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FGF-23-Klotho signaling stimulates proliferation and prevents vitamin D-induced apoptosis.

Medici D, Razzaque MS, Deluca S, Rector TL, Hou B, Kang K, Goetz R, Mohammadi M, Kuro-O M, Olsen BR, Lanske B - J. Cell Biol. (2008)

Bottom Line: Fibroblast growth factor 23 (FGF-23) and Klotho are secretory proteins that regulate mineral-ion metabolism.Because serum levels of active vitamin D are greatly increased upon genetic ablation of Fgf-23 or Klotho, we find that these molecules have a dual role in suppression of apoptotic actions of vitamin D through both negative regulation of 1alpha-hydroxylase expression and phosphoinositide-3 kinase-dependent inhibition of caspase activity.These data provide new insights into the physiological roles of FGF-23 and Klotho.

View Article: PubMed Central - PubMed

Affiliation: Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115, USA.

ABSTRACT
Fibroblast growth factor 23 (FGF-23) and Klotho are secretory proteins that regulate mineral-ion metabolism. Fgf-23(-/-) or Klotho(-/-) knockout mice exhibit several pathophysiological processes consistent with premature aging including severe atrophy of tissues. We show that the signal transduction pathways initiated by FGF-23-Klotho prevent tissue atrophy by stimulating proliferation and preventing apoptosis caused by excessive systemic vitamin D. Because serum levels of active vitamin D are greatly increased upon genetic ablation of Fgf-23 or Klotho, we find that these molecules have a dual role in suppression of apoptotic actions of vitamin D through both negative regulation of 1alpha-hydroxylase expression and phosphoinositide-3 kinase-dependent inhibition of caspase activity. These data provide new insights into the physiological roles of FGF-23 and Klotho.

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Related in: MedlinePlus

Signaling events induced by FGF-23–Klotho. Immunoblotting showing that FGF-23 or Klotho alone have no effect on kinase activity in PTEC or FHs74Int cells. Combined effects of FGF-23 and Klotho show increased phosphorylation of ERK1/2, p38, JNK, AKT, IκB, and GSK-3β. α-Tubulin was used as a loading control.
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fig1: Signaling events induced by FGF-23–Klotho. Immunoblotting showing that FGF-23 or Klotho alone have no effect on kinase activity in PTEC or FHs74Int cells. Combined effects of FGF-23 and Klotho show increased phosphorylation of ERK1/2, p38, JNK, AKT, IκB, and GSK-3β. α-Tubulin was used as a loading control.

Mentions: To investigate the role of FGF-23 and Klotho in regulation of systemic vitamin D and tissue atrophy, we first performed protein analyses by immunoblotting. We found that exposure of renal PTEC or small intestine epithelial cells (FHs74Int) to exogenous FGF-23 or Klotho alone had minimal effects on protein phosphorylation of ERK1/2, p38, JNK, AKT, inhibitor κB (IκB), and GSK-3β (glycogen synthase kinase-3β) compared with control (vehicle treated) cells. However, exposure to both FGF-23 and Klotho caused significant up-regulations in phosphorylation of all of these proteins (Fig. 1). These data were confirmed by multiplex ELISA, which also showed increases in CREB (cAMP response element binding), p70S6K, and STAT3 (signal transducer and activator of transcription 3) phosphorylation by FGF-23–Klotho. Addition of a small molecule Ras inhibitor before FGF-23 and Klotho treatment prevented increased phosphorylation of CREB, ERK1/2, JNK, p38, p70S6K, and STAT3. Addition of a small molecule inhibitor against phosphoinositide-3 kinase (PI3K) prevented increased phosphorylation of IκB, p70S6K, AKT, and GSK-3β. Combined effects of both Ras and PI3K inhibitors lowered all FGF-23–Klotho-induced phosphorylations to background levels (Fig. S1, A and B, available at http://www.jcb.org/cgi/content/full/jcb.200803024/DC1).


FGF-23-Klotho signaling stimulates proliferation and prevents vitamin D-induced apoptosis.

Medici D, Razzaque MS, Deluca S, Rector TL, Hou B, Kang K, Goetz R, Mohammadi M, Kuro-O M, Olsen BR, Lanske B - J. Cell Biol. (2008)

Signaling events induced by FGF-23–Klotho. Immunoblotting showing that FGF-23 or Klotho alone have no effect on kinase activity in PTEC or FHs74Int cells. Combined effects of FGF-23 and Klotho show increased phosphorylation of ERK1/2, p38, JNK, AKT, IκB, and GSK-3β. α-Tubulin was used as a loading control.
© Copyright Policy
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2500132&req=5

fig1: Signaling events induced by FGF-23–Klotho. Immunoblotting showing that FGF-23 or Klotho alone have no effect on kinase activity in PTEC or FHs74Int cells. Combined effects of FGF-23 and Klotho show increased phosphorylation of ERK1/2, p38, JNK, AKT, IκB, and GSK-3β. α-Tubulin was used as a loading control.
Mentions: To investigate the role of FGF-23 and Klotho in regulation of systemic vitamin D and tissue atrophy, we first performed protein analyses by immunoblotting. We found that exposure of renal PTEC or small intestine epithelial cells (FHs74Int) to exogenous FGF-23 or Klotho alone had minimal effects on protein phosphorylation of ERK1/2, p38, JNK, AKT, inhibitor κB (IκB), and GSK-3β (glycogen synthase kinase-3β) compared with control (vehicle treated) cells. However, exposure to both FGF-23 and Klotho caused significant up-regulations in phosphorylation of all of these proteins (Fig. 1). These data were confirmed by multiplex ELISA, which also showed increases in CREB (cAMP response element binding), p70S6K, and STAT3 (signal transducer and activator of transcription 3) phosphorylation by FGF-23–Klotho. Addition of a small molecule Ras inhibitor before FGF-23 and Klotho treatment prevented increased phosphorylation of CREB, ERK1/2, JNK, p38, p70S6K, and STAT3. Addition of a small molecule inhibitor against phosphoinositide-3 kinase (PI3K) prevented increased phosphorylation of IκB, p70S6K, AKT, and GSK-3β. Combined effects of both Ras and PI3K inhibitors lowered all FGF-23–Klotho-induced phosphorylations to background levels (Fig. S1, A and B, available at http://www.jcb.org/cgi/content/full/jcb.200803024/DC1).

Bottom Line: Fibroblast growth factor 23 (FGF-23) and Klotho are secretory proteins that regulate mineral-ion metabolism.Because serum levels of active vitamin D are greatly increased upon genetic ablation of Fgf-23 or Klotho, we find that these molecules have a dual role in suppression of apoptotic actions of vitamin D through both negative regulation of 1alpha-hydroxylase expression and phosphoinositide-3 kinase-dependent inhibition of caspase activity.These data provide new insights into the physiological roles of FGF-23 and Klotho.

View Article: PubMed Central - PubMed

Affiliation: Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115, USA.

ABSTRACT
Fibroblast growth factor 23 (FGF-23) and Klotho are secretory proteins that regulate mineral-ion metabolism. Fgf-23(-/-) or Klotho(-/-) knockout mice exhibit several pathophysiological processes consistent with premature aging including severe atrophy of tissues. We show that the signal transduction pathways initiated by FGF-23-Klotho prevent tissue atrophy by stimulating proliferation and preventing apoptosis caused by excessive systemic vitamin D. Because serum levels of active vitamin D are greatly increased upon genetic ablation of Fgf-23 or Klotho, we find that these molecules have a dual role in suppression of apoptotic actions of vitamin D through both negative regulation of 1alpha-hydroxylase expression and phosphoinositide-3 kinase-dependent inhibition of caspase activity. These data provide new insights into the physiological roles of FGF-23 and Klotho.

Show MeSH
Related in: MedlinePlus