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

2002; Cold Spring Harbor Laboratory Press; Volume: 16; Issue: 17 Linguagem: Inglês

10.1101/gad.229102

1549-5477

Anja Sterner‐Kock, Irmgard S. Thorey, Katri Koli, Frank Wempe, Jürgen Otte, Thorsten Bangsow, Katharina Kuhlmeier, Thomas Kirchner, Shenchu Jin, Jorma Keski‐Oja, Harald von Melchner,

Congenital heart defects research

Transforming growth factor-βs (TGF-βs) 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-β 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-β 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-β 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-β tissue deposition and signaling.