of COX1, a mitochondrial encoded subunit of cytochrome oxidase, in the G2/M phases. Taken together, these results show a new localization of Hcm1 and suggest that it acts as a mitochondrial transcription factor regulating the metabolism of this organelle.

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Human estrogen receptor α gene is a target of Runx2 transcription factor in osteoblasts

Experimental Cell Research ◽

10.1016/j.yexcr.2007.02.002 ◽

2007 ◽

Vol 313 (8) ◽

pp. 1548-1560 ◽

Cited By ~ 14

Author(s):

Elisabetta Lambertini ◽

Letizia Penolazzi ◽

Elisa Tavanti ◽

Gian Pietro Schincaglia ◽

Margherita Zennaro ◽

...

Keyword(s):

Estrogen Receptor ◽

Transcription Factor ◽

Estrogen Receptor Α ◽

Human Estrogen Receptor ◽

Estrogen Receptor Α Gene

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The first decade of estrogen receptor cistromics in breast cancer

Journal of Endocrinology ◽

10.1530/joe-16-0003 ◽

2016 ◽

Vol 229 (2) ◽

pp. R43-R56 ◽

Cited By ~ 12

Author(s):

Koen D Flach ◽

Wilbert Zwart

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Transcription Factor ◽

Tiling Array ◽

Estrogen Receptor Α ◽

Sequencing Technologies ◽

Hormone Receptor Positive ◽

Genome Wide ◽

A Genome ◽

On Chip

The advent of genome-wide transcription factor profiling has revolutionized the field of breast cancer research. Estrogen receptor α (ERα), the major drug target in hormone receptor-positive breast cancer, has been known as a key transcriptional regulator in tumor progression for over 30 years. Even though this function of ERα is heavily exploited and widely accepted as an Achilles heel for hormonal breast cancer, only since the last decade we have been able to understand how this transcription factor is functioning on a genome-wide scale. Initial ChIP-on-chip (chromatin immunoprecipitation coupled with tiling array) analyses have taught us that ERα is an enhancer-associated factor binding to many thousands of sites throughout the human genome and revealed the identity of a number of directly interacting transcription factors that are essential for ERα action. More recently, with the development of massive parallel sequencing technologies and refinements thereof in sample processing, a genome-wide interrogation of ERα has become feasible and affordable with unprecedented data quality and richness. These studies have revealed numerous additional biological insights into ERα behavior in cell lines and especially in clinical specimens. Therefore, what have we actually learned during this first decade of cistromics in breast cancer and where may future developments in the field take us?

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