title: Transforming growth factor-beta (TGF-beta) type I receptor/ALK5-dependent activation of the GADD45beta gene mediates the induction of biglycan expression by TGF-beta.
abstract: We have recently shown that induction of biglycan (BGN) expression by transforming growth factor-beta1 (TGF-beta1) required sequential activation of both Smad and p38 mitogen-activated protein kinase signaling (Ungefroren, H., Lenschow, W., Chen, W.-B., and Kalthoff, H. (2003) J. Biol. Chem. 278, 11041-11049). Here, we have analyzed the receptors through which TGF-beta1 controls expression of BGN and GADD45beta, the latter of which is postulated to link early Smad signaling to delayed activation of p38. Ectopic expression of a dominant-negative mutant of the TGF-beta type II receptor in PANC-1 cells abrogated TGF-beta-induced BGN up-regulation. Similarly, inhibition of the TGF-beta type I receptor/ALK5 with either SB431542 or by enforced stable expression of a kinase-dead mutant greatly attenuated the TGF-beta effect on both BGN and GADD45beta expression in PANC-1 and MG-63 cells. The enhancing effect of ALK5 on TGF-beta-mediated GADD45beta and BGN expression and on GADD45beta promoter activity was also dependent on its ability to activate Smad signaling, because an ALK5 mutant defective in Smad activation (TbetaRImL45) but with an otherwise functional kinase domain failed to mediate these responses. The TGF-beta/ALK5 effect on p38 activation and BGN expression was mimicked by overexpression of GADD45beta alone (in the absence of TGF-beta stimulation) and suppressed upon antisense inhibition of GADD45beta expression. These results show that TGF-beta induces BGN expression through (the Smad-activating function of) ALK5 and GADD45beta and suggest that the sensitivity of MyD118 to activation by TGF-beta, which varies between tissues, ultimately determines the strength of the TGF-beta effect on BGN.
authors.affiliation: Department of General Surgery and Thoracic Surgery, University Hospital Schleswig-Holstein, Campus Kiel, Arnold-Heller-Strasse 7, 24105 Kiel, Germany. hungefroren@chirurgie-sh.de
authors.forename: Hendrik
authors.initials: H
authors.lastname: Ungefroren
authors.forename: Stephanie
authors.initials: S
authors.lastname: Groth
authors.forename: Maren
authors.initials: M
authors.lastname: Ruhnke
authors.forename: Holger
authors.initials: H
authors.lastname: Kalthoff
authors.forename: Fred
authors.initials: F
authors.lastname: Fändrich
mesh_terms: D030201:Activin Receptors, Type I / Q000378:metabolism*; D000943:Antigens, Differentiation / Q000378:metabolism*; D058578:Biglycan; D002454:Cell Differentiation; D002460:Cell Line; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D016326:Extracellular Matrix Proteins; D005786:Gene Expression Regulation; D005799:Genes, Dominant; D017930:Genes, Reporter; D005822:Genetic Vectors; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D008954:Models, Biological; D009154:Mutation; D016376:Oligonucleotides, Antisense / Q000737:chemistry; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases; D011509:Proteoglycans / Q000096:biosynthesis*; D012313:RNA / Q000737:chemistry; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D012190:Retroviridae / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000097642:GADD45 Proteins
chemical_list: D030201:Activin Receptors, Type I; D000943:Antigens, Differentiation; D058578:Biglycan; D016326:Extracellular Matrix Proteins; D016376:Oligonucleotides, Antisense; D017346:Protein Serine-Threonine Kinases; D011509:Proteoglycans; D012313:RNA; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D048051:p38 Mitogen-Activated Protein Kinases; C546884:BGN protein, human; C086470:GADD45B protein, human; D000097642:GADD45 Proteins; C000625841:TGFBR1 protein, human