HES-1 inhibits 17β-estradiol and heregulin-β1-mediated upregulation of E2F-1

Hartman, Johan; Müller, Patrick; Foster, James S.; Wimalasena, Jay; Gustafsson, Jan Åke; Ström, Anders

doi:10.1038/sj.onc.1208139

Cited by 57 publications

(51 citation statements)

References 32 publications

(48 reference statements)

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“…Sustained Hes1 expression leads to G1 phase retardation of the cell cycle (Yoshiura et al, 2007). Hes1 can directly or indirectly repress the transcription of cell cycle-related genes, including E2f1, p21Cip1, p27Kip1, and p57Kip2 (Castella, et al, 2000;Georgia, et al, 2006;Hartman et al, 2004;Murata et al, 2005). Hes1 oscillation may be important for efficient cell proliferation.…”

Section: Hes1 Oscillation and Cell Proliferation In Cultured Cellsmentioning

confidence: 99%

Expression Dynamics and Functions of Hes Factors in Development and Diseases

Kobayashi

Kageyama

2014

Current Topics in Developmental Biology

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Hes genes, encoding basic helix-loop-helix (HLH) transcriptional repressors, are mammalian homologues of Drosophila hairy and Enhancer of split genes, both of which are required for normal neurogenesis in Drosophila. There are seven members in the human Hes family, Hes1 to Hes7, which are expressed in many tissues and play various roles mainly in development. All Hes proteins have three conserved domains: basic HLH (bHLH), Orange, and WRPW domains. The basic region binds to target DNA sequences while the HLH region forms homo-and hetero-dimers with other bHLH proteins, the Orange domain is responsible for the selection of partners during heterodimer formation, and the WRPW domain recruits co-repressors. Hes1, Hes5, and Hes7 are known as downstream effectors of canonical Notch signaling, which regulates cell differentiation via cell-cell interaction. Hes factors regulate many events in development by repressing the expression of target genes, many of which encode transcriptional activators that promote cell differentiation. For example, Hes1, Hes3, and Hes5 are highly expressed by neural stem cells, and inactivation of these genes results in insufficient maintenance of stem cell proliferation and prematurely promotes neuronal differentiation. Recently, it was shown that the expression dynamics of Hes1 plays crucial roles in proper developmental timings and fate determination steps of embryonic stem cells and neural progenitor cells. Here we discuss some key features of Hes factors in development and diseases.

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Section: Hes1 Oscillation and Cell Proliferation In Cultured Cellsmentioning

confidence: 99%

Expression Dynamics and Functions of Hes Factors in Development and Diseases

Kobayashi

Kageyama

2014

Current Topics in Developmental Biology

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“…This upregulation is important for the antiestrogenic effect of atRA (Muller et al 2002) and appears to affect the expression of the cell cycle regulator E2F-1. Forced expression of HES-1 inhibits an E 2 -mediated increase in E2F-1 and breast cancer cell proliferation (Hartman et al 2004). Estrogen response in target cells is mediated by estrogen receptors (ERs).…”

Section: Introductionmentioning

confidence: 99%

Estrogen-dependent downregulation of hairy and enhancer of split homolog-1 gene expression in breast cancer cells is mediated via a 3′ distal element

Müller¹,

Merrell²,

Crofts³

et al. 2008

Journal of Endocrinology

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Regulation of hairy and enhancer of split homologue-1 (HES-1) by estradiol and all-trans retinoic acid affects proliferation of human breast cancer cells. Here, we identify and characterize cis-regulatory elements involved in HES-1 regulation. In the distal 5 0 promoter of the HES-1 gene, we found a retinoic acid response element and in the distal 3 0 region, an estrogen receptor a(ER)a binding site. The ERa binding site, composed of an estrogen response element (ERE) and an ERE half-site, is important for both ERa binding and transcriptional regulation.Chromatin immunoprecipitation assays revealed that ERa is recruited to the ERE and associates with the HES-1 promoter. We also show recruitment of nuclear receptor co-regulators to the ERE in response to estradiol, followed by a decrease in histone acetylation and RNA polymerase II docking in the HES-1 promoter region. Our findings are consistent with a novel type of repressive estrogen response element in the distal 3 0 region of the HES-1 gene.

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“…In the case of osteoblast differentiation, ID4 has been shown to release Hes1 from Hes1-Hey2 complexes (44), a potentially exciting observation, because Hes1 has been shown to negatively regulate MCF7 (45) and T47D (46) proliferation stimulated by estrogen and E2F-1. In addition, these investigators have shown that the growth inhibitory effects of all-trans-retinoic acid on breast cells is mediated by Hes1 up-regulation (8), and we find that Hes1 expression is up-regulated in either CEACAM1-transfected or all-trans-retinoic acid-treated MCF7 cells (46). Thus, the sequestration of Hes1 by Hey2 may be relieved by ID4, allowing Hes1 to inhibit proliferation of MCF7 cells, a necessary step in their differentiation to lumen forming cells.…”

Section: Discussionmentioning

confidence: 49%

Induction of Lumen Formation in a Three-dimensional Model of Mammary Morphogenesis by Transcriptional Regulator ID4

Shively

2016

Journal of Biological Chemistry

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Concomitant loss of lumen formation and cell adhesion protein CEACAM1 is a hallmark feature of breast cancer. In a threedimensional culture model, transfection of CEACAM1 into MCF7 breast cells can restore lumen formation by an unknown mechanism. ID4, a transcriptional regulator lacking a DNA binding domain, is highly up-regulated in CEACAM1-transfected MCF7 cells, and when down-regulated with RNAi, abrogates lumen formation. Conversely, when MCF7 cells, which fail to form lumena in a three-dimensional culture, are transfected with ID4, lumen formation is restored, demonstrating that ID4 may substitute for CEACAM1. After showing the ID4 promoter is hypermethylated in MCF7 cells but hypomethylated in MCF/ CEACAM1 cells, ID4 expression was induced in MCF7 cells by agents affecting chromatin remodeling and methylation. Mechanistically, CaMK2D was up-regulated in CEACAM1-transfected cells, effecting phosphorylation of HDAC4 and its sequestration in the cytoplasm by the adaptor protein 14-3-3. CaMK2D also phosphorylates CEACAM1 on its cytoplasmic domain and mutation of these phosphorylation sites abrogates lumen formation. Thus, CEACAM1 is able to maintain the active transcription of ID4 by an epigenetic mechanism involving HDAC4 and CaMK2D, and the same kinase enables lumen formation by CEACAM1. Because ID4 can replace CEACAM1 in parental MCF7 cells, it must act downstream from CEACAM1 by inhibiting the activity of other transcription factors that would otherwise prevent lumen formation. This overall mechanism may be operative in other cancers, such as colon and prostate, where the down-regulation of CEACAM1 is observed.Lumen formation, a central feature of mammary morphogenesis, is lost during mammary tumorigenesis, starting with filling in the lumen with cancer cells in ductal carcinoma in situ (1) and becoming more evident in invasive solid tumors (2). Identification of the molecules that change during this process and the underlying mechanisms causing these changes are major goals of breast cancer research. Among the many molecules identified so far, CEACAM1 stands out as a luminal expressed protein that is rapidly down-regulated in both ductal carcinoma in situ (3) and invasive breast cancer (2). Not surprisingly, luminal expression of CEACAM1 occurs throughout ductal tissues such as the liver, digestive and urogenital tract, and prostate, and its loss upon malignant transformation is one of the earliest events observed (4). To study its role in lumen formation, we originally placed MCF10F, a cell line that expresses CEACAM1, in a three-dimensional culture system pioneered by Bissell and co-workers (5), and observed lumen formation with CEACAM1 at the luminal surface (3). When its expression was blocked by antisense, anti-CEACAM1 antibody, or peptides derived from the N terminus of CEACAM1, lumen formation was abrogated, demonstrating that its expression played a central role in the complex process of lumenogenesis (3). As a next step, we demonstrated that MCF7 breast cancer cells that fail to express CEACAM1 o...

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HES-1 inhibits 17β-estradiol and heregulin-β1-mediated upregulation of E2F-1

Cited by 57 publications

References 32 publications

Expression Dynamics and Functions of Hes Factors in Development and Diseases

Expression Dynamics and Functions of Hes Factors in Development and Diseases

Estrogen-dependent downregulation of hairy and enhancer of split homolog-1 gene expression in breast cancer cells is mediated via a 3′ distal element

Induction of Lumen Formation in a Three-dimensional Model of Mammary Morphogenesis by Transcriptional Regulator ID4

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