Extracellular matrix regulates whey acidic protein gene expression by suppression of TGF-alpha in mouse mammary epithelial cells: studies in culture and in transgenic mice.

Lin, Claudia Q.; Dempsey, Peter J.; Coffey, Robert J.; Bissell, Mina J.

doi:10.1083/jcb.129.4.1115

Cited by 86 publications

(55 citation statements)

References 62 publications

(79 reference statements)

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“…Therefore, the SWI/SNF chromatin remodeling complex may be recruited to the ␤-casein promoter by STAT5, C/EBP␤, and/or GR. Several other milk proteins, including ␣-casein, ␥-casein, whey acidic protein, and ␤-lactoglobulin, have been shown to be regulated by ECM and lacto- genic hormones (7,(42)(43)(44). The promoter or enhancer elements of these genes contain binding sites for STAT5 and GR (7,36,45).…”

Section: Resultsmentioning

confidence: 99%

Extracellular Matrix-regulated Gene Expression Requires Cooperation of SWI/SNF and Transcription Factors

Spencer

Bissell

2007

Journal of Biological Chemistry

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Extracellular cues play crucial roles in the transcriptional regulation of tissue-specific genes, but whether and how these signals lead to chromatin remodeling is not understood and subject to debate. Using chromatin immunoprecipitation assays and mammary-specific genes as models, we show here that extracellular matrix molecules and prolactin cooperate to induce histone acetylation and binding of transcription factors and the SWI/SNF complex to the ␤-and ␥-casein promoters. Introduction of a dominant negative Brg1, an ATPase subunit of SWI/ SNF complex, significantly reduced both ␤-and ␥-casein expression, suggesting that SWI/SNF-dependent chromatin remodeling is required for transcription of mammary-specific genes. Chromatin immunoprecipitation analyses demonstrated that the ATPase activity of SWI/SNF is necessary for recruitment of RNA transcriptional machinery, but not for binding of transcription factors or for histone acetylation. Co-immunoprecipitation analyses showed that the SWI/SNF complex is associated with STAT5, CCAAT/enhancer-binding protein ␤, and glucocorticoid receptor. Thus, extracellular matrix-and prolactin-regulated transcription of the mammary-specific casein genes requires the concerted action of chromatin remodeling enzymes and transcription factors.Differentiated function of mammary epithelial cells is regulated by signals from both ECM 2 and lactogenic hormones (1-3). The gene encoding the milk protein, ␤-casein, has been used widely as a marker for functional differentiation of MECs. We and others have shown that in both primary mouse mammary epithelial cells and immortalized mammary epithelial cell lines (4 -6), transcription of ␤-casein requires signals from both laminin-111 (previously referred to as laminin-1) and prolactin (1, 2, 7-10). A number of transcription factors, including STAT5, C/EBP␤, and GR, have been shown to be involved in this process (reviewed in Ref. 7).Modulation of chromatin structure by histone modifications and ATP-dependent remodeling has been implicated in cell differentiation and transcriptional control of tissue-specific and inducible genes (11-13). Histone-modifying enzymes are believed to be recruited to promoter regions through their association with transcription factors and are critical for tissue-specific gene expression and functional differentiation of specific cell types (14, 15). Histone acetylation is a dynamic process and is regulated by histone acetyltransferases and histone deacetylases (16). The mapping of global histone acetylation patterns has demonstrated that chromatin accessibility and gene expression are correlated with histone hyperacetylation of promoters and other cis-elements (17, 18). The p300 histone acetyltransferase cooperates with STAT5 to enhance exogenous ␤-casein promoter activity in COS cells, indicating that histone acetylation may play a role in ␤-casein transcription (19). Trichostatin A (TSA), an inhibitor of histone deacetylase, was shown to activate the bovine casein ECM response element (BCE-1) in an ECM-independent...

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Section: Resultsmentioning

confidence: 99%

Extracellular Matrix-regulated Gene Expression Requires Cooperation of SWI/SNF and Transcription Factors

Spencer

Bissell

2007

Journal of Biological Chemistry

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“…5) could not be reproduced with isolated ECM constituents and might thus be the result of synergistic cooperation of several ECM components and a need for three-dimensional structure analogous to the conditions described for WAP expression and for the regulation of apoptosis in culture (4,29,30).…”

Section: Stromelysin-1 Antisense Treatment Blocks Matrigel Invasionmentioning

confidence: 99%

“…Whereas mouse SL1 was readily amplified after 25 PCR cycles, only a weak PCR product was observed with rat SL1-specific primers after 31 cycles. This was expected because the transgene was constructed with a whey acidic protein (WAP) promoter (3), which is down-regulated in culture (29,30). Since, in addition, an active SL1 was not identified in TCL1 cells with zymograms or immunoblots (Fig.…”

Section: Matrigel Up-regulates Expression Of Sl1 In Tumorigenic Cellsmentioning

confidence: 99%

Misregulation of Stromelysin-1 Expression in Mouse Mammary Tumor Cells Accompanies Acquisition of Stromelysin-1-dependent Invasive Properties

Lochter

Srebrow

Sympson

et al. 1997

Journal of Biological Chemistry

135

128

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Stromelysin-1 is a member of the metalloproteinase family of extracellular matrix-degrading enzymes that regulates tissue remodeling. We previously established a transgenic mouse model in which rat stromelysin-1 targeted to the mammary gland augmented expression of endogenous stromelysin-1, disrupted functional differentiation, and induced mammary tumors. A cell line generated from an adenocarcinoma in one of these animals and a previously described mammary tumor cell line generated in culture readily invaded both a reconstituted basement membrane and type I collagen gels, whereas a nonmalignant, functionally normal epithelial cell line did not. The matrix metalloproteinases (MMPs) 1 are a family of extracellular matrix (ECM)-degrading enzymes that have been implicated in a variety of normal developmental and pathological processes, including tumorigenesis (1, 2). The MMP family comprises at least 15 members with different, albeit overlapping, substrate specificities. During activation of latent MMPs, their propeptides are cleaved and they are converted to a lower molecular weight form by other enzymes, including serine proteinases, and by autocatalytic cleavage.Among the MMPs, stromelysin-1 (SL1) possesses the broadest substrate specificity (1). Despite increasing knowledge about its enzymatic properties and the regulation of its expression, little is known about its function. We have generated transgenic animals that express an autoactivating mutant of rat SL1 targeted to the epithelial compartment of the mammary gland (3). Phenotypically, SL1 transgenic mice display increased branching morphogenesis and lactogenic differentiation at prepubertal stages and premature involution during late pregnancy (3, 4). Branching morphogenesis requires the invasion of epithelial cells into the adipose tissue, a process reminiscent of invasion of stromal compartments by tumor cells. Strikingly, a large number of SL1 transgenic animals also develop mammary tumors of various histotypes, including invasive adenocarcinomas (5). 2 Because tumor development is a late response of SL1 transgenic mice to overexpression of the transgene, it remains unclear whether SL1 plays a direct role in tumor growth and/or invasion or whether the observed tumors are a consequence of other molecular alterations in the microenvironment of the mammary gland before the onset of tumor growth. 3 Studies performed with synthetic inhibitors of MMP activity and tissue inhibitors of metalloproteinases (TIMPs) have shown that suppression of MMP activity also suppresses tumor growth and metastasis (6, 7). In many cases, the level of SL1 expression in tumors of the mammary gland and other tissues is positively correlated with the degree of malignancy (8, 9). However, the only direct evidence for the nature of the MMPs involved was provided by the demonstration that function-blocking antibodies against gelatinase A and antisense inhibition of matrilysin expression decreased the invasiveness of tumor cells in a reconstituted basement membrane assay (10, 11). The...

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“…Although the signals required for WAP expression are architectural in nature, they can be modified in a dynamic and reciprocal fashion by soluble factors present in the surrounding microenvironment [102,103]. Thus, third tier signalling downregulates the expression of TGF-α, a growth factor that inhibits WAP expression and prevents the formation of polarized three-dimensional structures in culture [103]. Another growth factor, hepatocyte growth factor (HGF), may also influence third tier signalling by inducing ductal branching when mammary epithelial cells are placed within collagen gels [104].…”

Section: Morphogenesismentioning

confidence: 99%

A hierarchy of ECM-mediated signalling regulates tissue-specific gene expression

Roskelley

Srebrow

Bissell

1995

Current Opinion in Cell Biology

365

199

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A dynamic and reciprocal flow of information between cells and the extracellular matrix contributes significantly to the regulation of form and function in developing systems. Signals generated by the extracellular matrix do not act in isolation. Instead, they are processed within the context of global signalling hierarchies whose constituent inputs and outputs are constantly modulated by all the factors present in the cell's surrounding microenvironment. This is particularly evident in the mammary gland, where the construction and subsequent destruction of such a hierarchy regulates changes in tissue-specific gene expression, morphogenesis and apoptosis during each developmental cycle of pregnancy, lactation and involution.

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Extracellular matrix regulates whey acidic protein gene expression by suppression of TGF-alpha in mouse mammary epithelial cells: studies in culture and in transgenic mice.

Cited by 86 publications

References 62 publications

Extracellular Matrix-regulated Gene Expression Requires Cooperation of SWI/SNF and Transcription Factors

Extracellular Matrix-regulated Gene Expression Requires Cooperation of SWI/SNF and Transcription Factors

Misregulation of Stromelysin-1 Expression in Mouse Mammary Tumor Cells Accompanies Acquisition of Stromelysin-1-dependent Invasive Properties

A hierarchy of ECM-mediated signalling regulates tissue-specific gene expression

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