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.
Sterner-Kock
Anja
A
Laboratory for Molecular Hematology, University of Frankfurt Medical School, 60596 Frankfurt am Main, Germany.
Thorey
Irmgard S
IS
Koli
Katri
K
Wempe
Frank
F
Otte
Jürgen
J
Bangsow
Thorsten
T
Kuhlmeier
Katharina
K
Kirchner
Thomas
T
Jin
Shenchu
S
Keski-Oja
Jorma
J
von Melchner
Harald
H
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D009202:Cardiomyopathies / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004547:Elastic Tissue / Q000378:metabolism / Q000473:pathology; D005109:Extracellular Matrix / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D018390:Gene Targeting; D006801:Humans; D007438:Introns; D053779:Latent TGF-beta Binding Proteins / Q000235:genetics* / Q000378:metabolism; D008168:Lung / Q000002:abnormalities* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010641:Phenotype; D011656:Pulmonary Emphysema / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C538753:LTBP-4 protein, mouse; C509032:LTBP1 protein, human; C509040:LTBP4 protein, human; D053779:Latent TGF-beta Binding Proteins; C509033:Ltbp1 protein, mouse; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1