PMID:12208849

Citation	Sterner-Kock, A, Thorey, IS, Koli, K, Wempe, F, Otte, J, Bangsow, T, Kuhlmeier, K, Kirchner, T, Jin, S, Keski-Oja, J and von Melchner, H (2002) Disruption of the gene encoding the latent transforming growth factor-beta binding protein 4 (LTBP-4) causes abnormal lung development, cardiomyopathy, and colorectal cancer. Genes Dev. 16:2264-73
Abstract	Transforming growth factor-betas (TGF-betas) are multifunctional growth factors that are secreted as inactive (latent) precursors in large protein complexes. These complexes include the latency-associated propeptide (LAP) and a latent transforming growth factor-beta binding protein (LTBP). Four isoforms of LTBPs (LTBP-1-LTBP-4) have been cloned and are believed to be structural components of connective tissue microfibrils and local regulators of TGF-beta tissue deposition and signaling. By using a gene trap strategy that selects for integrations into genes induced transiently during early mouse development, we have disrupted the mouse homolog of the human LTBP-4 gene. Mice homozygous for the disrupted allele develop severe pulmonary emphysema, cardiomyopathy, and colorectal cancer. These highly tissue-specific abnormalities are associated with profound defects in the elastic fiber structure and with a reduced deposition of TGF-beta in the extracellular space. As a consequence, epithelial cells have reduced levels of phosphorylated Smad2 proteins, overexpress c-myc, and undergo uncontrolled proliferation. This phenotype supports the predicted dual role of LTBP-4 as a structural component of the extracellular matrix and as a local regulator of TGF-beta tissue deposition and signaling.
Links	PubMed PMC186672 Online version:10.1101/gad.229102
Keywords	Adaptor Proteins, Signal Transducing; Animals; Cardiomyopathies/genetics; Cardiomyopathies/metabolism; Cardiomyopathies/pathology; Carrier Proteins/genetics; Carrier Proteins/metabolism; Colorectal Neoplasms/genetics; Colorectal Neoplasms/metabolism; Colorectal Neoplasms/pathology; Elastic Tissue/metabolism; Elastic Tissue/pathology; Extracellular Matrix/metabolism; Gene Expression Regulation, Developmental; Gene Targeting; Humans; Introns; Latent TGF-beta Binding Proteins/genetics; Latent TGF-beta Binding Proteins/metabolism; Lung/abnormalities; Lung/metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Phenotype; Pulmonary Emphysema/genetics; Pulmonary Emphysema/metabolism; Pulmonary Emphysema/pathology; Signal Transduction; Transforming Growth Factor beta/metabolism; Transforming Growth Factor beta1
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