MPHOSPH1: A Potential Therapeutic Target for Hepatocellular Carcinoma

Liu, Xinran; Zhou, Yafan; Liu, Xinyuan; Peng, Anlin; Gong, Hao; Huang, Lizi; Ji, Kaige; Petersen, Robert B.; Zheng, Ling; Huang, Kun

doi:10.1158/0008-5472.can-14-1279

Cited by 43 publications

(51 citation statements)

References 37 publications

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“…Since the Kif20b mouse mutant is a novel model for human microcephaly, it is important to know that there could be defects in connectivity in addition to the small brain size in some cases of microcephaly. Finally, KIF20B is elevated in several cancers [6, 32, 33], and while that could be due to its role in cell division, our data suggest it could also be due to effects on cell motility and morphology that could enhance metastasis.…”

Section: Discussionmentioning

confidence: 72%

Mutation of Kinesin-6 Kif20b causes defects in cortical neuron polarization and morphogenesis

et al. 2017

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BackgroundHow neurons change their cytoskeleton to adopt their complex polarized morphology is still not understood. Growing evidence suggests that proteins that help build microtubule structures during cell division are also involved in building and remodeling the complex cytoskeletons of neurons. Kif20b (previously called MPP1 or Mphosph1) is the most divergent member of the Kinesin-6 family of “mitotic” kinesins that also includes Kif23/MKLP1 and Kif20a/MKLP2. We previously isolated a loss-of-function mouse mutant of Kif20b and showed that it had a thalamocortical axon guidance defect and microcephaly.MethodsWe demonstrate here, using the mouse mutant, that Kif20b is required for neuron morphogenesis in the embryonic neocortex. In vivo and in vitro cortical neurons were labeled and imaged to analyze various aspects of morphogenesis.ResultsLoss of Kif20b disrupts polarization as well as neurite outgrowth, branching and caliber. In vivo, mutant cortical neurons show defects in orientation, and have shorter thinner apical dendrites that branch closer to the cell body. In vitro, without external polarity cues, Kif20b mutant neurons show a strong polarization defect. This may be due in part to loss of the polarity protein Shootin1 from the axonal growth cone. Those mutant neurons that do succeed in polarizing have shorter axons with more branches, and longer minor neurites. These changes in shape are not due to alterations in cell fate or neuron layer type. Surprisingly, both axons and minor neurites of mutant neurons have increased widths and longer growth cone filopodia, which correlate with abnormal microtubule organization. Live analysis of axon extension shows that Kif20b mutant axons display more variable growth with increased retraction.ConclusionsThese results demonstrate that Kif20b is required cell-autonomously for proper morphogenesis of cortical pyramidal neurons. Kif20b regulates neuron polarization, and axon and dendrite branching, outgrowth, and caliber. Kif20b protein may act by bundling microtubules into tight arrays and by localizing effectors such as Shootin1. Thus it may help shape neurites, sustain consistent axon growth, and inhibit branching. This work advances our understanding of how neurons regulate their cytoskeleton to build their elaborate shapes. Finally, it suggests that neuronal connectivity defects may be present in some types of microcephaly.Electronic supplementary materialThe online version of this article (doi:10.1186/s13064-017-0082-5) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 72%

Mutation of Kinesin-6 Kif20b causes defects in cortical neuron polarization and morphogenesis

et al. 2017

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“…RNA was extracted from cultured cells using RNAiso Plus (Takara Biotechnology, Dalian, China) as reported previously (Liu et al . ). cDNA synthesis was performed using the M‐MLV First Stand Kit (Invitrogen, Carlsbad, CA, USA).…”

Section: Methodsmentioning

confidence: 97%

Histone demethylase UTX is a therapeutic target for diabetic kidney disease

Hong

Huang

Xiu-qin

et al. 2018

The Journal of Physiology

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Key points Diabetic kidney disease (DKD) is a major complication of diabetes. We found that UTX (ubiquitously transcribed tetratricopeptide repeat on chromosome X, also known as KDM6A), a histone demethylase, was upregulated in the renal mesangial and tubular cells of diabetic mice and DKD patients. In cultured renal mesangial and tubular cells, UTX overexpression promoted palmitic acid‐induced elevation of inflammation and DNA damage, whereas UTX knockdown or GSK‐J4 treatment showed the opposite effects. We found that UTX demethylase activity‐dependently regulated the transcription of inflammatory genes and apoptosis; moreover, UTX bound with p53 and p53‐dependently exacerbated DNA damage. Administration of GSK‐J4, an H3K27 demethylase inhibitor, ameliorated the diabetes‐induced renal abnormalities in db/db mice, an animal model of type 2 diabetes. These results revealed the possible mechanisms underlying the regulation of histone methylation in DKD and suggest UTX as a potential therapeutic target for DKD. Abstract Diabetic kidney disease (DKD) is a microvascular complication of diabetes and the leading cause of end‐stage kidney disease worldwide without effective therapy available. UTX (ubiquitously transcribed tetratricopeptide repeat on chromosome X, also known as KDM6A), a histone demethylase that removes the di‐ and tri‐methyl groups from histone H3K27, plays important biological roles in gene activation, cell fate control and life span regulation in Caenorhabditis elegans. In the present study, we report upregulated UTX in the kidneys of diabetic mice and DKD patients. Administration of GSK‐J4, an H3K27 demethylase inhibitor, ameliorated the diabetes‐induced renal dysfunction, abnormal morphology, inflammation, apoptosis and DNA damage in db/db mice, comprising an animal model of type 2 diabetes. In cultured renal mesanglial and tubular cells, UTX overexpression promoted palmitic acid induced elevation of inflammation and DNA damage, whereas UTX knockdown or GSK‐J4 treatment showed the opposite effects. Mechanistically, we found that UTX demethylase activity‐dependently regulated the transcription of inflammatory genes; moreover, UTX bound with p53 and p53‐dependently exacerbated DNA damage. Collectively, our results suggest UTX as a potential therapeutic target for DKD.

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“…A total of 2 × 10 6 cells for each group were injected subcutaneously into the flanks of 6‐week‐old BALB/c nude mice. Tumor volume was measured and calculated as reported previously . For BIX01294 treatment, 10 days after the nude mice developed GAPDH‐ or control empty vector (CT)‐induced tumors, BIX01294 (Targetmol, Boston, MA) was injected either subcutaneously at 25 mg/kg each frank or intraperitoneally at 50 mg/kg, once a day for 3 days.…”

Section: Methodsmentioning

confidence: 99%