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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / metabolism
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Adaptor Proteins, Signal Transducing / physiology*
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Animals
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Blotting, Northern
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Bone Morphogenetic Protein 4
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Bone Morphogenetic Proteins / metabolism*
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Cell Differentiation
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DNA, Complementary / metabolism
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Electrophoresis, Polyacrylamide Gel
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Extracellular Matrix / metabolism
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Fibroblasts / metabolism
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Humans
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Immunohistochemistry
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Intercellular Signaling Peptides and Proteins / metabolism
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Latent TGF-beta Binding Proteins
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Lung / metabolism
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Mice
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Mice, Transgenic
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Microscopy, Fluorescence
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Oligonucleotide Array Sequence Analysis
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Oligonucleotides / chemistry
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Phenotype
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RNA / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction*
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Transfection
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Transforming Growth Factor beta / metabolism*
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Up-Regulation
Substances
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Adaptor Proteins, Signal Transducing
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BMP4 protein, human
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Bmp4 protein, mouse
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Bone Morphogenetic Protein 4
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Bone Morphogenetic Proteins
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DNA, Complementary
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GREM1 protein, human
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Intercellular Signaling Peptides and Proteins
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LTBP1 protein, human
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LTBP4 protein, human
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Latent TGF-beta Binding Proteins
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Ltbp1 protein, mouse
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Oligonucleotides
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Transforming Growth Factor beta
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RNA