Document Detail


Klotho inhibits transforming growth factor-beta1 (TGF-beta1) signaling and suppresses renal fibrosis and cancer metastasis in mice.
MedLine Citation:
PMID:  21209102     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Fibrosis is a pathological process characterized by infiltration and proliferation of mesenchymal cells in interstitial space. A substantial portion of these cells is derived from residing non-epithelial and/or epithelial cells that have acquired the ability to migrate and proliferate. The mesenchymal transition is also observed in cancer cells to confer the ability to metastasize. Here, we show that renal fibrosis induced by unilateral ureteral obstruction and metastasis of human cancer xenografts are suppressed by administration of secreted Klotho protein to mice. Klotho is a single-pass transmembrane protein expressed in renal tubular epithelial cells. The extracellular domain of Klotho is secreted by ectodomain shedding. Secreted Klotho protein directly binds to the type-II TGF-β receptor and inhibits TGF-β1 binding to cell surface receptors, thereby inhibiting TGF-β1 signaling. Klotho suppresses TGF-β1-induced epithelial-to-mesenchymal transition (EMT) responses in cultured cells, including decreased epithelial marker expression, increased mesenchymal marker expression, and/or increased cell migration. In addition to TGF-β1 signaling, secreted Klotho has been shown to inhibit Wnt and IGF-1 signaling that can promote EMT. These results have raised the possibility that secreted Klotho may function as an endogenous anti-EMT factor by inhibiting multiple growth factor signaling pathways simultaneously.
Authors:
Shigehiro Doi; Yonglong Zou; Osamu Togao; Johanne V Pastor; George B John; Lei Wang; Kazuhiro Shiizaki; Russell Gotschall; Susan Schiavi; Noriaki Yorioka; Masaya Takahashi; David A Boothman; Makoto Kuro-o
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2011-01-05
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  286     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2011 Mar 
Date Detail:
Created Date:  2011-03-07     Completed Date:  2011-05-11     Revised Date:  2014-09-24    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  8655-65     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Cell Line, Tumor
Epithelial-Mesenchymal Transition / genetics
Fibrosis / genetics,  metabolism,  pathology
Gene Expression Regulation, Neoplastic / genetics
Glucuronidase / genetics,  metabolism*
HEK293 Cells
Humans
Insulin-Like Growth Factor I / genetics,  metabolism
Kidney / metabolism*,  pathology
Kidney Neoplasms / genetics,  metabolism*,  pathology
Mice
Neoplasm Metastasis
Neoplasm Transplantation
Neoplasms, Experimental / genetics,  metabolism*,  pathology
Protein-Serine-Threonine Kinases / genetics,  metabolism
Rats
Receptors, Transforming Growth Factor beta / genetics,  metabolism
Signal Transduction*
Transforming Growth Factor beta1 / genetics,  metabolism*
Transplantation, Heterologous
Wnt Proteins / genetics,  metabolism
Grant Support
ID/Acronym/Agency:
P41 RR002584/RR/NCRR NIH HHS; R01AG019712/AG/NIA NIH HHS; R01CA102792/CA/NCI NIH HHS; R01CA129011/CA/NCI NIH HHS; R21EB009147/EB/NIBIB NIH HHS; U24 CA126608/CA/NCI NIH HHS; U24 CA126608-04/CA/NCI NIH HHS; U24 CA126608-05/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Receptors, Transforming Growth Factor beta; 0/Transforming Growth Factor beta1; 0/Wnt Proteins; 67763-96-6/Insulin-Like Growth Factor I; EC 2.7.1.11/TGF-beta type I receptor; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 3.2.1.31/Glucuronidase; EC 3.2.1.31/klotho protein
Comments/Corrections

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