CCAAT/Enhancer-binding Protein Isoforms γ and δ Are Expressed in Mammary Epithelial Cells and Bind to Multiple Sites in the β-Casein Gene Promoter

Doppler, Wolfgang; Welte, Thomas; Philipp, Sonja

doi:10.1074/jbc.270.30.17962

Cited by 81 publications

(60 citation statements)

References 61 publications

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“…6 and 8). The ␤-casein promoter has several binding sites for the CCAAT-enhancer binding protein (C/EBP) (38), and the isoforms C/EBP␤ and -␦ reportedly bind to these sites to increase expression during pregnancy (10). C/EBP␤ has been shown to control the proliferation and differentiation of mam-VOL.…”

Section: Discussionmentioning

confidence: 99%

The Homeodomain Protein CDP Regulates Mammary-Specific Gene Transcription and Tumorigenesis

Zhu

Maitra

Johnston

et al. 2004

Molecular and Cellular Biology

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The CCAAT-displacement protein (CDP) has been implicated in developmental and cell-type-specific regulation of many cellular and viral genes. We previously have shown that CDP represses mouse mammary tumor virus (MMTV) transcription in tissue culture cells. Since CDP-binding activity for the MMTV long terminal repeat declines during mammary development, we tested whether binding mutations could alter viral expression. Infection of mice with MMTV proviruses containing CDP binding site mutations elevated viral RNA levels in virgin mammary glands and shortened mammary tumor latency. To determine if CDP has direct effects on MMTV transcription rather than viral spread, virgin mammary glands of homozygous CDP-mutant mice lacking one of three Cut repeat DNA-binding domains (⌬CR1) were examined by reverse transcription-PCR. RNA levels of endogenous MMTV as well as ␣-lactalbumin and whey acidic protein (WAP) were elevated. Heterozygous mice with a different CDP mutation that eliminated the entire C terminus and the homeodomain (⌬C mice) showed increased levels of MMTV, ␤-casein, WAP, and ␣-lactalbumin RNA in virgin mammary glands compared to those from wild-type animals. No differences in amounts of WDNM1, -casein, or glyceraldehyde-3-phosphate dehydrogenase RNA were observed between the undifferentiated mammary tissues from wild-type and mutant mice, indicating the specificity of this effect. These data show independent contributions of different CDP domains to negative regulation of differentiation-specific genes in the mammary gland.The CCAAT displacement protein (CDP) family constitutes a highly conserved group of homeoproteins that are involved in cell growth, differentiation, and development. CDP (also known as Cut in Drosophila melanogaster, Clox in dogs, and Cux in mice) is a transcriptional repressor that contains four DNA-binding domains, three Cut repeats (CR1, -2, and -3), and a homeodomain (32). CDP is involved in suppressing transcription from many cellular genes, including c-myc, transforming growth factor ␤ type II receptor, phox, CD8, immunoglobulin heavy chain, and T-cell receptor ␤-chain (3,7,12,19,22,46), as well as viral genes, including those from mouse mammary tumor virus (MMTV) and human papillomaviruses (HPVs) (1, 55). In addition, CDP has been implicated as a tumor suppressor gene in human breast carcinomas and uterine leiomyomas (28,47,53).Many genes regulated by CDP are expressed in highly differentiated cells. CDP DNA-binding activity is downregulated during B-cell and myeloid cell development (22, 46), and CDP expression in the kidney is inversely related to the degree of cellular differentiation (44). We have shown that CDP is a repressor of MMTV long terminal repeat (LTR) reporter gene expression in cultured cell lines and that CDP-binding activity to the LTR declines during mammary gland development (55).These results suggest that CDP functions as a transcriptional repressor that inhibits expression of differentiation-specific genes in several tissues.The retrovirus MMTV is a paradigm fo...

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Section: Discussionmentioning

confidence: 99%

The Homeodomain Protein CDP Regulates Mammary-Specific Gene Transcription and Tumorigenesis

Zhu

Maitra

Johnston

et al. 2004

Molecular and Cellular Biology

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“…Extensive studies have defined multiple cis-acting elements and transcription factors involved in the regulation of milk protein production. These include binding sites for the glucocorticoid receptor (2), signal transducers and activators of transcription (3,4), CAAT/enhancer-binding protein (5), and nuclear factor 1 (NF1) 1 (4). In a previous paper (6), we demonstrated that a member(s) of the NF1 family plays an important role in the expression of the milk protein gene carboxyl ester lipase (CEL).…”

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confidence: 99%

Nuclear Factor 1-C2 Contributes to the Tissue-specific Activation of a Milk Protein Gene in the Differentiating Mammary Gland

Kannius-Janson¹,

Johansson²,

Bjursell³

et al. 2002

Journal of Biological Chemistry

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Members of the nuclear factor 1 (NF1) transcription factor family have been postulated to be involved in the regulation of milk genes. In this work we have been able to identify the splice variant NF1-C2 as an important member of a tissue-specific activating complex that regulates the milk gene encoding carboxyl ester lipase (CEL). Mutation of the NF1-binding site in the CEL gene promoter results in a drastic reduction of the gene expression to about 15% in mammary epithelial cells. Furthermore, we demonstrate that the NF1-C2 protein interacts with a higher affinity to the NF1-binding site in the CEL gene promoter than other NF1 family members do and that NF1-C2 in the mouse mammary gland is a phosphorylated protein. During development of the mouse mammary gland, binding of NF1-C2 to the CEL gene promoter is induced at midpregnancy, in correlation with the induction of CEL gene expression. The fact that the NF1-C2 involving complex remains throughout the lactation period and decreases during the weaning period, when the CEL gene is down-regulated, supports its importance in the regulation of CEL gene expression. To our knowledge, this is the first report identifying a specific, endogenously expressed NF1 isoform to be involved in the tissue-specific activation of a gene.

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“…STAT5 binding sites are found in many other milk protein promoters, with the STAT binding sites in the sheep ␤-lactoglobulin gene being particularly well characterized (5,6,51,58). C/EBP binding sites are required for the hormonal induction of ␤-casein expression (16,41,49), and its activity may be influenced by glucocorticoid receptor, which has been shown to enhance prolactin-induced expression of ␤-casein (15,25,41,44,50).…”

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Characterization of BCE-1, a Transcriptional Enhancer Regulated by Prolactin and Extracellular Matrix and Modulated by the State of Histone Acetylation

Myers

Schmidhauser²,

Mellentin-Michelotti

et al. 1998

Molecular and Cellular Biology

101

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We have previously described a 160-bp enhancer (BCE-1) in the bovine ␤-casein gene that is activated in the presence of prolactin and extracellular matrix (ECM). Here we report the characterization of the enhancer by deletion and site-directed mutagenesis, electrophoretic mobility shift analysis, and in vivo footprinting. Two essential regions were identified by analysis of mutant constructions: one binds C/EBP-␤ and the other binds MGF/STAT5 and an as-yet-unidentified binding protein. However, no qualitative or quantitative differences in the binding of these proteins were observed in electrophoretic mobility shift analysis using nuclear extracts derived from cells cultured in the presence or absence of ECM with or without prolactin, indicating that prolactin-and ECM-induced transcription was not dependent on the availability of these factors in the functional cell lines employed. An in vivo footprinting analysis of the factors bound to nuclear chromatin in the presence or absence of ECM and/or prolactin found no differences in the binding of C/EBP-␤ but did not provide definitive results for the other factors. Neither ECM nor prolactin activated BCE-1 in transient transfections, suggesting that the chromosomal structure of the integrated template may be required for ECM-induced transcription. Further evidence is that treatment of cells with inhibitors of histone deacetylase was sufficient to induce transcription of integrated BCE-1 in the absence of ECM. Together, these results suggest that the ECM induces a complex interaction between the enhancer-bound transcription factors, the basal transcriptional machinery, and a chromosomally integrated template responsive to the acetylation state of the histones.It is now well established that the processes of development and differentiation depend on a cell's ability to correctly perceive its microenvironment (reviewed in references 1 and 43). A key component of this environment is the extracellular matrix (ECM). The ECM is an organized network of glycoproteins, proteoglycans, and glycosaminoglycans, components important for cell morphology as well as for signal transduction via cell surface integrins and ultimately for tissue-specific gene expression (reviewed in reference 43).The mammary gland appears to be particularly well suited for the study of ECM-induced differentiation and gene expression. In the adult animal, the gland develops after puberty and functionally differentiates in response to pregnancy. The mechanisms involved in these developmental processes are complex and guided by various hormones (54), growth factors (53), and the ECM (3). Milk protein expression is initiated at mid-pregnancy and correlates with the synthesis and deposition of a specialized laminin-rich ECM during alveolar development. Expression of these milk proteins can be used as markers for the differentiated state of the gland. In the last decade, a number of model systems using mammary epithelial cells to study ECM-dependent gene regulation have been developed. These range from primar...

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CCAAT/Enhancer-binding Protein Isoforms γ and δ Are Expressed in Mammary Epithelial Cells and Bind to Multiple Sites in the β-Casein Gene Promoter

Cited by 81 publications

References 61 publications

The Homeodomain Protein CDP Regulates Mammary-Specific Gene Transcription and Tumorigenesis

The Homeodomain Protein CDP Regulates Mammary-Specific Gene Transcription and Tumorigenesis

Nuclear Factor 1-C2 Contributes to the Tissue-specific Activation of a Milk Protein Gene in the Differentiating Mammary Gland

Characterization of BCE-1, a Transcriptional Enhancer Regulated by Prolactin and Extracellular Matrix and Modulated by the State of Histone Acetylation

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