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Perturbation of transforming growth factor (TGF)-beta1 association with latent TGF-beta binding protein yields inflammation and tumors.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2008 Dec 02; Vol. 105 (48), pp. 18758-63. Date of Electronic Publication: 2008 Nov 20. - Publication Year :
- 2008
-
Abstract
- Transforming growth factor-beta (TGF-beta) activity is controlled at many levels including the conversion of the latent secreted form to its active state. TGF-beta is often released as part of an inactive tripartite complex consisting of TGF-beta, the TGF-beta propeptide, and a molecule of latent TGF-beta binding protein (LTBP). The interaction of TGF-beta and its cleaved propeptide renders the growth factor latent, and the liberation of TGF-beta from this state is crucial for signaling. To examine the contribution of LTBP to TGF-beta function, we generated mice in which the cysteines that link the propeptide to LTBP were mutated to serines, thereby blocking covalent association. Tgfb1(C33S/C33S) mice had multiorgan inflammation, lack of skin Langerhans cells (LC), and a shortened lifespan, consistent with decreased TGF-beta1 levels. However, the inflammatory response and decreased lifespan were not as severe as observed with Tgfb1(-/-) animals. Tgfb1(C33S/C33S) mice exhibited decreased levels of active TGF-beta1, decreased TGF-beta signaling, and tumors of the stomach, rectum, and anus. These data suggest that the association of LTBP with the latent TGF-beta complex is important for proper TGF-beta1 function and that Tgfb1(C33S/C33S) mice are hypomorphs for active TGF-beta1. Moreover, although mechanisms exist to activate latent TGF-beta1 in the absence of LTBP, these mechanisms are not as efficient as those that use the latent complex containing LTBP.
- Subjects :
- Animals
Cells, Cultured
Fibroblasts cytology
Gastric Mucosa cytology
Gastric Mucosa metabolism
Gastric Mucosa pathology
Inflammation pathology
Intestinal Mucosa cytology
Intestinal Mucosa metabolism
Intestinal Mucosa pathology
Langerhans Cells cytology
Langerhans Cells metabolism
Latent TGF-beta Binding Proteins genetics
Mice
Mice, Knockout
Neoplasms pathology
Protein Precursors genetics
Protein Precursors metabolism
Signal Transduction physiology
Transforming Growth Factor beta1 genetics
Inflammation metabolism
Latent TGF-beta Binding Proteins metabolism
Neoplasms metabolism
Transforming Growth Factor beta1 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 105
- Issue :
- 48
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 19022904
- Full Text :
- https://doi.org/10.1073/pnas.0805411105