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Vol. 16, No. 17, pp. 2264-2273, September 1, 2002
binding protein 4 (LTBP-4) causes abnormal lung development, cardiomyopathy, and colorectal cancer
1 Laboratory for Molecular Hematology and
2 Department of Pharmacology, University of Frankfurt Medical
School, 60596 Frankfurt am Main, Germany; 3 Departments of
Virology and Pathology, Haartman Institute and Helsinki University
Hospital, University of Helsinki, 00014 Helsinki, Finland;
4 Department of Pathology, University of Erlangen-Nürnberg,
91054 Erlangen, Germany
Transforming growth factor-
s (TGF-s) 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- 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- 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- 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- tissue
deposition and signaling.
[Key Words:
LTBP; TGF-; extracellular matrix; colorectal cancer; pulmonary emphysema; cardiomyopathy]
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