Disruption of the gene encoding the latent transforming growth factor-beta binding protein 4 (LTBP-4) causes abnormal lung development, cardiomyopathy, and colorectal cancer

• Published in: Genes & development 2002-09, Vol.16 (17), p.2264-2273
• Main Authors: Sterner-Kock, Anja, Thorey, Irmgard S, Koli, Katri, Wempe, Frank, Otte, Jürgen, Bangsow, Thorsten, Kuhlmeier, Katharina, Kirchner, Thomas, Jin, Shenchu, Keski-Oja, Jorma, von Melchner, Harald
• Format: Article
• Language: English
• Subjects: 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; Research Paper; Signal Transduction; Transforming Growth Factor beta - metabolism; Transforming Growth Factor beta1
• ISSN: 0890-9369; 1549-5477
• DOI: 10.1101/gad.229102

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.