Epimorphin Mediates Mammary Luminal Morphogenesis through Control of C/EBPβ

Abstract

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.

CCAAT/enhancer binding protein beta (C/EBPβ)-2 transforms normal mammary epithelial cells and induces epithelial to mesenchymal transition in culture

“…However, in cells where C/EBPb-2 is the only or predominant transactivator isoform, C/EBPb-3 overexpression may antagonize growth and invasion. Indeed, Hirai et al (2001) found that moderate levels of LIP expression in SCp2 mouse mammary epithelial cells, which express LAP (C/EBPb-2), promoted luminal morphogenesis, whereas high expression of LIP led to apoptosis. With regard to human breast tumor tissue, Zahnow et al (1997) reported that highgrade, invasive human mammary carcinomas exhibit high levels of LIP (p20) or C/EBPb-3 expression.…”

Involvement of epimorphin in the repair of experimental renal fibrosis in mice

“…35,36 Syntaxins are the target membrane soluble N-ethylmaleimide-sensitive factor attachment protein receptors (t-SNARE) that mediate intracellular vesicle targeting and fusion. 6,37,38 Among syntaxin members, epimorphin (syntaxin-2) is the only one reported to exert an effect extracellularly as an epithelial morphogen. To preliminarily analyze the possible roles of other syntaxin members in renal fibrosis, we analyzed the expression of mRNA for syntaxin1a, which shows a very high level of sequence similarity but has no activity as a morphogen, 39 by real-time RT-PCR.…”

“…Previous studies have shown that epimorphin has morphogenetic effects on multiple epithelial tissues, including those of skin, hair follicle, lung, intestine, mammary gland, pancreas, gall bladder and liver. [4][5][6][7][8][9][10] In addition, several investigators have reported changes in the distribution of epimorphin-positive cells in inflammatory diseases of the lung and liver. [11][12][13][14] Epimorphin not only regulates morphogenesis but also functions as a mesenchymal regulator of epithelial repair.…”

CCAAT/Enhancer-binding Proteins β and δ Mediate the Repression of Gene Transcription of Cartilage-derived Retinoic Acid-sensitive Protein Induced by Interleukin-1β

“…Human Sox9 expression vector was described before (35). Human Col2A1 promoter construct and C/EBP expression vectors were the kind gifts provided by the following: 4-kb promoter and enhancer construct spanning Ϫ577 to ϩ3426 bp of human COL2A1 in the pGL2-basic vector was obtained from Dr. Mary B. Goldring (36,37); human C/EBP-full-length in the pCDNA3 vector was from Dr. Erika Crouch (38); the rat pCI-neo-LIP was from Dr. Cynthia A. Zahnow (39); the rat pCMV-LAP was from Dr. Mina Bissell (40); and the rat pMSV-C/EBP␦ was from Dr. Alan Friedman (41). The empty expression vectors were made by excision of cDNAs from the corresponding C/EBP expression vectors.…”