α-Klotho as a Regulator of Calcium Homeostasis

Imura, Akihiro; Tsuji, Yoshihito; Murata, Miyahiko; Maeda, Ryota; Koyama, Koji; Iwano, Akiko; Obuse, Chikashi; Togashi, Katsumi; Tominaga, Makoto; Kita, Naoko; Tomiyama, Katsunori; Iijima, Junko; Nabeshima, Yoko; Fujioka, Makio; Asato, Ryo; Tanaka, Shinzo; Kojima, Ken; Ito, Juichi; Nozaki, Kazuhiko; Hashimoto, Nobuo; Ito, Tetsufumi; Nishio, Takeshi; Uchiyama, Takashi; Fujimori, Toshihiko; Nabeshima, Yo‐ichi

doi:10.1126/science.1135901

Cited by 369 publications

(330 citation statements)

References 26 publications

Supporting

Mentioning

309

Contrasting

Unclassified

Order By: Relevance

“…Klotho is a type I transmembrane protein that localizes at the plasma membrane, as well as in the cytoplasm, where it dimerizes with Na þ K þ -ATPase in the Golgi apparatus (Imura et al, 2007). In accordance with these data, our immunostaining analysis revealed klotho expression both in the plasma membrane and in the cytoplasm.…”

Section: Klotho In Breast Cancer I Wolf Et Alsupporting

confidence: 75%

“…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%

See 1 more Smart Citation

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

et al. 2008

View full text Add to dashboard Cite

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.

show abstract

Section: Klotho In Breast Cancer I Wolf Et Alsupporting

confidence: 75%

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

View full text Add to dashboard Cite

show abstract

“…Klothodeficient mice manifest a syndrome resembling human aging, whereas overexpression of klotho extends lifespan (1,4). Major physiologic activities of klotho include regulation of phosphate and calcium homeostasis as well as of metabolic activity (5)(6)(7). To date, several mechanisms of action of klotho have been described.…”

Section: Introductionmentioning

confidence: 99%

Tumor Suppressor Activity of Klotho in Breast Cancer Is Revealed by Structure–Function Analysis

Ligumsky

Rubinek

Merenbakh-Lamin

et al. 2015

Molecular Cancer Research

View full text Add to dashboard Cite

Klotho is a transmembrane protein containing two internal repeats, KL1 and KL2, both displaying significant homology to members of the b-glycosidase family. Klotho is expressed in the kidney, brain, and various endocrine tissues, but can also be cleaved and act as a circulating hormone. Klotho is an essential cofactor for binding of fibroblast growth factor 23 (FGF23) to the FGF receptor and can also inhibit the insulin-like growth factor-1 (IGF-1) pathway. Data from a wide array of malignancies indicate klotho as a tumor suppressor; however, the structure-function relationships governing its tumor suppressor activities have not been deciphered. Here, the tumor suppressor activities of the KL1 and KL2 domains were examined. Overexpression of either klotho or KL1, but not of KL2, inhibited colony formation by MCF-7 and MDA-MB-231 cells. Moreover, in vivo administration of KL1 was not only well tolerated but significantly slowed tumor formation in nude mice. Further studies indicated that KL1, but not KL2, interacted with the IGF-1R and inhibited the IGF-1 pathway. Based on computerized structural modeling, klotho constructs were generated in which critical amino acids have been mutated. Interestingly, the mutated proteins retained their tumor suppressor activity but showed reduced ability to modulate FGF23 signaling. These data indicate differential activity of the klotho domains, KL1 and KL2, in breast cancer and reveal that the tumor suppressor activities of klotho can be dissected from its physiologic activities.Implications: These findings pave the way for a rational design of safe klotho-based molecules for the treatment of breast cancer.

show abstract

“…Membrane-bound Klotho serves as a coreceptor for fibroblast growth factor 23 (FGF23) [5,6] and thus has an important role in the renal effects of FGF23 on phosphate transport and calcitriol production. Soluble Klotho (sKlotho) inhibits insulin ⁄ insulin-like growth factor 1 (IGF-1) signalling and regulates calcium homoeostasis [7,8]. A sandwich enzyme-linked immunosorbent assay (ELISA) to measure sKlotho has become available recently [9].…”

Section: Introductionmentioning

confidence: 99%

Excessively high soluble Klotho in patients with acromegaly

Sze

Bernays

Zwimpfer³

et al. 2012

Journal of Internal Medicine

View full text Add to dashboard Cite

Objectives. Klotho-deficient mice develop a syndrome resembling accelerated ageing, and genetic variants of Klotho have been associated with human ageing. In humans, serum levels of soluble Klotho decrease with age and with chronic renal failure. The aim of our study was to examine the relationship between excess growth hormone (GH) and serum levels of Klotho in patients with acromegaly, a disease usually caused by a pituitary adenoma, which is associated with high phosphate levels and reduced life expectancy.Patients and design. We determined the levels of soluble Klotho, GH and insulin-like growth factor 1 (IGF-1) in serum samples from 24 consecutive patients with acromegaly (nine women ⁄ 15 men, age 28-76 years) before and after transsphenoidal surgery.Results. Soluble Klotho levels were excessively high at baseline (mean ± SEM, 4.2 ± 0.7 ng mL )1 ) and correlated with GH (r = 0.64), IGF-1 (r = 0.57) and tumour size (r = 0.5). In multiple regression analysis, soluble Klotho was associated with GH after correction for age, gender and levels of creatinine and phosphate (P = 0.029). After surgery, GH and IGF-1 levels decreased in all patients (from 26.3 ± 5.2 to 2.6 ± 0.6 lg L )1 , P < 0.0001, and from 588 ± 35 to 193 ± 12 lg L )1 , P < 0.001, 0.0001, respectively). Creatinine increased from 71 ± 3 to 80 ± 3 lmol L )1 (P < 0.001), and phosphate decreased from 1.37 ± 0.04 to 1.06 ± 0.02 mmol L )1 (P < 0.001). The markedly increased preoperative levels of soluble Klotho returned towards normal after surgery (0.7 ± 0.1 ng mL )1 , P < 0.0001).Conclusions. This is the first study to show dramatically increased soluble Klotho levels in an acquired disease in humans. Reversal following tumour removal suggests a causal relation between the GH-producing adenoma and high serum Klotho concentration in acromegaly.

show abstract

α-Klotho as a Regulator of Calcium Homeostasis

Cited by 369 publications

References 26 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

Tumor Suppressor Activity of Klotho in Breast Cancer Is Revealed by Structure–Function Analysis

Excessively high soluble Klotho in patients with acromegaly

Contact Info

Product

Resources

About