The elongation of primary cilia via the acetylation of α-tubulin by the treatment with lithium chloride in human fibroblast KD cells

Nakakura, Takashi; Asano-Hoshino, Anshin; Suzuki, Takeshi; Arisawa, Kenjiro; Tanaka, Hideyuki; Sekino, Yoshihisa; Kiuchi, Yoshiko; Kawai, Kazuhiro; Hagiwara, Haruo

doi:10.1007/s00795-014-0076-x

Cited by 50 publications

(38 citation statements)

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“…Nakakura et al (14) reported that in fibroblasts, LiCl‐mediated inhibition of GSK releases an inhibitory block on the enzyme α‐tubulin acetyl transferase 1, causing a dramatic increase in whole‐cell acetylated tubulin levels and an increase in cilia length. Immunocytochemistry revealed that the distribution of acetylated tubulin was altered in chondrocytes treated with 50 mM LiCl ( Fig .…”

Section: Resultsmentioning

confidence: 99%

“…Cilia assembly and disassembly is initiated at the distal tip; IFT is thus essential to maintain the size of the ciliary compartment (29). Studies have shown that LiCl promotes significant elongation of the ciliary axoneme in fibroblasts (14, 15) and neuronal cells (13); however, the consequences of this elongation for cilia‐mediated signaling pathways has not been explored.…”

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confidence: 99%

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Lithium chloride modulates chondrocyte primary cilia and inhibits Hedgehog signaling

et al. 2015

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Lithium chloride (LiCl) exhibits significant therapeutic potential as a treatment for osteoarthritis. Hedgehog signaling is activated in osteoarthritis, where it promotes chondrocyte hypertrophy and cartilage matrix catabolism. Hedgehog signaling requires the primary cilium such that maintenance of this compartment is essential for pathway activity. Here we report that LiCl (50 mM) inhibits Hedgehog signaling in bovine articular chondrocytes such that the induction of GLI1 and PTCH1 expression is reduced by 71 and 55%, respectively. Pathway inhibition is associated with a 97% increase in primary cilia length from 2.09 ± 0.7 μm in untreated cells to 4.06 ± 0.9 μm in LiCl-treated cells. We show that cilia elongation disrupts trafficking within the axoneme with a 38% reduction in Arl13b ciliary localization at the distal region of the cilium, consistent with the role of Arl13b in modulating Hedgehog signaling. In addition, we demonstrate similar increases in cilia length in human chondrocytes in vitro and after administration of dietary lithium to Wistar rats in vivo. Our data provide new insights into the effects of LiCl on chondrocyte primary cilia and Hedgehog signaling and shows for the first time that pharmaceutical targeting of the primary cilium may have therapeutic benefits in the treatment of osteoarthritis.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

Lithium chloride modulates chondrocyte primary cilia and inhibits Hedgehog signaling

et al. 2015

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Section: Tubulin Acetylation and Ciliamentioning

confidence: 99%

“…Treatment of human KD diploid fibroblasts with 25-50 mM LiCl promotes a-tubulin acetylation and elongation of primary cilia [137]. siRNA-mediated depletion of ATAT1 expression showed that this enzyme is required for induced a-tubulin acetylation in these cells [137]. Similar depletion of ATAT1 expression in human telomerase-expressing retinal pigment epithelial cells slows down the kinetics of ciliary disassembly [48].…”

Section: Tubulin Acetylation and Ciliamentioning

confidence: 99%

Tubulin acetylation: responsible enzymes, biological functions and human diseases

Yang

2015

Cell. Mol. Life Sci.

222

184

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Microtubules have important functions ranging from maintenance of cell morphology to subcellular transport, cellular signaling, cell migration, and formation of cell polarity. At the organismal level, microtubules are crucial for various biological processes, such as viral entry, inflammation, immunity, learning and memory in mammals. Microtubules are subject to various covalent modifications. One such modification is tubulin acetylation, which is associated with stable microtubules and conserved from protists to humans. In the past three decades, this reversible modification has been studied extensively. In mammals, its level is mainly governed by opposing actions of α-tubulin acetyltransferase 1 (ATAT1) and histone deacetylase 6 (HDAC6). Knockout studies of the mouse enzymes have yielded new insights into biological functions of tubulin acetylation. Abnormal levels of this modification are linked to neurological disorders, cancer, heart diseases and other pathological conditions, thereby yielding important therapeutic implications. This review summarizes related studies and concludes that tubulin acetylation is important for regulating microtubule architecture and maintaining microtubule integrity. Together with detyrosination, glutamylation and other modifications, tubulin acetylation may form a unique 'language' to regulate microtubule structure and function.

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“…Immunofluorescence methods were performed as described previously [13, 15]. Briefly, LβT2 cells and AtT20 cells were transfected with pCMV-Gluc 2 or pcDNA3.1 as described above and cultured on poly-D-lysine-coated cover glass.…”

Section: Methodsmentioning

confidence: 99%

Easy detection of hormone secretion from LβT2 cells by using Gaussia luciferase

Satou

Mochimaru

Nakakura

et al. 2017

Journal of Reproduction and Development

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Reproduction is regulated by gonadotropins secreted from gonadotrophs. The production and secretion of gonadotropins are mainly regulated by gonadotropin-releasing hormone (GnRH). Agonists or antagonists that influence GnRH action on gonadotrophs are important to regulate reproduction; however, these factors have not been fully characterized due to the lack of simple and easy-to-use techniques to detect gonadotropin secretion from gonadotropin-producing cells. In the present study, we found that Gaussia luciferase (Gluc), which was expressed in LβT2 cells, can be secreted like a luteinizing-hormone (LH) upon stimulation with GnRH. The Gluc secreted into the medium was easily monitored as luminescence signals. The detection range of the GnRH-induced Gluc activity was comparable to that of the enzyme-linked immunosorbent assay for LH. In addition, when the Gluc was expressed in AtT20 cells, which produce adrenocorticotropic hormone (ACTH), the Gluc activity in the medium increased in parallel with the ACTH secretion upon stimulation with corticotropin-releasing hormone. Thus, the Gluc assay in the present study can be easily used for high-throughput screening of factors that influence LH or ACTH secretion from LβT2 or AtT20 cells, respectively.

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The elongation of primary cilia via the acetylation of α-tubulin by the treatment with lithium chloride in human fibroblast KD cells

Cited by 50 publications

References 50 publications

Lithium chloride modulates chondrocyte primary cilia and inhibits Hedgehog signaling

Lithium chloride modulates chondrocyte primary cilia and inhibits Hedgehog signaling

Tubulin acetylation: responsible enzymes, biological functions and human diseases

Easy detection of hormone secretion from LβT2 cells by using Gaussia luciferase

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