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J Cell Biol. 1995 May 1; 129(3): 591–603.
PMCID: PMC2120432

Laminin mediates tissue-specific gene expression in mammary epithelia


Tissue-specific gene expression in mammary epithelium is dependent on the extracellular matrix as well as hormones. There is good evidence that the basement membrane provides signals for regulating beta-casein expression, and that integrins are involved in this process. Here, we demonstrate that in the presence of lactogenic hormones, laminin can direct expression of the beta-casein gene. Mouse mammary epithelial cells plated on gels of native laminin or laminin-entactin undergo functional differentiation. On tissue culture plastic, mammary cells respond to soluble basement membrane or purified laminin, but not other extracellular matrix components, by synthesizing beta-casein. In mammary cells transfected with chloramphenicol acetyl transferase reporter constructs, laminin activates transcription from the beta- casein promoter through a specific enhancer element. The inductive effect of laminin on casein expression was specifically blocked by the E3 fragment of the carboxy terminal region of the alpha 1 chain of laminin, by antisera raised against the E3 fragment, and by a peptide corresponding to a sequence within this region. Our results demonstrate that laminin can direct tissue-specific gene expression in epithelial cells through its globular domain.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Adams JC, Watt FM. Changes in keratinocyte adhesion during terminal differentiation: reduction in fibronectin binding precedes alpha 5 beta 1 integrin loss from the cell surface. Cell. 1990 Oct 19;63(2):425–435. [PubMed]
  • Aggeler J, Ward J, Blackie LM, Barcellos-Hoff MH, Streuli CH, Bissell MJ. Cytodifferentiation of mouse mammary epithelial cells cultured on a reconstituted basement membrane reveals striking similarities to development in vivo. J Cell Sci. 1991 Jun;99(Pt 2):407–417. [PubMed]
  • Aumailley M, Battaglia C, Mayer U, Reinhardt D, Nischt R, Timpl R, Fox JW. Nidogen mediates the formation of ternary complexes of basement membrane components. Kidney Int. 1993 Jan;43(1):7–12. [PubMed]
  • Barcellos-Hoff MH, Aggeler J, Ram TG, Bissell MJ. Functional differentiation and alveolar morphogenesis of primary mammary cultures on reconstituted basement membrane. Development. 1989 Feb;105(2):223–235. [PMC free article] [PubMed]
  • Berdichevsky F, Gilbert C, Shearer M, Taylor-Papadimitriou J. Collagen-induced rapid morphogenesis of human mammary epithelial cells: the role of the alpha 2 beta 1 integrin. J Cell Sci. 1992 Jul;102(Pt 3):437–446. [PubMed]
  • Bissell MJ, Hall HG, Parry G. How does the extracellular matrix direct gene expression? J Theor Biol. 1982 Nov 7;99(1):31–68. [PubMed]
  • Bissell DM, Arenson DM, Maher JJ, Roll FJ. Support of cultured hepatocytes by a laminin-rich gel. Evidence for a functionally significant subendothelial matrix in normal rat liver. J Clin Invest. 1987 Mar;79(3):801–812. [PMC free article] [PubMed]
  • Blum JL, Zeigler ME, Wicha MS. Regulation of rat mammary gene expression by extracellular matrix components. Exp Cell Res. 1987 Dec;173(2):322–340. [PubMed]
  • Blum JL, Wicha MS. Role of the cytoskeleton in laminin induced mammary gene expression. J Cell Physiol. 1988 Apr;135(1):13–22. [PubMed]
  • Bronner-Fraser M. Mechanisms of neural crest cell migration. Bioessays. 1993 Apr;15(4):221–230. [PubMed]
  • Calof AL, Lander AD. Relationship between neuronal migration and cell-substratum adhesion: laminin and merosin promote olfactory neuronal migration but are anti-adhesive. J Cell Biol. 1991 Nov;115(3):779–794. [PMC free article] [PubMed]
  • Caron JM. Induction of albumin gene transcription in hepatocytes by extracellular matrix proteins. Mol Cell Biol. 1990 Mar;10(3):1239–1243. [PMC free article] [PubMed]
  • Chakravarti S, Tam MF, Chung AE. The basement membrane glycoprotein entactin promotes cell attachment and binds calcium ions. J Biol Chem. 1990 Jun 25;265(18):10597–10603. [PubMed]
  • Charonis AS, Skubitz AP, Koliakos GG, Reger LA, Dege J, Vogel AM, Wohlhueter R, Furcht LT. A novel synthetic peptide from the B1 chain of laminin with heparin-binding and cell adhesion-promoting activities. J Cell Biol. 1988 Sep;107(3):1253–1260. [PMC free article] [PubMed]
  • Damsky CH, Werb Z. Signal transduction by integrin receptors for extracellular matrix: cooperative processing of extracellular information. Curr Opin Cell Biol. 1992 Oct;4(5):772–781. [PubMed]
  • David M, Petricoin EF, 3rd, Igarashi K, Feldman GM, Finbloom DS, Larner AC. Prolactin activates the interferon-regulated p91 transcription factor and the Jak2 kinase by tyrosine phosphorylation. Proc Natl Acad Sci U S A. 1994 Jul 19;91(15):7174–7178. [PMC free article] [PubMed]
  • Davies J. How to build a kidney. Semin Cell Biol. 1993 Jun;4(3):213–219. [PubMed]
  • DiPersio CM, Jackson DA, Zaret KS. The extracellular matrix coordinately modulates liver transcription factors and hepatocyte morphology. Mol Cell Biol. 1991 Sep;11(9):4405–4414. [PMC free article] [PubMed]
  • Emerman JT, Pitelka DR. Maintenance and induction of morphological differentiation in dissociated mammary epithelium on floating collagen membranes. In Vitro. 1977 May;13(5):316–328. [PubMed]
  • Emerman JT, Enami J, Pitelka DR, Nandi S. Hormonal effects on intracellular and secreted casein in cultures of mouse mammary epithelial cells on floating collagen membranes. Proc Natl Acad Sci U S A. 1977 Oct;74(10):4466–4470. [PMC free article] [PubMed]
  • Engel J. Laminins and other strange proteins. Biochemistry. 1992 Nov 10;31(44):10643–10651. [PubMed]
  • Fuortes M, Jin WW, Nathan C. Adhesion-dependent protein tyrosine phosphorylation in neutrophils treated with tumor necrosis factor. J Cell Biol. 1993 Feb;120(3):777–784. [PMC free article] [PubMed]
  • Gehlsen KR, Sriramarao P, Furcht LT, Skubitz AP. A synthetic peptide derived from the carboxy terminus of the laminin A chain represents a binding site for the alpha 3 beta 1 integrin. J Cell Biol. 1992 Apr;117(2):449–459. [PMC free article] [PubMed]
  • Goodman SL, Risse G, von der Mark K. The E8 subfragment of laminin promotes locomotion of myoblasts over extracellular matrix. J Cell Biol. 1989 Aug;109(2):799–809. [PMC free article] [PubMed]
  • Goodman SL, Aumailley M, von der Mark H. Multiple cell surface receptors for the short arms of laminin: alpha 1 beta 1 integrin and RGD-dependent proteins mediate cell attachment only to domains III in murine tumor laminin. J Cell Biol. 1991 May;113(4):931–941. [PMC free article] [PubMed]
  • Grant DS, Tashiro K, Segui-Real B, Yamada Y, Martin GR, Kleinman HK. Two different laminin domains mediate the differentiation of human endothelial cells into capillary-like structures in vitro. Cell. 1989 Sep 8;58(5):933–943. [PubMed]
  • Hall DE, Reichardt LF, Crowley E, Holley B, Moezzi H, Sonnenberg A, Damsky CH. The alpha 1/beta 1 and alpha 6/beta 1 integrin heterodimers mediate cell attachment to distinct sites on laminin. J Cell Biol. 1990 Jun;110(6):2175–2184. [PMC free article] [PubMed]
  • Hayashi K, Madri JA, Yurchenco PD. Endothelial cells interact with the core protein of basement membrane perlecan through beta 1 and beta 3 integrins: an adhesion modulated by glycosaminoglycan. J Cell Biol. 1992 Nov;119(4):945–959. [PMC free article] [PubMed]
  • Hynes RO. Integrins: versatility, modulation, and signaling in cell adhesion. Cell. 1992 Apr 3;69(1):11–25. [PubMed]
  • Iida J, Skubitz AP, Furcht LT, Wayner EA, McCarthy JB. Coordinate role for cell surface chondroitin sulfate proteoglycan and alpha 4 beta 1 integrin in mediating melanoma cell adhesion to fibronectin. J Cell Biol. 1992 Jul;118(2):431–444. [PMC free article] [PubMed]
  • Ingber DE. The riddle of morphogenesis: a question of solution chemistry or molecular cell engineering? Cell. 1993 Dec 31;75(7):1249–1252. [PubMed]
  • Kalb E, Engel J. Binding and calcium-induced aggregation of laminin onto lipid bilayers. J Biol Chem. 1991 Oct 5;266(28):19047–19052. [PubMed]
  • Klein G, Langegger M, Timpl R, Ekblom P. Role of laminin A chain in the development of epithelial cell polarity. Cell. 1988 Oct 21;55(2):331–341. [PubMed]
  • Lee EY, Parry G, Bissell MJ. Modulation of secreted proteins of mouse mammary epithelial cells by the collagenous substrata. J Cell Biol. 1984 Jan;98(1):146–155. [PMC free article] [PubMed]
  • Lee EY, Lee WH, Kaetzel CS, Parry G, Bissell MJ. Interaction of mouse mammary epithelial cells with collagen substrata: regulation of casein gene expression and secretion. Proc Natl Acad Sci U S A. 1985 Mar;82(5):1419–1423. [PMC free article] [PubMed]
  • Li ML, Aggeler J, Farson DA, Hatier C, Hassell J, Bissell MJ. Influence of a reconstituted basement membrane and its components on casein gene expression and secretion in mouse mammary epithelial cells. Proc Natl Acad Sci U S A. 1987 Jan;84(1):136–140. [PMC free article] [PubMed]
  • Matter ML, Laurie GW. A novel laminin E8 cell adhesion site required for lung alveolar formation in vitro. J Cell Biol. 1994 Mar;124(6):1083–1090. [PMC free article] [PubMed]
  • Mecham RP. Receptors for laminin on mammalian cells. FASEB J. 1991 Aug;5(11):2538–2546. [PubMed]
  • Mercurio AM, Shaw LM. Laminin binding proteins. Bioessays. 1991 Sep;13(9):469–473. [PubMed]
  • Petersen OW, Rønnov-Jessen L, Howlett AR, Bissell MJ. Interaction with basement membrane serves to rapidly distinguish growth and differentiation pattern of normal and malignant human breast epithelial cells. Proc Natl Acad Sci U S A. 1992 Oct 1;89(19):9064–9068. [PMC free article] [PubMed]
  • Rivas RJ, Burmeister DW, Goldberg DJ. Rapid effects of laminin on the growth cone. Neuron. 1992 Jan;8(1):107–115. [PubMed]
  • Roskelley CD, Desprez PY, Bissell MJ. Extracellular matrix-dependent tissue-specific gene expression in mammary epithelial cells requires both physical and biochemical signal transduction. Proc Natl Acad Sci U S A. 1994 Dec 20;91(26):12378–12382. [PMC free article] [PubMed]
  • Schittny JC, Yurchenco PD. Terminal short arm domains of basement membrane laminin are critical for its self-assembly. J Cell Biol. 1990 Mar;110(3):825–832. [PMC free article] [PubMed]
  • Schmidhauser C, Bissell MJ, Myers CA, Casperson GF. Extracellular matrix and hormones transcriptionally regulate bovine beta-casein 5' sequences in stably transfected mouse mammary cells. Proc Natl Acad Sci U S A. 1990 Dec;87(23):9118–9122. [PMC free article] [PubMed]
  • Schmidhauser C, Casperson GF, Myers CA, Sanzo KT, Bolten S, Bissell MJ. A novel transcriptional enhancer is involved in the prolactin- and extracellular matrix-dependent regulation of beta-casein gene expression. Mol Biol Cell. 1992 Jun;3(6):699–709. [PMC free article] [PubMed]
  • Schuger L, Skubitz AP, O'Shea KS, Chang JF, Varani J. Identification of laminin domains involved in branching morphogenesis: effects of anti-laminin monoclonal antibodies on mouse embryonic lung development. Dev Biol. 1991 Aug;146(2):531–541. [PubMed]
  • Schwartz MA. Transmembrane signalling by integrins. Trends Cell Biol. 1992 Oct;2(10):304–308. [PubMed]
  • Skubitz AP, Letourneau PC, Wayner E, Furcht LT. Synthetic peptides from the carboxy-terminal globular domain of the A chain of laminin: their ability to promote cell adhesion and neurite outgrowth, and interact with heparin and the beta 1 integrin subunit. J Cell Biol. 1991 Nov;115(4):1137–1148. [PMC free article] [PubMed]
  • Sonnenberg A, Linders CJ, Modderman PW, Damsky CH, Aumailley M, Timpl R. Integrin recognition of different cell-binding fragments of laminin (P1, E3, E8) and evidence that alpha 6 beta 1 but not alpha 6 beta 4 functions as a major receptor for fragment E8. J Cell Biol. 1990 Jun;110(6):2145–2155. [PMC free article] [PubMed]
  • Sorokin LM, Conzelmann S, Ekblom P, Battaglia C, Aumailley M, Timpl R. Monoclonal antibodies against laminin A chain fragment E3 and their effects on binding to cells and proteoglycan and on kidney development. Exp Cell Res. 1992 Jul;201(1):137–144. [PubMed]
  • Sorokin L, Sonnenberg A, Aumailley M, Timpl R, Ekblom P. Recognition of the laminin E8 cell-binding site by an integrin possessing the alpha 6 subunit is essential for epithelial polarization in developing kidney tubules. J Cell Biol. 1990 Sep;111(3):1265–1273. [PMC free article] [PubMed]
  • Stoker AW, Streuli CH, Martins-Green M, Bissell MJ. Designer microenvironments for the analysis of cell and tissue function. Curr Opin Cell Biol. 1990 Oct;2(5):864–874. [PubMed]
  • Streuli CH, Bissell MJ. Expression of extracellular matrix components is regulated by substratum. J Cell Biol. 1990 Apr;110(4):1405–1415. [PMC free article] [PubMed]
  • Streuli CH, Bailey N, Bissell MJ. Control of mammary epithelial differentiation: basement membrane induces tissue-specific gene expression in the absence of cell-cell interaction and morphological polarity. J Cell Biol. 1991 Dec;115(5):1383–1395. [PMC free article] [PubMed]
  • Streuli CH. Extracellular matrix and gene expression in mammary epithelium. Semin Cell Biol. 1993 Jun;4(3):203–212. [PubMed]
  • Streuli CH, Schmidhauser C, Kobrin M, Bissell MJ, Derynck R. Extracellular matrix regulates expression of the TGF-beta 1 gene. J Cell Biol. 1993 Jan;120(1):253–260. [PMC free article] [PubMed]
  • Sympson CJ, Talhouk RS, Alexander CM, Chin JR, Clift SM, Bissell MJ, Werb Z. 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. J Cell Biol. 1994 May;125(3):681–693. [PMC free article] [PubMed]
  • Talhouk RS, Bissell MJ, Werb Z. Coordinated expression of extracellular matrix-degrading proteinases and their inhibitors regulates mammary epithelial function during involution. J Cell Biol. 1992 Sep;118(5):1271–1282. [PMC free article] [PubMed]
  • Tryggvason K. The laminin family. Curr Opin Cell Biol. 1993 Oct;5(5):877–882. [PubMed]
  • Vukicevic S, Kleinman HK, Luyten FP, Roberts AB, Roche NS, Reddi AH. Identification of multiple active growth factors in basement membrane Matrigel suggests caution in interpretation of cellular activity related to extracellular matrix components. Exp Cell Res. 1992 Sep;202(1):1–8. [PubMed]
  • Wakao H, Gouilleux F, Groner B. Mammary gland factor (MGF) is a novel member of the cytokine regulated transcription factor gene family and confers the prolactin response. EMBO J. 1994 May 1;13(9):2182–2191. [PMC free article] [PubMed]
  • Whitby DJ, Ferguson MW. The extracellular matrix of lip wounds in fetal, neonatal and adult mice. Development. 1991 Jun;112(2):651–668. [PubMed]
  • Wilke MS, Skubitz AP. Human keratinocytes adhere to multiple distinct peptide sequences of laminin. J Invest Dermatol. 1991 Jul;97(1):141–146. [PubMed]
  • Woods A, Couchman JR. Protein kinase C involvement in focal adhesion formation. J Cell Sci. 1992 Feb;101(Pt 2):277–290. [PubMed]
  • Wrana JL, Attisano L, Wieser R, Ventura F, Massagué J. Mechanism of activation of the TGF-beta receptor. Nature. 1994 Aug 4;370(6488):341–347. [PubMed]
  • Yamada Y, Kleinman HK. Functional domains of cell adhesion molecules. Curr Opin Cell Biol. 1992 Oct;4(5):819–823. [PubMed]
  • Yelian FD, Edgeworth NA, Dong LJ, Chung AE, Armant DR. Recombinant entactin promotes mouse primary trophoblast cell adhesion and migration through the Arg-Gly-Asp (RGD) recognition sequence. J Cell Biol. 1993 May;121(4):923–929. [PMC free article] [PubMed]
  • Yurchenco PD, Tsilibary EC, Charonis AS, Furthmayr H. Laminin polymerization in vitro. Evidence for a two-step assembly with domain specificity. J Biol Chem. 1985 Jun 25;260(12):7636–7644. [PubMed]
  • Yurchenco PD, Cheng YS, Colognato H. Laminin forms an independent network in basement membranes. J Cell Biol. 1992 Jun;117(5):1119–1133. [PMC free article] [PubMed]
  • Yurchenco PD, O'Rear JJ. Basal lamina assembly. Curr Opin Cell Biol. 1994 Oct;6(5):674–681. [PubMed]
  • Yurochko AD, Liu DY, Eierman D, Haskill S. Integrins as a primary signal transduction molecule regulating monocyte immediate-early gene induction. Proc Natl Acad Sci U S A. 1992 Oct 1;89(19):9034–9038. [PMC free article] [PubMed]

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