Transcriptional Profiling of Estrogen-Regulated Gene Expression via Estrogen Receptor (ER) α or ERβ in Human Osteosarcoma Cells: Distinct and Common Target Genes for These Receptors

Stossi, Fabio; Barnett, Daniel H.; Frasor, Jonna; Komm, Barry S.; Lyttle, C. Richard; Katzenellenbogen, Benita S.

doi:10.1210/en.2003-1682

Cited by 202 publications

(190 citation statements)

References 77 publications

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“…These data have been confirmed by other laboratories (28,29). Our laboratory reported a similar ER isoform specificity using the selective estrogen receptor modulator 4-hydroxytamoxifen and further showed that E2 and 4-hydroxytamoxifen regulated unique patterns of gene expression.…”

Section: Discussionsupporting

confidence: 85%

“…Although coregulator recruitment and activation is largely mediated through AF2, the A/B domain (AF1) is known to bind the p160 and p300/CBP (CREB-binding protein) families of coregulators (16 -20) as well as p68/p72 (21,22), steroid receptor RNA activator (23,24), and MMS19 (25) proteins. Recent data from our laboratory (26,27) and others (28,29) have demonstrated that significant differences exist in gene expression patterns, elicited by ER␣ and ER␤ homodimers and ER␣/ER␤ heterodimers, in a human osteosarcoma (U2OS) model system. Specifically, only ϳ20% of all genes regulated through either ER isoform are regulated by both ER isoforms.…”

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confidence: 99%

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Estrogen Receptor Isoform-specific Regulation of the Retinoblastoma-binding Protein 1 (RBBP1) Gene

Monroe

Secreto

Hawse

et al. 2006

Journal of Biological Chemistry

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Estrogen (E2) is involved in mediating many important functions relevant to osteoblast biology through the actions of the estrogen receptors (ER) ␣ and ␤. To further understand the mechanisms of ER-specific regulation, we used microarray and reverse transcription-PCR analyses of E2-treated U2OS-ER␣ or -ER␤ cells and identified retinoblastoma-binding protein 1 (RBBP1) as a major E2-regulated gene. RBBP1 is a retinoblastoma cofactor involved in the control of osteoblastic proliferation. Although RBBP1 mRNA levels rapidly increased after 2 h of E2 treatment in both U2OS-ER-expressing lines, a sustained induction was only observed in U2OS-ER␣ cells. Examination of the RBBP1 genomic sequence revealed an ER response element and a Sp1 site located within the first intron. Chromatin immunoprecipitation analyses demonstrated that E2-dependent ER␣ binding to the intron 1 enhancer region was constitutive, whereas ER␤ binding was transient, consistent with the mRNA time course. Interestingly, transient transfection and receptor mutational studies revealed that RBBP1 induction by ER␣ only requires the Sp1 site, whereas ER␤ utilizes both the Sp1 and estrogen response elements binding sites for maximal E2-dependent activation. Stable U2OS transfectants containing a deletion of the ER␣ activation function 1 (AF1) resulted in a temporal mRNA induction profile similar to that of wild type ER␤. Further, overexpression and chromatin immunoprecipitation analyses also demonstrated that E2-dependent RBBP1 induction is SRC2-dependent for both ER isoforms. These results describe an E2-dependent, ER isoform-specific transcriptional activation of the RBBP1 gene, which in part, is explained by the differential activity of ER AF1 and enhancer element binding.The transcriptional effects of estrogens (e.g. 17␤-estradiol or E2) 2 are largely mediated by two related, but distinct, estrogen receptor (ER) isoforms ER␣ and ER␤ (1-7). The ERs are ligandinducible transcription factors that bind E2 through a C-terminally located ligand-binding domain (or E/F domain). The ER isoforms contain a centrally located and highly conserved DNA-binding domain (or C domain) that associates directly with estrogen response elements (ERE) or indirectly through protein tethering to AP1 or Sp1 (8, 9). Both ER␣ and ER␤ contain two activation functions (AF); a highly divergent N-terminal A/B (AF1) domain and a more conserved C-terminal E/F (AF2) domain that overlaps with the ligand-binding domain (10 -13). Activation of transcription is achieved through the recruitment of specific transcriptional coregulators resulting in chromatin remodeling and the recruitment of the basal transcriptional machinery (1, 9, 14 -16). Although coregulator recruitment and activation is largely mediated through AF2, the A/B domain (AF1) is known to bind the p160 and p300/CBP (CREB-binding protein) families of coregulators (16 -20) as well as p68/p72 (21, 22), steroid receptor RNA activator (23, 24), and MMS19 (25) proteins. Recent data from our laboratory (26, 27) and others (28, 29) have...

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Section: Discussionsupporting

confidence: 85%

mentioning

confidence: 99%

Estrogen Receptor Isoform-specific Regulation of the Retinoblastoma-binding Protein 1 (RBBP1) Gene

Monroe

Secreto

Hawse

et al. 2006

Journal of Biological Chemistry

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“…Total RNA was harvested and isolated using Trizol reagent (Invitrogen, Carlsbad, CA), following the manufacturer's instructions. Quantitative real-time PCR (qPCR) was performed as previously described (39). All PCR primer sequences are available upon request.…”

Section: Methodsmentioning

confidence: 99%

Estrogen Receptor Alpha Represses Transcription of Early Target Genes via p300 and CtBP1

Stossi

Madak-Erdoğan

Katzenellenbogen

2009

Molecular and Cellular Biology

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The regulation of gene expression by nuclear receptors controls the phenotypic properties and diverse biologies of target cells. In breast cancer cells, estrogen receptor alpha (ER␣) is a master regulator of transcriptional stimulation and repression, yet the mechanisms by which agonist-bound ER␣ elicits repression are poorly understood. We analyzed early estrogen-repressed genes and found that ER␣ is recruited to ER␣ binding sites of these genes, albeit more transiently and less efficiently than for estrogen-stimulated genes. Of multiple cofactors studied, only p300 was recruited to ER␣ binding sites of repressed genes, and its knockdown prevented estrogen-mediated gene repression. Because p300 is involved in transcription initiation, we tested whether ER␣ might be trying to stimulate transcription at repressed genes, with ultimately failure and a shift to a repressive program. We found that estrogen increases transcription in a rapid but transient manner at early estrogen-repressed genes but that this is followed by recruitment of the corepressor CtBP1, a p300-interacting partner that plays an essential role in the repressive process. Thus, at early estrogen-repressed genes, ER␣ initiates transient stimulation of transcription but fails to maintain the transcriptional process observed at estrogen-stimulated genes; rather, it uses p300 to recruit CtBP1-containing complexes, eliciting chromatin modifications that lead to transcriptional repression.

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“…The metallothionein gene is known to be specifically upregulated by E2 via ERb in SAOS-2 cells (Harris et al 2001). However, recently, Stossi et al (2004) have compared the generegulatory activities of ERa and ERb in bone and showed high similarity but also significant differences in gene targets for these two ERs. Thus, genes encoding for cystatin D, autotaxin or stromal antigen 2 appear to be E2-regulated specifically by ERb in human osteosarcoma cells.…”

Section: Structural Properties Of Era and Erb And Effects On Their Trmentioning

confidence: 99%

Loss of ERβ expression as a common step in estrogen-dependent tumor progression

Bardin¹,

Boulle²,

Lazennec³

et al. 2004

Endocr Relat Cancer

381

304

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The characterization of estrogen receptor beta (ERb) brought new insight into the mechanisms underlying estrogen signaling. Estrogen induction of cell proliferation is a crucial step in carcinogenesis of gynecologic target tissues, and the mitogenic effects of estrogen in these tissues (such as breast, endometrium and ovary) are well documented both in vitro and in vivo. There is also an emerging body of evidence that colon and prostate cancer growth is influenced by estrogens. In all of these tissues, most studies have shown decreased ERb expression in cancer as compared with benign tumors or normal tissues, whereas ERa expression persists. The loss of ERb expression in cancer cells could reflect tumor cell dedifferentiation but may also represent a critical stage in estrogen-dependent tumor progression. Modulation of the expression of ERa target genes by ERb or ERb-specific gene induction could explain that ERb has a differential effect on proliferation as compared with ERa. ERb may exert a protective effect and thus constitute a new target for hormone therapy, such as ligand specific activation. The potential distinct roles of ERa and ERb expression in carcinogenesis, as suggested by experimental and clinical data, are discussed in this review.

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Transcriptional Profiling of Estrogen-Regulated Gene Expression via Estrogen Receptor (ER) α or ERβ in Human Osteosarcoma Cells: Distinct and Common Target Genes for These Receptors

Cited by 202 publications

References 77 publications

Estrogen Receptor Isoform-specific Regulation of the Retinoblastoma-binding Protein 1 (RBBP1) Gene

Estrogen Receptor Isoform-specific Regulation of the Retinoblastoma-binding Protein 1 (RBBP1) Gene

Estrogen Receptor Alpha Represses Transcription of Early Target Genes via p300 and CtBP1

Loss of ERβ expression as a common step in estrogen-dependent tumor progression

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