Temporal and spatial expression patterns for the tumor suppressor Maspin and its binding partner interferon regulatory factor 6 during breast development

Children's Memorial Research Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60614-3394, USA.
Development Growth and Regeneration (Impact Factor: 2.42). 07/2009; 51(5):473-81. DOI: 10.1111/j.1440-169X.2009.01110.x
Source: PubMed

ABSTRACT Interferon regulatory factor 6 (IRF6) is a non-canonical member of the interferon regulatory factor family of transcription factors. We recently identified IRF6 as a novel Maspin-interacting protein in mammary epithelial cells. Maspin is a tumor suppressor in the breast and has also been implicated in mammary gland morphogenesis. To explore a possible role for IRF6 in conjunction with Maspin during mammary gland growth and differentiation, we examined the expression of IRF6 and Maspin during post-utero mammary gland development using a combination of in vitro and in vivo approaches. The data revealed that the expression of IRF6 and Maspin is temporally and spatially regulated throughout mammary gland development, with maximal expression of both proteins occurring in fully differentiated, lactating lobuloalveolar cells. We further show that IRF6 adopts a lumenal localization pattern following complete epithelial cell polarization and present new evidence for the secretion of IRF6 into the milk. These results support the hypothesis that IRF6 and Maspin are important for mammary epithelial cell differentiation, and advance our understanding of the Maspin-IRF6 partnership during normal mammary gland development.

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Available from: Zhila Khalkhali-Ellis, Nov 10, 2014
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    • "The role of Irf6 during development is largely unknown, however its role during epidermal and mammary formation highlights its effect on the cell cycle and cellular differentiation [2], [3], [26]. The decrease in proliferation throughout the Irf6−/− lingual tissue suggested that (1) Irf6 was acting directly on the SPM in a cell-autonomous fashion to affect cell cycle progression and/or (2) acting in a non-cell-autonomous fashion on the CNC, which then may signal back to the SPM, similar to the results seen in the Wnt1-cre;Tgfbr2 F/F mice. "
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    ABSTRACT: Interferon regulatory factor 6 () encodes a highly conserved helix-turn-helix DNA binding protein and is a member of the interferon regulatory family of DNA transcription factors. Mutations in lead to isolated and syndromic forms of cleft lip and palate, most notably Van der Woude syndrome (VWS) and Popliteal Ptyerigium Syndrome (PPS). Mice lacking both copies of have severe limb, skin, palatal and esophageal abnormalities, due to significantly altered and delayed epithelial development. However, a recent report showed that , an enhancer near , is active in the tongue, suggesting that may also be expressed in the tongue. Indeed, we detected Irf6 staining in the mesoderm-derived muscle during development of the tongue. Dual labeling experiments demonstrated that Irf6 was expressed only in the + cell lineage, which originates from the segmental paraxial mesoderm and gives rise to the muscles of the tongue. Fate mapping of the segmental paraxial mesoderm cells revealed a cell-autonomous function with reduced and poorly organized + cell lineage in the tongue. Molecular analyses showed that the -/- embryos had aberrant cytoskeletal formation of the segmental paraxial mesoderm in the tongue. Fate mapping of the cranial neural crest cells revealed non-cell-autonomous function with the loss of the inter-molar eminence. Loss of function altered , , , and signaling suggesting that these genes are involved in Irf6 signaling. Based on these data, plays important cell-autonomous and non-cell-autonomous roles in muscular differentiation and cytoskeletal formation in the tongue.
    PLoS ONE 02/2013; 8(2):e56270. DOI:10.1371/journal.pone.0056270 · 3.23 Impact Factor
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    • "On the other hand, when mouse mammary tumor cells (TM40D) expressing maspin are starved, maspin itself can translocate to the mitochondria and initiate apoptosis by the release of cytochrome c (Latha et al. 2005). Interestingly, in the mouse mammary gland, maspin expression peaks at lactation and not during involution , when cells are undergoing apoptosis (Bailey et al. 2009). Therefore, rather than inducing apoptosis, maspin could maintain the differentiated epithelial phenotype in nontransformed cells. "
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    ABSTRACT: Maspin, a member of the serpin family of serine protease inhibitors, was originally identified as a tumor suppressor that is expressed in normal mammary epithelial cells but is reduced or absent in breast carcinomas. Early enthusiasm for maspin as a biomarker for disease progression has been tempered by clinical data that associates maspin with favourable outcomes in some studies and poor prognosis in others. Here, we review all of the published clinical studies for maspin in breast and ovarian cancers and propose that the apparent discordance between clinical reports is a consequence of differential cellular distribution of maspin. Indeed, it was thought that an extracellular pool of maspin possessed tumor suppressor activity, acting by inhibiting migration and increasing cell adhesion. Recent evidence from our group and others indicates, however, that the nuclear localization of maspin in cancer cells is necessary for its tumor suppressor activity. We provide additional data here to demonstrate that nuclear-localized maspin binds to chromatin and is required to effectively prevent cells from metastasizing. Our knowledge of other serpins that localize to the nucleus should help to inform future studies of nuclear maspin. Elucidation of the molecular mechanisms regulating the localization and activities of maspin should pave the way for the development of improved diagnostics and therapies for cancer.
    Biochemistry and Cell Biology 11/2011; 90(1):22-38. DOI:10.1139/o11-053 · 2.15 Impact Factor
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    ABSTRACT: Maspin, an inhibitor of cell migration and a stimulator of adhesion of cells to the ECM, is synthesized and released by corneal keratocytes into the extracellular matrix. When the cornea is wounded, the quiescent stromal keratocytes underlying the wound undergo apoptosis and cells adjacent to this apoptotic area convert to fibroblasts or myofibroblasts. This study explores the effect of extracellular maspin on the plasminogen-plasminogen activator system of corneal stromal cells following wounding. Treatment of corneal fibroblasts and myofibroblasts with r-maspin increased extracellular but not cell-associated tissue-type plasminogen activator (tPA), urinary-type plasminogen activator (uPA) or plasminogen activator inhibitor-1 (PAI-1). Despite the extracellular increase in PAI-1, the net effect of maspin treatment was an increase in plasminogen activation. At physiological levels, maspin did not alter uPA or tPA mRNA levels, in these cells. The increase in pro and active uPA was due to decreased clearance in the presence of maspin for myofibroblasts but not for fibroblasts. The clearance of pro and active tPA was normal in fibroblasts indicating different mechanisms for the increase of these homologous enzymes in the two cell types. Increased generation of plasmin by maspin treated corneal stromal fibroblasts and myofibroblasts led to conversion of plasminogen to active plasmin degradation products and angiostatin-like molecules. This study suggests that extracellular maspin increased pro and active uPA and tPA released by corneal fibroblasts and myofibroblasts on the short time scale of 1-4 h, but by 24 h there was no increase over the levels produced without maspin. This augmentation of plasminogen activator activity increases plasmin activation and angiostatin generation. It further indicates that the effect of maspin on uPA and tPA levels is cell type dependent.
    Experimental Eye Research 07/2011; 93(5):618-27. DOI:10.1016/j.exer.2011.07.008 · 2.71 Impact Factor
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