Disruption of the gene encoding the latent transforming growth factor-beta binding protein 4 (LTBP-4) causes abnormal lung development, cardiomyopathy, and colorectal cancer.
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.
Pubmed ID: 12208849 RIS Download
Adaptor Proteins, Signal Transducing | Animals | Cardiomyopathies | Carrier Proteins | Colorectal Neoplasms | Elastic Tissue | Extracellular Matrix | Gene Expression Regulation, Developmental | Gene Targeting | Humans | Introns | Latent TGF-beta Binding Proteins | Lung | Mice | Mice, Inbred C57BL | Mice, Knockout | Mice, Transgenic | Phenotype | Pulmonary Emphysema | Signal Transduction | Transforming Growth Factor beta | Transforming Growth Factor beta1