Disruption of LTBP-4 function reduces TGF-beta activation and enhances BMP-4 signaling in the lung.

Abstract	Disruption of latent TGF-beta binding protein (LTBP)-4 expression in the mouse leads to abnormal lung development and colorectal cancer. Lung fibroblasts from these mice produced decreased amounts of active TGF-beta, whereas secretion of latent TGF-beta was significantly increased. Expression and secretion of TGF-beta2 and -beta3 increased considerably. These results suggested that TGF-beta activation but not secretion would be severely impaired in LTBP-4 -/- fibroblasts. Microarrays revealed increased expression of bone morphogenic protein (BMP)-4 and decreased expression of its inhibitor gremlin. This finding was accompanied by enhanced expression of BMP-4 target genes, inhibitors of differentiation 1 and 2, and increased deposition of fibronectin-rich extracellular matrix. Accordingly, increased expression of BMP-4 and decreased expression of gremlin were observed in mouse lung. Transfection of LTBP-4 rescued the -/- fibroblast phenotype, while LTBP-1 was inefficient. Treatment with active TGF-beta1 rescued BMP-4 and gremlin expression to wild-type levels. Our results indicate that the lack of LTBP-4-mediated targeting and activation of TGF-beta1 leads to enhanced BMP-4 signaling in mouse lung.
Authors	Katri Koli, Frank Wempe, Anja Sterner-Kock, Anna Kantola, Martina Komor, Wolf-K Hofmann, Harald von Melchner, Jorma Keski-Oja
Journal	The Journal of cell biology (J Cell Biol) Vol. 167 Issue 1 Pg. 123-33 (Oct 11 2004) ISSN: 0021-9525 [Print] United States
PMID	15466481 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Adaptor Proteins, Signal Transducing BMP4 protein, human Bmp4 protein, mouse Bone Morphogenetic Protein 4 Bone Morphogenetic Proteins DNA, Complementary GREM1 protein, human Intercellular Signaling Peptides and Proteins LTBP1 protein, human LTBP4 protein, human Latent TGF-beta Binding Proteins Ltbp1 protein, mouse Oligonucleotides Transforming Growth Factor beta RNA
Topics	Adaptor Proteins, Signal Transducing (metabolism, physiology) Animals Blotting, Northern Bone Morphogenetic Protein 4 Bone Morphogenetic Proteins (metabolism) Cell Differentiation DNA, Complementary (metabolism) Electrophoresis, Polyacrylamide Gel Extracellular Matrix (metabolism) Fibroblasts (metabolism) Humans Immunohistochemistry Intercellular Signaling Peptides and Proteins (metabolism) Latent TGF-beta Binding Proteins Lung (metabolism) Mice Mice, Transgenic Microscopy, Fluorescence Oligonucleotide Array Sequence Analysis Oligonucleotides (chemistry) Phenotype RNA (metabolism) Reverse Transcriptase Polymerase Chain Reaction Signal Transduction Transfection Transforming Growth Factor beta (metabolism) Up-Regulation

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