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

  1. Anja Sterner-Kock1,5,
  2. Irmgard S. Thorey1,5,
  3. Katri Koli3,
  4. Frank Wempe1,
  5. Jürgen Otte1,
  6. Thorsten Bangsow1,
  7. Katharina Kuhlmeier1,
  8. Thomas Kirchner4,
  9. Shenchu Jin1,2,
  10. Jorma Keski-Oja3, and
  11. Harald von Melchner1,6
  12. 1Laboratory for Molecular Hematology and2Department of Pharmacology, University of Frankfurt Medical School, 60596 Frankfurt am Main, Germany; 3Departments of Virology and Pathology, Haartman Institute and Helsinki University Hospital, University of Helsinki, 00014 Helsinki, Finland;4Department of Pathology, University of Erlangen-Nürnberg, 91054 Erlangen, Germany

Abstract

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.

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