ATBF1 Inhibits Estrogen Receptor (ER) Function by Selectively Competing with AIB1 for Binding to the ER in ER-positive Breast Cancer Cells*

Dong, Xiao-yuan; Sun, Xiaodong; Guo, Peng; Li, Qunna; Sasahara, Masakiyo; Ikoma, Yoko; Dong, Jin‐Tang

doi:10.1074/jbc.m110.128330

Cited by 48 publications

(91 citation statements)

References 48 publications

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“…We found that estrogen-ER signaling regulates ATBF1 by inducing its transcription while causing its protein degradation. Together with our earlier study (13), these results establish an autoregulatory feedback loop between ATBF1 and estrogen-ER signaling.…”

supporting

confidence: 50%

“…RNA interference (RNAi)-RNAi against ATBF1 and ER genes was performed as previously described (13). Four ATBF1-specific siRNAs targeting different regions of the ATBF1 gene and the negative control siRNA against the luciferase gene, which does not match any human genomic sequences, were also described previously (13).…”

Section: Methodsmentioning

confidence: 99%

“…In addition to breast and prostate cancers, ATBF1 was also reported to be involved in the development of other types of cancers including gastric, cervical, and hepatocellular carcinomas (10 -12). Our examination of the amino acid sequence of ATBF1 revealed multiple putative nuclear receptor boxes, including one consensus LXXLL motif and 31 of its variants LXXXL in the ATBF1 protein (13). These nuclear receptor boxes are often found in the coactivators and corepressors of nuclear receptors for the binding to nuclear receptors.…”

mentioning

confidence: 99%

“…These nuclear receptor boxes are often found in the coactivators and corepressors of nuclear receptors for the binding to nuclear receptors. We demonstrated that ATBF1 inhibits estrogen-mediated cell proliferation and gene regulation in ER-positive breast cancer cells by selectively competing for binding to the ER with the ER coactivator amplified in breast cancer 1 (AIB1) (13). AIB1 is the only SRC family member that is amplified and overexpressed in human breast cancer and is essential for breast oncogenesis (14 -16).…”

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confidence: 99%

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Estrogen Up-regulates ATBF1 Transcription but Causes Its Protein Degradation in Estrogen Receptor-α-positive Breast Cancer Cells

Dong

Guo

Sun

et al. 2011

Journal of Biological Chemistry

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The proper level of estrogen-estrogen receptor (ER) signaling is important for the maintenance of epithelial homeostasis in the breast. In a previous study we demonstrated that ATBF1, which has been suggested as a tumor suppressor in breast cancer, inhibited estrogen-mediated cell proliferation by selectively competing with AIB1 for binding to the ER. However, the expression of ATBF1 mRNA was shown to positively correlate with ER in breast cancer specimens. We, therefore, examined whether estrogen regulates ATBF1. We demonstrated that estrogen up-regulated the transcription of ATBF1, which was mediated by the direct binding of the ER onto the ATBF1 promoter, and that a half-estrogen-responsive element in the ATBF1 promoter was essential for ER direct binding. Furthermore, we found that estrogen at lower levels increased, but at higher levels decreased the expression of ATBF1 protein, which involved the degradation of ATBF1 protein by the estrogen-responsive proteasome system. ATBF1 protein levels fluctuate with estrogen levels. Although lower levels of estrogen increased ATBF1 protein expression, ATBF1 still inhibited cell proliferation caused by lower levels of estrogen. These findings not only reveal an autoregulatory feedback loop between ATBF1 and estrogen-ER signaling but also suggest that ATBF1 plays a role in both the maintenance of breast epithelial homeostasis and breast tumorigenesis caused by elevated estrogen levels.Extensive studies have established that estrogen is important for the development of the mammary gland and is positively associated with the initiation and development of breast cancer (1). Estrogen exerts its effect through the activation of estrogen receptors, mainly the ␣ subtype (ER␣, 2 or ER hereafter), a member of the nuclear receptor superfamily of transcription factors, which in turn regulates the expression of a variety of genes involved in multiple physiopathological processes including proliferation, differentiation, and apoptosis (2). Tight regulation of estrogen-ER signaling is important for the maintenance of epithelial homeostasis in the breast. In normal mammary epithelial cells, the level and function of ER fluctuates during the menstrual cycle in response to cyclical changes in estrogen (3, 4). ER regulates the expression of a variety of genes through the recruitment of coactivators and corepressors, which are often oncoproteins and tumor suppressors, respectively (5). Estrogen, ER, and coregulators are present in limiting amounts in normal cells. In breast cancer, however, their levels and/or structure are often interrupted, which contributes to the initiation and development of breast cancer (5).The AT-motif binding factor 1 (ATBF1) is a transcription factor composed of 3703 amino acid residues. It was originally identified for its direct binding to and negative regulation of the ␣-fetoprotein gene in a hepatoma cell line (6). In recent studies we identified ATBF1 as a strong candidate for the 16q22 tumor suppressor gene in human cancers, including prostate and breast ...

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confidence: 50%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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Estrogen Up-regulates ATBF1 Transcription but Causes Its Protein Degradation in Estrogen Receptor-α-positive Breast Cancer Cells

Dong

Guo

Sun

et al. 2011

Journal of Biological Chemistry

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“…Zinc finger homeobox 3 (ZFHX3) is a transcriptional repressor of 3,703 amino acids containing one ATPase A-motif, two DEAH box-like sequences, four homeodomains, and 23 zinc finger motifs involved in transcriptional regulation ( Fig. 1) (Dong et al 2010). ZFHX3 inhibits the enhancer of the alpha-fetoprotein (AFP) gene by binding to its AT-rich core sequence, and it also regulates myoblasts differentiation through the binding to the AT-rich sequence of MYF6 promoter (Li et al 2013).…”

Section: Introductionmentioning

confidence: 99%

The CAA Repeat Polymorphism in the <i>ZFHX3</i> Gene Is Associated with Risk of Coronary Heart Disease in a Chinese Population

Sun

Zhang

Chen

et al. 2015

Tohoku J. Exp. Med.

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Heterozygous deletion of Atbf1 by the Cre‐loxP system in mice causes preweaning mortality

Sun

et al. 2012

Genesis

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SummaryATBF1 is a large nuclear protein that contains multiple zinc-finger motifs and four homeodomains. In mammals, ATBF1 regulates differentiation, and its mutation and/or downregulation is involved in tumorigenesis in several organs. To gain more insight into the physiological functions of ATBF1, we generated and validated a conditional allele of mouse Atbf1 in which exons 7 and 8 were flanked by loxP sites (Atbf1 flox ). Germline deletion of a single Atbf1 allele was achieved by breeding to EIIa-cre transgenic mice, and Atbf1 heterozygous mice displayed reduced body weight, preweaning mortality, increased cell proliferation, and attenuated cytokeratin 18 (CK18) expression, indicating haploinsufficiency of Atbf1. Floxed Atbf1 mice will help us understand such biological processes as neuronal differentiation and tumorigenesis. KeywordsAtbf1; Cre-loxP; conditional knockout; heterozygous; preweaning mortality ATBF1 (AT-motif binding factor 1), also named ZFHX3 for zinc finger homeobox 3, belongs to a small family that is structurally characterized by multiple zinc-finger motifs and three or four homeodomains. In human and mouse, the ATBF1 gene contains 11 exons, and exon 10 is the largest (5454 bps). Using distinct promoters, ATBF1 produces two splicing variants, ATBF1-A and -B, which share exons 4 to 11 but differ in 5′ exons. Both isoforms encode large proteins. ATBF1-A uses a start codon in exon 3 to generate a protein of 404-kD. ATBF1-B uses a start codon in exon 4 to produce a protein of 300-kD (Miura et al., 1995a;Morinaga et al., 1991). Although both isoforms were reported, ATBF1-A is the predominant one with an expression level much higher than ATBF1-B. In mouse, only Atbf1-A was detectable at the mRNA and protein levels (Ishii et al., 2003;Miura et al., 1995b). ATBF1 functions in multiple biological processes including cell differentiation and tumorigenesis. It could regulate region-specific central nervous system differentiation (Ishii et al., 2003); its expression decreases at postnatal stage but remains detectable in mature neurons (Jung et al., 2005;Watanabe et al., 1996); and its expression is up-regulated in retinoic acid-treated p19 cells, an in vitro model of neuronal differentiation (Ido et al., 1994 Jung et al., 2005;Miura et al., 1995a). ATBF1 may also function in myogenic differentiation (Berry et al., 2001). ATBF1 regulates several differentiation genes including alphafetoprotein (AFP), aminopeptidase N and neurod1 (Jung et al., 2005;Kataoka et al., 2000;Morinaga et al., 1991;Yasuda et al., 1994). ATBF1 may affect atrial fibrillation, since genetic variations in introns of ATBF1 are associated with atrial fibrillation (Benjamin et al., 2009;Gudbjartsson et al., 2009;Li et al., 2011).ATBF1 has also been suggested to be a tumor suppressor in cancers of the breast, prostate, stomach and liver. In humans, ATBF1 is located at 16q22, frequently deleted in prostate and breast cancers (Dong, 2001). ATBF1 undergoes frequent somatic mutations in human prostate cancer, some of which are protein-trunca...

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ATBF1 Inhibits Estrogen Receptor (ER) Function by Selectively Competing with AIB1 for Binding to the ER in ER-positive Breast Cancer Cells*

Cited by 48 publications

References 48 publications

Estrogen Up-regulates ATBF1 Transcription but Causes Its Protein Degradation in Estrogen Receptor-α-positive Breast Cancer Cells

Estrogen Up-regulates ATBF1 Transcription but Causes Its Protein Degradation in Estrogen Receptor-α-positive Breast Cancer Cells

The CAA Repeat Polymorphism in the <i>ZFHX3</i> Gene Is Associated with Risk of Coronary Heart Disease in a Chinese Population

Heterozygous deletion of Atbf1 by the Cre‐loxP system in mice causes preweaning mortality

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