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Klotho inhibits transforming growth factor-beta1 (TGF-beta1) signaling and suppresses renal fibrosis and cancer metastasis in mice.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2011 Mar 11; Vol. 286 (10), pp. 8655-8665. Date of Electronic Publication: 2011 Jan 05. - Publication Year :
- 2011
-
Abstract
- 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.
- Subjects :
- Animals
Cell Line, Tumor
Epithelial-Mesenchymal Transition genetics
Fibrosis genetics
Fibrosis metabolism
Fibrosis pathology
Gene Expression Regulation, Neoplastic genetics
Glucuronidase genetics
HEK293 Cells
Humans
Insulin-Like Growth Factor I genetics
Insulin-Like Growth Factor I metabolism
Kidney pathology
Kidney Neoplasms genetics
Kidney Neoplasms pathology
Klotho Proteins
Mice
Neoplasm Metastasis
Neoplasm Transplantation
Neoplasms, Experimental genetics
Neoplasms, Experimental pathology
Protein Serine-Threonine Kinases genetics
Protein Serine-Threonine Kinases metabolism
Rats
Receptor, Transforming Growth Factor-beta Type I
Receptors, Transforming Growth Factor beta genetics
Receptors, Transforming Growth Factor beta metabolism
Transforming Growth Factor beta1 genetics
Transplantation, Heterologous
Wnt Proteins genetics
Wnt Proteins metabolism
Glucuronidase metabolism
Kidney metabolism
Kidney Neoplasms metabolism
Neoplasms, Experimental metabolism
Signal Transduction
Transforming Growth Factor beta1 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 286
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 21209102
- Full Text :
- https://doi.org/10.1074/jbc.M110.174037