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Epimorphin Mediates Mammary Luminal Morphogenesis through Control of C/EBPβ

Journal Article · · Journal of Cell Biology
 [1];  [2];  [2];  [2];  [3];  [4];  [4];  [4];  [2]
  1. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Life Science Division; Sumitomo Electric Industries Ltd., Yokohama (Japan). Osaka R&D Lab. (Yokohama-lab); DOE/OSTI
  2. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Life Science Division
  3. Life Science Division, Lawrence Berkeley National Laboratory, University of California, Berkeley, California 94720
  4. Sumitomo Electric Industries Ltd., Yokohama (Japan). Osaka R&D Lab. (Yokohama-lab)

We have shown previously that epimorphin (EPM), a protein expressed on the surface of myoepithelial and fibroblast cells of the mammary gland, acts as a multifunctional morphogen of mammary epithelial cells. Here, we present the molecular mechanism by which EPM mediates luminal morphogenesis. Treatment of cells with EPM to induce lumen formation greatly increases the overall expression of transcription factor CCAAT/enhancer binding protein (C/EBP)β and alters the relative expression of its two principal isoforms, LIP and LAP. These alterations were shown to be essential for the morphogenetic activities, since constitutive expression of LIP was sufficient to produce lumen formation, whereas constitutive expression of LAP blocked EPM-mediated luminal morphogenesis. Furthermore, in a transgenic mouse model in which EPM expression was expressed in an apolar fashion on the surface of mammary epithelial cells, we found increased expression of C/EBPβ, increased relative expression of LIP to LAP, and enlarged ductal lumina. Together, our studies demonstrate a role for EPM in luminal morphogenesis through control of C/EBPβ expression.

Research Organization:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). National Energy Research Scientific Computing Center (NERSC)
Sponsoring Organization:
USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division
Grant/Contract Number:
AC02-05CH11231
OSTI ID:
1625124
Journal Information:
Journal of Cell Biology, Journal Name: Journal of Cell Biology Journal Issue: 4 Vol. 153; ISSN 0021-9525
Publisher:
Rockefeller University PressCopyright Statement
Country of Publication:
United States
Language:
English

References (87)

LAP (NF-IL-6), a tissue-specific transcriptional activator, is an inhibitor of hepatoma cell proliferation. journal February 1994
A dramatic shift in the transmembrane topology of a viral envelope glycoprotein accompanies hepatitis B viral morphogenesis. journal March 1994
Transmembrane orientation of signal-anchor proteins is affected by the folding state but not the size of the N-terminal domain. journal December 1995
Lymphoproliferative disorder and imbalanced T-helper response in C/EBP beta-deficient mice. journal May 1995
Molecular Cloning of Human Epimorphin: Identification of Isoforms and Their Unique Properties journal March 1993
A New Function of Ito Cells in Liver Morphogenesis: Evidence Using a Novel Morphogenic Protein, Epimorphin,in Vitro journal August 1996
Identification of Cellular Recognition Sequence of Epimorphin and Critical Role of Cell/Epimorphin Interaction in Lung Branching Morphogenesis journal May 1997
A Novel Hepatic Stellate (Ito) Cell-Derived Protein, Epimorphin, Plays a Key Role in the Late Stages of Liver Regeneration journal September 1998
Selective induction of CCAAT/enhancer binding protein isoforms occurs during rat liver development journal June 1994
A liver-enriched transcriptional activator protein, LAP, and a transcriptional inhibitory protein, LIP, are translated from the sam mRNA journal November 1991
Epithelial morphogenesis journal May 1992
Is epimorphin involved in vesicular transport? journal May 1993
Membrane fusion takes excitatory turn: Syntaxin, vesicle docking protein, or glutamate receptor? journal December 1993
The syntaxin family of vesicular transport receptors journal September 1993
Targeted disruption of the NF-IL6 gene discloses its essential role in bacteria killing and tumor cytotoxicity by macrophages journal January 1995
ECM and Cell Surface Proteolysis: Regulating Cellular Ecology journal November 1997
Metalloprotease-Disintegrins: Links to Cell Adhesion and Cleavage of TNFα and Notch journal August 1997
Relocation of the t-SNARE SNAP-23 from Lamellipodia-like Cell Surface Projections Regulates Compound Exocytosis in Mast Cells journal August 1998
Immunolocalization of epimorphin in skin journal December 1996
Molecular mechanisms of liver development and differentiation journal December 1999
Novel isoform of syntaxin 1 is expressed in mammalian cells journal January 1997
Induction of Long-Term Potentiation In Vivo Regulates Alternate Splicing to Alter Syntaxin 3 Isoform Expression in Rat Dentate Gyrus journal November 2002
CCAAT/enhancer-binding protein mRNA is translated into multiple proteins with different transcription activation potentials. journal September 1993
Inhibition of CCAAT/Enhancer-binding Protein α and β Translation by Upstream Open Reading Frames journal April 1998
Biological Role of the CCAAT/Enhancer-binding Protein Family of Transcription Factors journal November 1998
Generation of Truncated C/EBPβ Isoforms by in VitroProteolysis journal August 2000
Multiple Determinants Direct the Orientation of Signal–Anchor Proteins: The Topogenic Role of the Hydrophobic Signal Domain journal May 1997
Effects of Age on the Posttranscriptional Regulation of CCAAT/Enhancer Binding Protein α and CCAAT/Enhancer Binding Protein β Isoform Synthesis in Control and LPS-Treated Livers journal June 1998
CUG repeat binding protein (CUGBP1) interacts with the 5' region of C/EBP  mRNA and regulates translation of C/EBP  isoforms journal November 1999
An essential role for C/EBPbeta in female reproduction journal September 1997
The C/EBPbeta transcription factor regulates epithelial cell proliferation and differentiation in the mammary gland journal June 1998
C/EBPbeta , but not C/EBPalpha , is essential for ductal morphogenesis, lobuloalveolar proliferation, and functional differentiation in the mouse mammary gland journal June 1998
Think globally, act locally: the making of a mouse mammary gland journal February 1998
Sodium-Dodecyl-Sulfate-Resistant Complex Formation of Epimorphin Monomers and Interaction of the 150-kDa Complex with the Cell Surface journal November 1994
Characterization of a presynaptic glutamate receptor journal October 1993
Transsynaptic expression of a presynaptic glutamate receptor during hippocampal long-term potentiation journal October 1993
Evidence for posttranscriptional regulation of C/EBPalpha and C/EBPbeta isoform expression during the lipopolysaccharide-mediated acute-phase response. journal May 1996
The ability of C/EBP beta but not C/EBP alpha to synergize with an Sp1 protein is specified by the leucine zipper and activation domain. journal April 1997
C/EBPβ Modulates the Early Events of Keratinocyte Differentiation Involving Growth Arrest and Keratin 1 and Keratin 10 Expression journal October 1999
SRα Promoter: an Efficient and Versatile Mammalian cDNA Expression System Composed of the Simian Virus 40 Early Promoter and the R-U5 Segment of Human T-Cell Leukemia Virus Type 1 Long Terminal Repeat journal January 1988
Time course of milk accumulation-induced opening of mammary tight junctions, and blood clearance of milk components journal July 1997
Hormones and Growth Factors in Milk journal December 1993
Characterization of SNARE protein expression in beta cell lines and pancreatic islets. journal April 1996
Comparison of the Regulation of the Whey Acidic Protein Gene with that of a Hybrid Gene Containing the Whey Acidic Protein Gene Promoter in Transgenic Mice journal November 1988
C/EBPβ (CCAAT/Enhancer Binding Protein) Controls Cell Fate Determination during Mammary Gland Development journal March 2000
Developmentally and hormonally regulated CCAAT/enhancer-binding protein isoforms influence beta-casein gene expression. journal September 1995
Apoptosis in the terminal endbud of the murine mammary gland: a mechanism of ductal morphogenesis journal December 1996
Signaling through the stromal epidermal growth factor receptor is necessary for mammary ductal development journal January 1999
Syntaxin 2 splice variants exhibit differential expression patterns, biochemical properties and subcellular localizations journal December 1999
Non-functional role of syntaxin 2 in insulin exocytosis by pancreatic β cells journal December 1997
Inductive Influences of Epimorphin on Endothelial Cellsin Vitro journal January 1996
Heads or tails - what determines the orientation of proteins in the membrane journal August 1995
Epimorphin: A mesenchymal protein essential for epithelial morphogenesis journal May 1992
Neu differentiation factor: A transmembrane glycoprotein containing an EGF domain and an immunoglobulin homology unit journal May 1992
Is epimorphin involved in vesicular transport? journal May 1993
Reexamination of the properties of epimorphin and its possible roles journal May 1993
Membrane fusion takes excitatory turn: Syntaxin, vesicle docking protein, or glutamate receptor? journal December 1993
Evidence for an alternate model of human P-glycoprotein structure and biogenesis. journal April 1993
Translational Induction of Liver-enriched Transcriptional Inhibitory Protein during Acute Phase Response Leads to Repression of CCAAT/Enhancer Binding Protein α mRNA journal September 2000
ECM and Cell Surface Proteolysis: Regulating Cellular Ecology journal November 1997
Metalloprotease-Disintegrins: Links to Cell Adhesion and Cleavage of TNFα and Notch journal August 1997
Relocation of the t-SNARE SNAP-23 from Lamellipodia-like Cell Surface Projections Regulates Compound Exocytosis in Mast Cells journal August 1998
Immunolocalization of epimorphin in skin journal December 1996
Molecular mechanisms of liver development and differentiation journal December 1999
Origin and Secretion of Milk Lipids journal January 1998
Secretion of Milk Proteins journal January 1998
Transferrin and Prolactin Transcytosis in the Lactating Mammary Epithelial Cell journal July 1998
Crystal structure of a SNARE complex involved in synaptic exocytosis at 2.4 Å resolution journal September 1998
Mechanisms of intracellular protein transport journal November 1994
Extracellular matrix-dependent tissue-specific gene expression in mammary epithelial cells requires both physical and biochemical signal transduction. journal December 1994
A conserved domain is present in different families of vesicular fusion proteins: A new superfamily journal April 1997
Generation of Truncated C/EBPβ Isoforms by in VitroProteolysis journal August 2000
Targeted expression of stromelysin-1 in mammary gland provides evidence for a role of proteinases in branching morphogenesis and the requirement for an intact basement membrane for tissue-specific gene expression [published erratum appears in J Cell Biol 1996 Feb;132(4):following 752] journal May 1994
Epimorphin Functions as a Key Morphoregulator for Mammary Epithelial Cells journal January 1998
Autocrine Stimulation of Human Pancreatic Duct–Like Development by Soluble Isoforms of Epimorphin in Vitro journal February 2001
A novel transcriptional enhancer is involved in the prolactin- and extracellular matrix-dependent regulation of beta-casein gene expression. journal June 1992
An isoform of the Golgi t-SNARE, syntaxin 5, with an endoplasmic reticulum retrieval signal. journal September 1997
Defective adipocyte differentiation in mice lacking the C/EBPbeta and/or C/EBPdelta gene journal December 1997
Regenerating livers of old rats contain high levels of C/EBPalpha that correlate with altered expression of cell cycle associated proteins journal July 1998
Translational control of C/EBPα and C/EBPβ isoform expression journal August 2000
Evidence for posttranscriptional regulation of C/EBPalpha and C/EBPbeta isoform expression during the lipopolysaccharide-mediated acute-phase response. journal May 1996
The ability of C/EBP beta but not C/EBP alpha to synergize with an Sp1 protein is specified by the leucine zipper and activation domain. journal April 1997
C/EBPβ Modulates the Early Events of Keratinocyte Differentiation Involving Growth Arrest and Keratin 1 and Keratin 10 Expression journal October 1999
C/EBPα Regulates Generation of C/EBPβ Isoforms through Activation of Specific Proteolytic Cleavage journal March 1999
SR alpha promoter: an efficient and versatile mammalian cDNA expression system composed of the simian virus 40 early promoter and the R-U5 segment of human T-cell leukemia virus type 1 long terminal repeat. journal January 1988
Membrane Fusion and Exocytosis journal June 1999
Autocrine Signals Control CCAAT/Enhancer Binding Protein β Expression, Localization, and Activity in Macrophages journal December 1998

Cited By (15)

Matrix Metalloproteinase-Induced Epithelial-Mesenchymal Transition in Breast Cancer journal May 2010
Angiotensin stimulation of adrenal fasciculata cells journal July 1988
Epimorphin acts extracellularly to promote cell sorting and aggregation during the condensation of vertebral cartilage journal March 2006
Membrane translocation of t-SNARE protein syntaxin-4 abrogates ground-state pluripotency in mouse embryonic stem cells journal January 2017
Epimorphin expression in interstitial pneumonia journal January 2005
Myoepithelial cells: good fences make good neighbors journal July 2005
Epimorphin Regulates Bile Duct Formation via Effects on Mitosis Orientation in Rat Liver Epithelial Stem-Like Cells journal March 2010
Regulation of Epithelial-Mesenchymal Transition in Breast Cancer Cells by Cell Contact and Adhesion journal January 2015
Myoepithelial Cells in the Control of Mammary Development and Tumorigenesis: Data From Genetically Modified Mice journal July 2005
Polarized epithelial membrane traffic: conservation and plasticity journal April 2003
Modelling glandular epithelial cancers in three-dimensional cultures journal September 2005
CCAAT/enhancer binding protein beta (C/EBPβ)-2 transforms normal mammary epithelial cells and induces epithelial to mesenchymal transition in culture journal February 2003
Cyclin D1 and C/EBPβ LAP1 Operate in a Common Pathway To Promote Mammary Epithelial Cell Differentiation journal August 2014
Morphogenic protein epimorphin protects intestinal epithelial cells from oxidative stress by the activation of EGF receptor and MEK/ERK, PI3 kinase/Akt signals journal January 2007
Epimorphin expression in intestinal myofibroblasts induces epithelial morphogenesis journal December 2002

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