Molecular cloning and expression analyses of mouse βklotho, which encodes a novel Klotho family protein

Ito, Shinji; Kinoshita, Shigeyoshi; Shiraishi, Norihiko; Nakagawa, Satoshi; Sekine, Susumu; Fujimori, Toshihiko; Nabeshima, Yo‐ichi

doi:10.1016/s0925-4773(00)00439-1

Cited by 277 publications

(229 citation statements)

References 12 publications

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“…Mice homozygous for a mutated klotho allele exhibit a syndrome resembling human aging and suffer from osteoporosis, atherosclerosis and a short lifespan, whereas klotho overexpression extends lifespan and is associated with reduced fertility and insulin resistance (Kuro-o et al, 1997;Kurosu et al, 2005). Klotho is a 1014-amino-acid single pass transmembrane protein that is located at the cell membrane (Kuro-o et al, 1997;Matsumura et al, 1998;Shiraki-Iida et al, 1998;Ito et al, 2000) and is also detected in the Golgi apparatus (Imura et al, 2007). The extracellular domain of klotho is composed of two internal repeats, KL1 and KL2, that share amino-acid sequence homology to b-glucosidase but lack glucosidase catalytic activity (Kuro-o et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Klotho: a tumor suppressor and a modulator of the IGF-1 and FGF pathways in human breast cancer

et al. 2008

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Klotho is an anti-aging gene, which has been shown to inhibit the insulin and insulin-like growth factor 1 (IGF-1) pathways in mice hepatocytes and myocytes. As IGF-1 and insulin regulate proliferation, survival and metastasis of breast cancer, we studied klotho expression and activities in human breast cancer. Immunohistochemistry analysis of klotho expression in breast tissue arrays revealed high klotho expression in normal breast samples, but very low expression in breast cancer. In cancer samples, high klotho expression was associated with smaller tumor size and reduced KI67 staining. Forced expression of klotho reduced proliferation of MCF-7 and MDA-MB-231 breast cancer cells, whereas klotho silencing in MCF-7 cells, which normally express klotho, enhanced proliferation. Moreover, forced expression of klotho in these cells, or treatment with soluble klotho, inhibited the activation of IGF-1 and insulin pathways, and induced upregulation of the transcription factor CCAAT/enhancer-binding protein b, a breast cancer growth inhibitor that is negatively regulated by the IGF-1-AKT axis. Co-immunoprecipitation revealed an interaction between klotho and the IGF-1 receptor. Klotho is also a known modulator of the fibroblast growth factor (FGF) pathway, a pathway that inhibits proliferation of breast cancer cells. Studies in breast cancer cells revealed increased activation of the FGF pathway by basic FGF following klotho overexpression. Klotho did not affect activation of the epidermal growth factor pathway in breast cancer cells. These data suggest klotho as a potential tumor suppressor and identify it as an inhibitor of the IGF-1 pathway and activator of the FGF pathway in human breast cancer.

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Section: Introductionmentioning

confidence: 99%

Klotho: a tumor suppressor and a modulator of the IGF-1 and FGF pathways in human breast cancer

et al. 2008

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“…1,2 aKlotho has extremely pleiotropic effects on multiple organs and is involved in many physiologic processes. 3,4 Two other paralogs that share homology to aKlotho, are bKlotho, 5 and Klotho/lactase-phlorizin hydrolaserelated protein (Klph); also called gKlotho. 6 Both a-and b-Klotho function as co-receptors of different fibroblast growth factor (FGF) isoforms and serve distinct biologic actions.…”

mentioning

confidence: 99%

“…4,[7][8][9] aKlotho is a type-I single-pass transmembrane protein with a long extracellular region harboring b-glucosidase-like motifs called Kl domains. 1,5,6,10 aKlotho expression is restricted to a few organs including the kidney, 1 parathyroid glands, 11 and sinoatrial node 12 where it forms tetrameric complexes with FGFR1c, 3c, or 4 (2Klotho:2FGFR), and serves as the high-affinity receptor for circulating FGF23 to regulate mineral metabolism. 4,[13][14][15] bKlotho is expressed in the liver and fat and forms complexes with FGFR1c or 4 to support FGF15/19 and FGF21 signaling.…”

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confidence: 99%

Renal Production, Uptake, and Handling of Circulating αKlotho

Shi

Zhang³

et al. 2016

Journal of the American Society of Nephrology

211

232

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ABSTRACTaKlotho is a multifunctional protein highly expressed in the kidney. Soluble aKlotho is released through cleavage of the extracellular domain from membrane aKlotho by secretases to function as an endocrine/paracrine substance. The role of the kidney in circulating aKlotho production and handling is incompletely understood, however. Here, we found higher aKlotho concentration in suprarenal compared with infrarenal inferior vena cava in both rats and humans. In rats, serum aKlotho concentration dropped precipitously after bilateral nephrectomy or upon treatment with inhibitors of aKlotho extracellular domain shedding. Furthermore, the serum half-life of exogenous aKlotho in anephric rats was four-to five-fold longer than that in normal rats, and exogenously injected labeled recombinant aKlotho was detected in the kidney and in urine of rats. Both in vivo (micropuncture) and in vitro (proximal tubule cell line) studies showed that aKlotho traffics from the basal to the apical side of the proximal tubule via transcytosis. Thus, we conclude that the kidney has dual roles in aKlotho homeostasis, producing and releasing aKlotho into the circulation and clearing aKlotho from the blood into the urinary lumen.

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“…Although FGF19 binds only to FGFR4, the liver-specific activity of FGF19 cannot be explained solely by the distribution of this receptor because of its wide tissue expression. Klotho beta (KLB) encodes a 130-kDa type 1 transmembrane protein with a short (29 amino acids) intracellular domain that has no predicted kinase activity (13). KLB has two extracellular glycosidase domains that lack a characteristic glutamic acid residue essential for enzymatic activity.…”

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Liver-specific Activities of FGF19 Require Klotho beta

Lin

Wang

Blackmore

et al. 2007

Journal of Biological Chemistry

247

230

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Hepatocyte function is regulated by members of the fibroblast growth factor (FGF) family of proteins, but little is known about the specific molecular mechanisms of this endocrine pathway. FGF19 regulates bile acid homeostasis and gall bladder filling; FGF19 binds only to FGF receptor 4 (FGFR4), but its liver-specific activity cannot be explained solely by the distribution of this receptor. Although it has been suggested that Klotho beta (KLB) may have a role in mediating FGF19 activity, we have provided for the first time definitive evidence that KLB is required for FGF19 binding to FGFR4, intracellular signaling, and downstream modulation of gene expression. We have shown that FGFR4 is widely distributed in mouse, whereas KLB distribution is more restricted. Liver was the only organ in which both genes were abundantly expressed. We show that in mice, FGF19 injection triggers liver-specific induction of c-Fos and repression of CYP7A1. The tissue-specific activity of FGF19 supports the unique intersection of KLB and FGFR4 distribution in liver. These studies define KLB as a novel FGFR4 coreceptor required for FGF19 liver specific functions.Bile acids are amphipathic cholesterol metabolites essential for the absorption of lipophilic nutrients and cholesterol homeostasis (1). They are synthesized by the liver and stored in the gall bladder (2). The cycle of gallbladder filling and emptying controls the flow of bile into the intestine for digestion. Because bile acid accumulation can lead to hepatotoxicity and cholestasis, this process is tightly regulated (3) by a negative feedback mechanism. Bile acids bind to the farnesoid X receptor, a member of the nuclear receptor family of ligand-regulated transcription factors, which is highly expressed in liver and intestine. In the liver, farnesoid X receptor activation represses the transcription of cholesterol 7␣-hydroxylase (CYP7A1), 2 a rate-limiting enzyme in the biosynthesis of bile acids (4, 5). In the small intestine, bile acid activation of farnesoid X receptor induces the expression of fibroblast growth factor 15 (FGF15; mouse orthologue of human FGF19). The secreted FGF15 signals from the intestine to the liver to repress CYP7A1 expression through a FGF receptor 4 (FGFR4)-mediated mechanism (6). In addition, the FGF15/FGF19 feedback loop prevents bile excretion into the digestive tract by promoting gallbladder filling (7).The role of FGF15/FGF19 in bile acid homeostasis is supported by the increased liver CYP7A1 expression and decreased gallbladder volume that occurs in FGF15-deficient mice (FGF15 Ϫ/Ϫ mice) and in FGFR4-deficient mice (FGFR4

show abstract

Molecular cloning and expression analyses of mouse βklotho, which encodes a novel Klotho family protein

Cited by 277 publications

References 12 publications

Klotho: a tumor suppressor and a modulator of the IGF-1 and FGF pathways in human breast cancer

Klotho: a tumor suppressor and a modulator of the IGF-1 and FGF pathways in human breast cancer

Renal Production, Uptake, and Handling of Circulating αKlotho

Liver-specific Activities of FGF19 Require Klotho beta

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