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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

Authors

  • Sterner-Kock A
  • Thorey IS
  • Koli K
  • Wempe F
  • Otte J
  • Bangsow T
  • Kuhlmeier K
  • Kirchner T
  • Jin S
  • Keski-Oja J
  • von Melchner H

Journal

Genes & development

Publication Data

September 1, 2002

Associated Grants

None

Mesh Terms

  • 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