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EMBO J. Mar 1, 1999; 18(5): 1345–1356.
PMCID: PMC1171224

TGF-beta induces fibronectin synthesis through a c-Jun N-terminal kinase-dependent, Smad4-independent pathway.

Abstract

Transforming growth factor-beta (TGF-beta) exerts its effects on cell proliferation, differentiation and migration in part through its modulation of extracellular matrix components, such as fibronectin and plasminogen activator inhibitor-1 (PAI-1). Although the SMAD family of proteins recently has been shown to be a key participant in TGF-beta signaling, other signaling pathways have also been shown to be activated by TGF-beta. We report here that c-Jun N-terminal kinase (JNK), a member of the MAP kinase family, is activated in response to TGF-beta in the human fibrosarcoma HT1080-derived cell line BAHgpt. Stable expression of dominant-negative forms of JNK1 and MKK4, an upstream activator of JNK, results in loss of TGF-beta-stimulated fibronectin mRNA and protein induction, while having little effect on TGF-beta-induced levels of PAI-1. The human fibronectin promoter contains three CRE elements, one of which has been shown to bind a c-Jun-ATF-2 heterodimer. Utilizing a GAL4 fusion trans-reporting system, we demonstrate a decrease in transactivating potential of GAL4-c-Jun and GAL4-ATF-2 in dominant-negative JNK1- and MKK4-expressing cells. Finally, we show that TGF-beta-induced fibronectin synthesis is independent of Smad4. These results demonstrate that TGF-beta-mediated fibronectin induction requires activation of JNK which in turn modulates the activity of c-Jun and ATF-2 in a Smad4independent manner.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Abdollah S, Macías-Silva M, Tsukazaki T, Hayashi H, Attisano L, Wrana JL. TbetaRI phosphorylation of Smad2 on Ser465 and Ser467 is required for Smad2-Smad4 complex formation and signaling. J Biol Chem. 1997 Oct 31;272(44):27678–27685. [PubMed]
  • Alessi DR, Cuenda A, Cohen P, Dudley DT, Saltiel AR. PD 098059 is a specific inhibitor of the activation of mitogen-activated protein kinase kinase in vitro and in vivo. J Biol Chem. 1995 Nov 17;270(46):27489–27494. [PubMed]
  • Angel P, Karin M. The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation. Biochim Biophys Acta. 1991 Dec 10;1072(2-3):129–157. [PubMed]
  • Angel P, Hattori K, Smeal T, Karin M. The jun proto-oncogene is positively autoregulated by its product, Jun/AP-1. Cell. 1988 Dec 2;55(5):875–885. [PubMed]
  • Atfi A, Buisine M, Mazars A, Gespach C. Induction of apoptosis by DPC4, a transcriptional factor regulated by transforming growth factor-beta through stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) signaling pathway. J Biol Chem. 1997 Oct 3;272(40):24731–24734. [PubMed]
  • Atfi A, Djelloul S, Chastre E, Davis R, Gespach C. Evidence for a role of Rho-like GTPases and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) in transforming growth factor beta-mediated signaling. J Biol Chem. 1997 Jan 17;272(3):1429–1432. [PubMed]
  • Border WA, Noble NA. Transforming growth factor beta in tissue fibrosis. N Engl J Med. 1994 Nov 10;331(19):1286–1292. [PubMed]
  • Bowlus CL, McQuillan JJ, Dean DC. Characterization of three different elements in the 5'-flanking region of the fibronectin gene which mediate a transcriptional response to cAMP. J Biol Chem. 1991 Jan 15;266(2):1122–1127. [PubMed]
  • Campbell CE, Flenniken AM, Skup D, Williams BR. Identification of a serum- and phorbol ester-responsive element in the murine tissue inhibitor of metalloproteinase gene. J Biol Chem. 1991 Apr 15;266(11):7199–7206. [PubMed]
  • Cárcamo J, Zentella A, Massagué J. Disruption of transforming growth factor beta signaling by a mutation that prevents transphosphorylation within the receptor complex. Mol Cell Biol. 1995 Mar;15(3):1573–1581. [PMC free article] [PubMed]
  • Chen X, Rubock MJ, Whitman M. A transcriptional partner for MAD proteins in TGF-beta signalling. Nature. 1996 Oct 24;383(6602):691–696. [PubMed]
  • Chung KY, Agarwal A, Uitto J, Mauviel A. An AP-1 binding sequence is essential for regulation of the human alpha2(I) collagen (COL1A2) promoter activity by transforming growth factor-beta. J Biol Chem. 1996 Feb 9;271(6):3272–3278. [PubMed]
  • Cohen P. The search for physiological substrates of MAP and SAP kinases in mammalian cells. Trends Cell Biol. 1997 Sep;7(9):353–361. [PubMed]
  • Coito AJ, Binder J, Brown LF, de Sousa M, Van de Water L, Kupiec-Weglinski JW. TNF-alpha upregulates the expression of fibronectin in acutely rejecting rat cardiac allografts. Transplant Proc. 1995 Feb;27(1):463–465. [PubMed]
  • Danielson PE, Forss-Petter S, Brow MA, Calavetta L, Douglass J, Milner RJ, Sutcliffe JG. p1B15: a cDNA clone of the rat mRNA encoding cyclophilin. DNA. 1988 May;7(4):261–267. [PubMed]
  • Dean DC, Bowlus CL, Bourgeois S. Cloning and analysis of the promotor region of the human fibronectin gene. Proc Natl Acad Sci U S A. 1987 Apr;84(7):1876–1880. [PMC free article] [PubMed]
  • Dean DC, Newby RF, Bourgeois S. Regulation of fibronectin biosynthesis by dexamethasone, transforming growth factor beta, and cAMP in human cell lines. J Cell Biol. 1988 Jun;106(6):2159–2170. [PMC free article] [PubMed]
  • Dean DC, Blakeley MS, Newby RF, Ghazal P, Hennighausen L, Bourgeois S. Forskolin inducibility and tissue-specific expression of the fibronectin promoter. Mol Cell Biol. 1989 Apr;9(4):1498–1506. [PMC free article] [PubMed]
  • Dean DC, McQuillan JJ, Weintraub S. Serum stimulation of fibronectin gene expression appears to result from rapid serum-induced binding of nuclear proteins to a cAMP response element. J Biol Chem. 1990 Feb 25;265(6):3522–3527. [PubMed]
  • De Cesare D, Vallone D, Caracciolo A, Sassone-Corsi P, Nerlov C, Verde P. Heterodimerization of c-Jun with ATF-2 and c-Fos is required for positive and negative regulation of the human urokinase enhancer. Oncogene. 1995 Jul 20;11(2):365–376. [PubMed]
  • Dennler S, Itoh S, Vivien D, ten Dijke P, Huet S, Gauthier JM. Direct binding of Smad3 and Smad4 to critical TGF beta-inducible elements in the promoter of human plasminogen activator inhibitor-type 1 gene. EMBO J. 1998 Jun 1;17(11):3091–3100. [PMC free article] [PubMed]
  • Dérijard B, Hibi M, Wu IH, Barrett T, Su B, Deng T, Karin M, Davis RJ. JNK1: a protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain. Cell. 1994 Mar 25;76(6):1025–1037. [PubMed]
  • Dérijard B, Raingeaud J, Barrett T, Wu IH, Han J, Ulevitch RJ, Davis RJ. Independent human MAP-kinase signal transduction pathways defined by MEK and MKK isoforms. Science. 1995 Feb 3;267(5198):682–685. [PubMed]
  • Descheemaeker KA, Wyns S, Nelles L, Auwerx J, Ny T, Collen D. Interaction of AP-1-, AP-2-, and Sp1-like proteins with two distinct sites in the upstream regulatory region of the plasminogen activator inhibitor-1 gene mediates the phorbol 12-myristate 13-acetate response. J Biol Chem. 1992 Jul 25;267(21):15086–15091. [PubMed]
  • de Winter JP, Roelen BA, ten Dijke P, van der Burg B, van den Eijnden-van Raaij AJ. DPC4 (SMAD4) mediates transforming growth factor-beta1 (TGF-beta1) induced growth inhibition and transcriptional response in breast tumour cells. Oncogene. 1997 Apr 24;14(16):1891–1899. [PubMed]
  • Du W, Thanos D, Maniatis T. Mechanisms of transcriptional synergism between distinct virus-inducible enhancer elements. Cell. 1993 Sep 10;74(5):887–898. [PubMed]
  • Farhadian F, Contard F, Corbier A, Barrieux A, Rappaport L, Samuel JL. Fibronectin expression during physiological and pathological cardiac growth. J Mol Cell Cardiol. 1995 Apr;27(4):981–990. [PubMed]
  • Frey RS, Mulder KM. Involvement of extracellular signal-regulated kinase 2 and stress-activated protein kinase/Jun N-terminal kinase activation by transforming growth factor beta in the negative growth control of breast cancer cells. Cancer Res. 1997 Feb 15;57(4):628–633. [PubMed]
  • George EL, Georges-Labouesse EN, Patel-King RS, Rayburn H, Hynes RO. Defects in mesoderm, neural tube and vascular development in mouse embryos lacking fibronectin. Development. 1993 Dec;119(4):1079–1091. [PubMed]
  • Greiling D, Clark RA. Fibronectin provides a conduit for fibroblast transmigration from collagenous stroma into fibrin clot provisional matrix. J Cell Sci. 1997 Apr;110(Pt 7):861–870. [PubMed]
  • Gupta S, Campbell D, Dérijard B, Davis RJ. Transcription factor ATF2 regulation by the JNK signal transduction pathway. Science. 1995 Jan 20;267(5196):389–393. [PubMed]
  • Gupta S, Barrett T, Whitmarsh AJ, Cavanagh J, Sluss HK, Dérijard B, Davis RJ. Selective interaction of JNK protein kinase isoforms with transcription factors. EMBO J. 1996 Jun 3;15(11):2760–2770. [PMC free article] [PubMed]
  • Hai T, Curran T. Cross-family dimerization of transcription factors Fos/Jun and ATF/CREB alters DNA binding specificity. Proc Natl Acad Sci U S A. 1991 May 1;88(9):3720–3724. [PMC free article] [PubMed]
  • Hannigan M, Zhan L, Ai Y, Huang CK. The role of p38 MAP kinase in TGF-beta1-induced signal transduction in human neutrophils. Biochem Biophys Res Commun. 1998 May 8;246(1):55–58. [PubMed]
  • Hartsough MT, Mulder KM. Transforming growth factor beta activation of p44mapk in proliferating cultures of epithelial cells. J Biol Chem. 1995 Mar 31;270(13):7117–7124. [PubMed]
  • Heldin CH, Miyazono K, ten Dijke P. TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature. 1997 Dec 4;390(6659):465–471. [PubMed]
  • Hibi M, Lin A, Smeal T, Minden A, Karin M. Identification of an oncoprotein- and UV-responsive protein kinase that binds and potentiates the c-Jun activation domain. Genes Dev. 1993 Nov;7(11):2135–2148. [PubMed]
  • Hocevar BA, Howe PH. Isolation and characterization of mutant cell lines defective in transforming growth factor beta signaling. Proc Natl Acad Sci U S A. 1996 Jul 23;93(15):7655–7660. [PMC free article] [PubMed]
  • Hua X, Liu X, Ansari DO, Lodish HF. Synergistic cooperation of TFE3 and smad proteins in TGF-beta-induced transcription of the plasminogen activator inhibitor-1 gene. Genes Dev. 1998 Oct 1;12(19):3084–3095. [PMC free article] [PubMed]
  • Hynes R. Molecular biology of fibronectin. Annu Rev Cell Biol. 1985;1:67–90. [PubMed]
  • Ignotz RA, Massagué J. Transforming growth factor-beta stimulates the expression of fibronectin and collagen and their incorporation into the extracellular matrix. J Biol Chem. 1986 Mar 25;261(9):4337–4345. [PubMed]
  • Iordanov M, Bender K, Ade T, Schmid W, Sachsenmaier C, Engel K, Gaestel M, Rahmsdorf HJ, Herrlich P. CREB is activated by UVC through a p38/HOG-1-dependent protein kinase. EMBO J. 1997 Mar 3;16(5):1009–1022. [PMC free article] [PubMed]
  • Jiang Y, Chen C, Li Z, Guo W, Gegner JA, Lin S, Han J. Characterization of the structure and function of a new mitogen-activated protein kinase (p38beta). J Biol Chem. 1996 Jul 26;271(30):17920–17926. [PubMed]
  • Jin G, Howe PH. Regulation of clusterin gene expression by transforming growth factor beta. J Biol Chem. 1997 Oct 17;272(42):26620–26626. [PubMed]
  • Ivashkiv LB, Liou HC, Kara CJ, Lamph WW, Verma IM, Glimcher LH. mXBP/CRE-BP2 and c-Jun form a complex which binds to the cyclic AMP, but not to the 12-O-tetradecanoylphorbol-13-acetate, response element. Mol Cell Biol. 1990 Apr;10(4):1609–1621. [PMC free article] [PubMed]
  • Karin M, Smeal T. Control of transcription factors by signal transduction pathways: the beginning of the end. Trends Biochem Sci. 1992 Oct;17(10):418–422. [PubMed]
  • Keeton MR, Curriden SA, van Zonneveld AJ, Loskutoff DJ. Identification of regulatory sequences in the type 1 plasminogen activator inhibitor gene responsive to transforming growth factor beta. J Biol Chem. 1991 Dec 5;266(34):23048–23052. [PubMed]
  • Kim SJ, Angel P, Lafyatis R, Hattori K, Kim KY, Sporn MB, Karin M, Roberts AB. Autoinduction of transforming growth factor beta 1 is mediated by the AP-1 complex. Mol Cell Biol. 1990 Apr;10(4):1492–1497. [PMC free article] [PubMed]
  • Kim SJ, Wagner S, Liu F, O'Reilly MA, Robbins PD, Green MR. Retinoblastoma gene product activates expression of the human TGF-beta 2 gene through transcription factor ATF-2. Nature. 1992 Jul 23;358(6384):331–334. [PubMed]
  • Kornblihtt AR, Vibe-Pedersen K, Baralle FE. Isolation and characterization of cDNA clones for human and bovine fibronectins. Proc Natl Acad Sci U S A. 1983 Jun;80(11):3218–3222. [PMC free article] [PubMed]
  • Kornblihtt AR, Pesce CG, Alonso CR, Cramer P, Srebrow A, Werbajh S, Muro AF. The fibronectin gene as a model for splicing and transcription studies. FASEB J. 1996 Feb;10(2):248–257. [PubMed]
  • Kyriakis JM, Avruch J. Sounding the alarm: protein kinase cascades activated by stress and inflammation. J Biol Chem. 1996 Oct 4;271(40):24313–24316. [PubMed]
  • Kyriakis JM, Banerjee P, Nikolakaki E, Dai T, Rubie EA, Ahmad MF, Avruch J, Woodgett JR. The stress-activated protein kinase subfamily of c-Jun kinases. Nature. 1994 May 12;369(6476):156–160. [PubMed]
  • Labbé E, Silvestri C, Hoodless PA, Wrana JL, Attisano L. Smad2 and Smad3 positively and negatively regulate TGF beta-dependent transcription through the forkhead DNA-binding protein FAST2. Mol Cell. 1998 Jul;2(1):109–120. [PubMed]
  • Dai JL, Turnacioglu KK, Schutte M, Sugar AY, Kern SE. Dpc4 transcriptional activation and dysfunction in cancer cells. Cancer Res. 1998 Oct 15;58(20):4592–4597. [PubMed]
  • Lee YJ, Han Y, Lu HT, Nguyen V, Qin H, Howe PH, Hocevar BA, Boss JM, Ransohoff RM, Benveniste EN. TGF-beta suppresses IFN-gamma induction of class II MHC gene expression by inhibiting class II transactivator messenger RNA expression. J Immunol. 1997 Mar 1;158(5):2065–2075. [PubMed]
  • Leof EB, Proper JA, Getz MJ, Moses HL. Transforming growth factor type beta regulation of actin mRNA. J Cell Physiol. 1986 Apr;127(1):83–88. [PubMed]
  • Li JM, Shen X, Hu PP, Wang XF. Transforming growth factor beta stimulates the human immunodeficiency virus 1 enhancer and requires NF-kappaB activity. Mol Cell Biol. 1998 Jan;18(1):110–121. [PMC free article] [PubMed]
  • Lin A, Minden A, Martinetto H, Claret FX, Lange-Carter C, Mercurio F, Johnson GL, Karin M. Identification of a dual specificity kinase that activates the Jun kinases and p38-Mpk2. Science. 1995 Apr 14;268(5208):286–290. [PubMed]
  • Liu X, Sun Y, Constantinescu SN, Karam E, Weinberg RA, Lodish HF. Transforming growth factor beta-induced phosphorylation of Smad3 is required for growth inhibition and transcriptional induction in epithelial cells. Proc Natl Acad Sci U S A. 1997 Sep 30;94(20):10669–10674. [PMC free article] [PubMed]
  • Marais R, Marshall CJ. Control of the ERK MAP kinase cascade by Ras and Raf. Cancer Surv. 1996;27:101–125. [PubMed]
  • Martin P. Wound healing--aiming for perfect skin regeneration. Science. 1997 Apr 4;276(5309):75–81. [PubMed]
  • Massagué J. The transforming growth factor-beta family. Annu Rev Cell Biol. 1990;6:597–641. [PubMed]
  • Massagué J. TGF-beta signal transduction. Annu Rev Biochem. 1998;67:753–791. [PubMed]
  • Minden A, Lin A, McMahon M, Lange-Carter C, Dérijard B, Davis RJ, Johnson GL, Karin M. Differential activation of ERK and JNK mitogen-activated protein kinases by Raf-1 and MEKK. Science. 1994 Dec 9;266(5191):1719–1723. [PubMed]
  • Molossi S, Clausell N, Rabinovitch M. Reciprocal induction of tumor necrosis factor-alpha and interleukin-1 beta activity mediates fibronectin synthesis in coronary artery smooth muscle cells. J Cell Physiol. 1995 Apr;163(1):19–29. [PubMed]
  • Moriguchi T, Toyoshima F, Masuyama N, Hanafusa H, Gotoh Y, Nishida E. A novel SAPK/JNK kinase, MKK7, stimulated by TNFalpha and cellular stresses. EMBO J. 1997 Dec 1;16(23):7045–7053. [PMC free article] [PubMed]
  • Pertovaara L, Sistonen L, Bos TJ, Vogt PK, Keski-Oja J, Alitalo K. Enhanced jun gene expression is an early genomic response to transforming growth factor beta stimulation. Mol Cell Biol. 1989 Mar;9(3):1255–1262. [PMC free article] [PubMed]
  • Raingeaud J, Gupta S, Rogers JS, Dickens M, Han J, Ulevitch RJ, Davis RJ. Pro-inflammatory cytokines and environmental stress cause p38 mitogen-activated protein kinase activation by dual phosphorylation on tyrosine and threonine. J Biol Chem. 1995 Mar 31;270(13):7420–7426. [PubMed]
  • Rasmussen LM, Wolf YG, Ruoslahti E. Vascular smooth muscle cells from injured rat aortas display elevated matrix production associated with transforming growth factor-beta activity. Am J Pathol. 1995 Oct;147(4):1041–1048. [PMC free article] [PubMed]
  • Read MA, Whitley MZ, Gupta S, Pierce JW, Best J, Davis RJ, Collins T. Tumor necrosis factor alpha-induced E-selectin expression is activated by the nuclear factor-kappaB and c-JUN N-terminal kinase/p38 mitogen-activated protein kinase pathways. J Biol Chem. 1997 Jan 31;272(5):2753–2761. [PubMed]
  • Schutte M, Hruban RH, Hedrick L, Cho KR, Nadasdy GM, Weinstein CL, Bova GS, Isaacs WB, Cairns P, Nawroz H, et al. DPC4 gene in various tumor types. Cancer Res. 1996 Jun 1;56(11):2527–2530. [PubMed]
  • Serini G, Bochaton-Piallat ML, Ropraz P, Geinoz A, Borsi L, Zardi L, Gabbiani G. The fibronectin domain ED-A is crucial for myofibroblastic phenotype induction by transforming growth factor-beta1. J Cell Biol. 1998 Aug 10;142(3):873–881. [PMC free article] [PubMed]
  • Shino Y, Shirasawa H, Kinoshita T, Simizu B. Human papillomavirus type 16 E6 protein transcriptionally modulates fibronectin gene expression by induction of protein complexes binding to the cyclic AMP response element. J Virol. 1997 Jun;71(6):4310–4318. [PMC free article] [PubMed]
  • Shirakabe K, Yamaguchi K, Shibuya H, Irie K, Matsuda S, Moriguchi T, Gotoh Y, Matsumoto K, Nishida E. TAK1 mediates the ceramide signaling to stress-activated protein kinase/c-Jun N-terminal kinase. J Biol Chem. 1997 Mar 28;272(13):8141–8144. [PubMed]
  • Sluss HK, Barrett T, Dérijard B, Davis RJ. Signal transduction by tumor necrosis factor mediated by JNK protein kinases. Mol Cell Biol. 1994 Dec;14(12):8376–8384. [PMC free article] [PubMed]
  • Song CZ, Siok TE, Gelehrter TD. Smad4/DPC4 and Smad3 mediate transforming growth factor-beta (TGF-beta) signaling through direct binding to a novel TGF-beta-responsive element in the human plasminogen activator inhibitor-1 promoter. J Biol Chem. 1998 Nov 6;273(45):29287–29290. [PubMed]
  • Souchelnytskyi S, Tamaki K, Engström U, Wernstedt C, ten Dijke P, Heldin CH. Phosphorylation of Ser465 and Ser467 in the C terminus of Smad2 mediates interaction with Smad4 and is required for transforming growth factor-beta signaling. J Biol Chem. 1997 Oct 31;272(44):28107–28115. [PubMed]
  • Tong L, Pav S, White DM, Rogers S, Crane KM, Cywin CL, Brown ML, Pargellis CA. A highly specific inhibitor of human p38 MAP kinase binds in the ATP pocket. Nat Struct Biol. 1997 Apr;4(4):311–316. [PubMed]
  • Tournier C, Whitmarsh AJ, Cavanagh J, Barrett T, Davis RJ. Mitogen-activated protein kinase kinase 7 is an activator of the c-Jun NH2-terminal kinase. Proc Natl Acad Sci U S A. 1997 Jul 8;94(14):7337–7342. [PMC free article] [PubMed]
  • Treisman R. Regulation of transcription by MAP kinase cascades. Curr Opin Cell Biol. 1996 Apr;8(2):205–215. [PubMed]
  • van Dam H, Duyndam M, Rottier R, Bosch A, de Vries-Smits L, Herrlich P, Zantema A, Angel P, van der Eb AJ. Heterodimer formation of cJun and ATF-2 is responsible for induction of c-jun by the 243 amino acid adenovirus E1A protein. EMBO J. 1993 Feb;12(2):479–487. [PMC free article] [PubMed]
  • Villanueva A, García C, Paules AB, Vicente M, Megías M, Reyes G, de Villalonga P, Agell N, Lluís F, Bachs O, et al. Disruption of the antiproliferative TGF-beta signaling pathways in human pancreatic cancer cells. Oncogene. 1998 Oct 15;17(15):1969–1978. [PubMed]
  • Wang W, Zhou G, Hu MC, Yao Z, Tan TH. Activation of the hematopoietic progenitor kinase-1 (HPK1)-dependent, stress-activated c-Jun N-terminal kinase (JNK) pathway by transforming growth factor beta (TGF-beta)-activated kinase (TAK1), a kinase mediator of TGF beta signal transduction. J Biol Chem. 1997 Sep 5;272(36):22771–22775. [PubMed]
  • Westerhausen DR, Jr, Hopkins WE, Billadello JJ. Multiple transforming growth factor-beta-inducible elements regulate expression of the plasminogen activator inhibitor type-1 gene in Hep G2 cells. J Biol Chem. 1991 Jan 15;266(2):1092–1100. [PubMed]
  • Whitman M. Signal transduction. Feedback from inhibitory SMADs. Nature. 1997 Oct 9;389(6651):549–551. [PubMed]
  • Whitmarsh AJ, Shore P, Sharrocks AD, Davis RJ. Integration of MAP kinase signal transduction pathways at the serum response element. Science. 1995 Jul 21;269(5222):403–407. [PubMed]
  • Woodgett JR, Avruch J, Kyriakis J. The stress activated protein kinase pathway. Cancer Surv. 1996;27:127–138. [PubMed]
  • Wrana JL, Overall CM, Sodek J. Regulation of the expression of a secreted acidic protein rich in cysteine (SPARC) in human fibroblasts by transforming growth factor beta. Comparison of transcriptional and post-transcriptional control with fibronectin and type I collagen. Eur J Biochem. 1991 Apr 23;197(2):519–528. [PubMed]
  • Wrana JL, Attisano L, Cárcamo J, Zentella A, Doody J, Laiho M, Wang XF, Massagué J. TGF beta signals through a heteromeric protein kinase receptor complex. Cell. 1992 Dec 11;71(6):1003–1014. [PubMed]
  • Wun TC, Kretzmer KK. cDNA cloning and expression in E. coli of a plasminogen activator inhibitor (PAI) related to a PAI produced by Hep G2 hepatoma cell. FEBS Lett. 1987 Jan 1;210(1):11–16. [PubMed]
  • Xing J, Ginty DD, Greenberg ME. Coupling of the RAS-MAPK pathway to gene activation by RSK2, a growth factor-regulated CREB kinase. Science. 1996 Aug 16;273(5277):959–963. [PubMed]
  • Yamaguchi K, Shirakabe K, Shibuya H, Irie K, Oishi I, Ueno N, Taniguchi T, Nishida E, Matsumoto K. Identification of a member of the MAPKKK family as a potential mediator of TGF-beta signal transduction. Science. 1995 Dec 22;270(5244):2008–2011. [PubMed]
  • Yingling JM, Datto MB, Wong C, Frederick JP, Liberati NT, Wang XF. Tumor suppressor Smad4 is a transforming growth factor beta-inducible DNA binding protein. Mol Cell Biol. 1997 Dec;17(12):7019–7028. [PMC free article] [PubMed]
  • Zhang K, Rekhter MD, Gordon D, Phan SH. Myofibroblasts and their role in lung collagen gene expression during pulmonary fibrosis. A combined immunohistochemical and in situ hybridization study. Am J Pathol. 1994 Jul;145(1):114–125. [PMC free article] [PubMed]
  • Zhang Y, Feng X, We R, Derynck R. Receptor-associated Mad homologues synergize as effectors of the TGF-beta response. Nature. 1996 Sep 12;383(6596):168–172. [PubMed]
  • Zhang Y, Feng XH, Derynck R. Smad3 and Smad4 cooperate with c-Jun/c-Fos to mediate TGF-beta-induced transcription. Nature. 1998 Aug 27;394(6696):909–913. [PubMed]
  • Zhou S, Buckhaults P, Zawel L, Bunz F, Riggins G, Dai JL, Kern SE, Kinzler KW, Vogelstein B. Targeted deletion of Smad4 shows it is required for transforming growth factor beta and activin signaling in colorectal cancer cells. Proc Natl Acad Sci U S A. 1998 Mar 3;95(5):2412–2416. [PMC free article] [PubMed]

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