Changes in expression of klotho affect physiological processes, diseases, and cancer

Abstract

<em>Klotho (KL)</em> encodes a single-pass transmembrane protein and is predominantly expressed in the kidney, parathyroid glands, and choroid plexus. Genetic studies on the <em>KL </em>gene have revealed that DNA hypermethylation is one of the major risk factors for aging, diseases, and cancer. Besides, KL exerts anti-inflammatory and anti-tumor effects by regulating signaling pathways and the expression of target genes. KL participates in modulation of the insulin/insulin-like growth factor-1 (IGF-1) signaling, which induces the growth hormone (GH) secretion. Accordingly, <em>KL</em> mutant mice display multiple aging-like phenotypes, which are ameliorated by overexpression of KL. Therefore, KL is an important contributor to lifespan. KL is further identified as a regulator of calcium (Ca²⁺) channel-dependent cell physiological processes. KL has been also shown to induce cancer cell apoptosis, thus, it is considered as a potential tumor suppressor. Our recent studies have indicated that KL modulates an influx of Ca²⁺ from the extracellular space, leading to a change in CCL21-dependent migration in dendritic cells (DCs). Interestingly, the regulation of the expression of KL was mediated through a phosphoinositide 3-kinase (PI3K) pathway in DCs. Moreover, downregulating of KL expression by using siRNA knockdown technique, we observed that the expression of Ca²⁺channels including Orai3, but not Orai1, Orai2, TRPV5 and TRPV6 was significantly reduced in <em>KL</em>-silenced as compared to control BMDCs. Clearly, additional research is required to define the role of KL in the regulation of organismic and cellular functions through the PI3K signaling and the expression of the Ca²⁺channels.