Perturbation of transforming growth factor (TGF)-β1 association with latent TGF-β binding protein yields inflammation and tumors

Yoshinaga, Keiji, Obata, Hiroto, Jurukovski, Vladimir, Mazzieri, Roberta, Chen, Yan, Zilberberg, Lior, Huso, David, Melamed, Jonathan, Prijatelj, Petra, Todorovic, Vesna, Dabovic, Branka and Rifkin, Daniel B. (2008) Perturbation of transforming growth factor (TGF)-β1 association with latent TGF-β binding protein yields inflammation and tumors. Proceedings of the National Academy of Sciences, 105 48: 18758-18763. doi:10.1073/pnas.0805411105


Author Yoshinaga, Keiji
Obata, Hiroto
Jurukovski, Vladimir
Mazzieri, Roberta
Chen, Yan
Zilberberg, Lior
Huso, David
Melamed, Jonathan
Prijatelj, Petra
Todorovic, Vesna
Dabovic, Branka
Rifkin, Daniel B.
Title Perturbation of transforming growth factor (TGF)-β1 association with latent TGF-β binding protein yields inflammation and tumors
Formatted title
Perturbation of transforming growth factor (TGF)-β1 association with latent TGF-β binding protein yields inflammation and tumors
Journal name Proceedings of the National Academy of Sciences   Check publisher's open access policy
ISSN 0027-8424
1091-6490
Publication date 2008-12-02
Year available 2008
Sub-type Article (original research)
DOI 10.1073/pnas.0805411105
Open Access Status Not yet assessed
Volume 105
Issue 48
Start page 18758
End page 18763
Total pages 6
Place of publication Washington, DC, United States
Publisher National Academy of Sciences
Language eng
Formatted abstract
Transforming growth factor-β (TGF-β) activity is controlled at many levels including the conversion of the latent secreted form to its active state. TGF-β is often released as part of an inactive tripartite complex consisting of TGF-β, the TGF-β propeptide, and a molecule of latent TGF-β binding protein (LTBP). The interaction of TGF-β and its cleaved propeptide renders the growth factor latent, and the liberation of TGF-β from this state is crucial for signaling. To examine the contribution of LTBP to TGF-β function, we generated mice in which the cysteines that link the propeptide to LTBP were mutated to serines, thereby blocking covalent association. Tgfb1C33S/C33S mice had multiorgan inflammation, lack of skin Langerhans cells (LC), and a shortened lifespan, consistent with decreased TGF-β1 levels. However, the inflammatory response and decreased lifespan were not as severe as observed with Tgfb1-/- animals. Tgfb1C33S/C33S mice exhibited decreased levels of active TGF-β1, decreased TGF-β signaling, and tumors of the stomach, rectum, and anus. These data suggest that the association of LTBP with the latent TGF-β complex is important for proper TGF-β1 function and that Tgfb1C33S/C33S mice are hypomorphs for active TGF-β1. Moreover, although mechanisms exist to activate latent TGF-β1 in the absence of LTBP, these mechanisms are not as efficient as those that use the latent complex containing LTBP.
Keyword Tgf-β activation
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID CA034282
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: UQ Diamantina Institute Publications
 
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