Oncogenic Role of MPHOSPH1, a Cancer-Testis Antigen Specific to Human Bladder Cancer

Kanehira, Mitsugu; Katagiri, Toyomasa; Shimo, Arata; Takata, Ryo; Shuin, Taro; Miki, Tsuneharu; Fujioka, Tomoaki; Nakamura, Yusuke

doi:10.1158/0008-5472.can-06-3748

Cited by 101 publications

(103 citation statements)

References 30 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: 71%

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: 71%

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

et al. 2017

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“…As a critical protein of cytokinesis, dysregulated expression of PRC1 gives rise to disorder of cytokinesis. The previous studies [8, 9, 11, 13] have implicated that PRC1 as an oncogenic factor in tumorigenesis of breast, bladder cancer, hepatocellular carcinoma and gastric carcinoma. Herein, we demonstrated that both mRNA and protein expressions of PRC1 were upregulated in lung adenocarcinoma tissues compared with adjacent normal lung tissues.…”

Section: Discussionmentioning

confidence: 99%

“…It has already been documented that PRC1 is overexpressed in different cancers, such as breast cancer [8], bladder cancer [9], hepatocellular carcinoma [10, 11], and pancreatic cancer [12]. An in vitro study showed that knockdown of PRC1 by using siRNA significantly inhibited the proliferation of breast and bladder cancer cells [8, 9].…”

Section: Introductionmentioning

confidence: 99%

“…An in vitro study showed that knockdown of PRC1 by using siRNA significantly inhibited the proliferation of breast and bladder cancer cells [8, 9]. Recently, Chen et al found that PRC1 had an oncogenic function in promoting cancer proliferation, metastasis and tumorigenesis of hepatocellular carcinoma through a positive feedback loop of the Wnt signaling pathway [11].…”

Section: Introductionmentioning

confidence: 99%

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PRC1 contributes to tumorigenesis of lung adenocarcinoma in association with the Wnt/β-catenin signaling pathway

Zhan

Zhang

et al. 2017

Mol Cancer

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BackgroundProtein regulator of cytokinesis-1 (PRC1) belongs to the microtubule-associated proteins (MAPs) family, and is involved in cytokinesis. Recent investigations suggest PRC1 involvement in human carcinogenesis, including breast carcinoma, hepatocellular carcinoma and etc. However, whether PRC1 contributes to lung adenocarcinoma tumorigenesis remains unknown.MethodsQuantitative reverse-transcription polymerase chain reaction (qRT-PCR), Western blotting and Immunohistochemical staining (IHC) were used to evaluate and contrast the PRC1 expression profile in lung adenocarcinoma and adjacent normal lung tissues. We examined the clinical use of PRC1 in lung adenocarcinoma prognosis. Additionally, the tumorigenesis impact of PRC1 in lung adenocarcinoma cells was verified via in vitro and in vivo metastasis and tumorigenesis assays. Notably, Next Generation Sequencing (NGS) was performed to investigate the molecular mechanism underlying the oncogenic role of PRC1 in lung adenocarcinoma.ResultsPRC1 mRNA and protein expressions were upregulated in lung adenocarcinoma tissues compared to adjacent normal lung tissues. PRC1 protein overexpression correlated with lymph node metastasis and was an independent poor prognostic factor for lung adenocarcinoma patients. Our data implied that PRC1 depletion limited the proliferation and invasion of lung adenocarcinoma cells in vitro and lowered tumor development and lung metastasis in vivo. Remarkably, limiting PRC1 substantially prompted G2/M phase cell cycle arrest and apoptosis. Mechanistically, by conducting NGS on PRC1-depleted A549 cells and control cells, we discovered that PRC1 expression was significantly correlated with the Wnt signaling pathway.ConclusionsThis investigation offers confirmation that PRC1 is a prognostic and promising therapeutic biomarker for people with lung adenocarcinoma and takes on a key part in the activation of the Wnt/β-catenin pathway in lung adenocarcinoma development.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-017-0682-z) contains supplementary material, which is available to authorized users.

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“…10 The mRNA of MPP1 has been shown to be significantly upregulated in bladder cancer (and in a variety of bladder cancer tumor cell lines) as well as large B cell lymphoma. 9,11 In total, MPP1's interaction with PRC1 and its subsequent implication in bladder carcinogenesis make MPP1 a potential target for bladder cancer drug development. 12 2-Phenylquinoxalines 13 have been reported as small-molecule inhibitors of MPP1, but the patent has subsequently been withdrawn.…”

Section: * S Supporting Informationmentioning

confidence: 99%

Depsidones from Lichens as Natural Product Inhibitors of M-Phase Phosphoprotein 1, a Human Kinesin Required for Cytokinesis

et al. 2016

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M-Phase Phosphoprotein 1 (MPP1), a microtubule plus end directed kinesin, is required for the completion of cytokinesis. Previous studies have shown that MPP1 is upregulated in various types of bladder cancer. This article describes inhibitor screening leading to the identification of a new class of natural product inhibitors of MPP1. Two compounds with structural similarity, norlobaridone (1) and physodic acid (2), were found to inhibit MPP1. Physodic acid is not competitive with ATP, indicating the presence of an allosteric inhibitor-binding pocket. Initial drug-like property screening indicates that physodic acid is more soluble than norlobaridone and has more favorable lipophilicity. However, both suffer from high clearance in human microsomal stability assays mediated by the lability of the lactone ring as well as hydroxylation of the alkyl chains as shown by metabolite identification studies. In cell-based assays physodic acid is a weak inhibitor with EC50 values of about 30 μM in a range of tumor cell lines. The two depsidones identified and characterized here could be used for future improvement of their activity against MPP1 and will be useful chemical probes for studying this unique molecular motor in more depth.

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Oncogenic Role of MPHOSPH1, a Cancer-Testis Antigen Specific to Human Bladder Cancer

Cited by 101 publications

References 30 publications

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

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

PRC1 contributes to tumorigenesis of lung adenocarcinoma in association with the Wnt/β-catenin signaling pathway

Depsidones from Lichens as Natural Product Inhibitors of M-Phase Phosphoprotein 1, a Human Kinesin Required for Cytokinesis

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