87 results match your criteria mouse cdt1

Live Imaging and Analysis of Cilia and Cell Cycle Dynamics with the Arl13bCerulean-Fucci2a Biosensor and Fucci Tools.

Methods Mol Biol 2021 ;2329:291-309

Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster, UK.

The cell and cilia cycles are inextricably linked through the dual functions of the centrioles at both the basal body of cilia and at mitotic centrosomes. How cilia assembly and disassembly, either through slow resorption or rapid deciliation, are coordinated with cell cycle progression remains unclear in many cell types and developmental paradigms. Moreover, little is known about how additional cilia parameters including changes in ciliary length or frequency of distal tip shedding change with cell cycle stage. Read More

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Intermittent hypoxia-induced downregulation of microRNA-320b promotes lung cancer tumorigenesis by increasing CDT1 via USP37.

Mol Ther Nucleic Acids 2021 Jun 1;24:528-541. Epub 2021 Jan 1.

Department of Thoracic Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, P.R. China.

Obstructive sleep apnea-hypopnea (OSAH) is correlated with an increased incidence of lung cancer. In our study, we explored the functional roles of microRNAs (miRNAs) in lung cancer patients that were complicated with OSAH involving the deubiquitination enzyme. The miR-320b expression pattern in lung cancer tissues and cells was determined. Read More

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Cell shape-based chemical screening reveals an epigenetic network mediated by focal adhesions.

FEBS J 2021 Mar 26. Epub 2021 Mar 26.

Institute for Protein Research, Osaka University, Suita, Japan.

Adapter proteins CRK and CRKL participate in a variety of signaling pathways, including cell adhesion, and fate regulation of mammalian cells. However, the molecular functions of CRK/CRKL in epigenetic regulation remain largely unknown. Here, we developed a pipeline to evaluate cell morphology using high-content image analysis combined with chemical screening of kinase and epigenetic modulators. Read More

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SIRT3 promotion reduces resistance to cisplatin in lung cancer by modulating the FOXO3/CDT1 axis.

Cancer Med 2021 02;10(4):1394-1404

Department of Oncology, Dongfang Hospital of Beijing University of Chinese Medicine, Beijing, P. R. China.

Background: Cisplatin is an extensively used chemotherapy agent for lung cancer, but its drug resistance serves as a huge obstacle for chemotherapy failure of lung cancer patients. Hence, researchers aimed to determine role of sirtuin 3 (SIRT3) considering its action in cisplatin resistance of lung cancer.

Methods: The expression patterns of SIRT3, FOXO3, and CDT1 were determined using RT-qPCR and Immunoblotting in lung cancer. Read More

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February 2021

Inhibitors of cullin-RING E3 ubiquitin ligase 4 with antitumor potential.

Proc Natl Acad Sci U S A 2021 02;118(8)

Department of Oncological Sciences, The Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574;

Cullin-RING (really intersting new gene) E3 ubiquitin ligases (CRLs) are the largest E3 family and direct numerous protein substrates for proteasomal degradation, thereby impacting a myriad of physiological and pathological processes including cancer. To date, there are no reported small-molecule inhibitors of the catalytic activity of CRLs. Here, we describe high-throughput screening and medicinal chemistry optimization efforts that led to the identification of two compounds, 33-11 and KH-4-43, which inhibit E3 CRL4 and exhibit antitumor potential. Read More

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February 2021

Cell cycle during neuronal migration and neocortical lamination.

Int J Dev Neurosci 2021 Apr 24;81(2):209-219. Epub 2021 Jan 24.

National Health Commission, Key Laboratory of Birth Defect Prevention, Henan Scientific and Technical Institute of Reproductive Health, Zhengzhou, China.

Objectives: In order to understand the relationships between neocortical lamination and cell cycle, various cells, such as neural stem cell, migrating postmitotic neuron, Cajal-Retzius (CR) cell, and mature pyramidal cell in various cell phases were investigated in mouse cortices.

Methods: With mouse neocortex and hippocampus, the immunofluorescent labeling, BrdU assay, and DiI tracing technique were implemented in the study.

Results: (1) During mouse development, the neocortex expressed different proteins, such as FOXP2, CDP, and Nestin, which could be used as the markers for cortical lamination. Read More

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Syndecan-1 Stimulates Adult Neurogenesis in the Mouse Ventricular-Subventricular Zone after Injury.

iScience 2020 Dec 7;23(12):101784. Epub 2020 Nov 7.

Université de Paris and Université Paris-Saclay, Inserm, LRP/iRCM/IBFJ CEA, UMR Stabilité Génétique Cellules Souches et Radiations, 92265 Fontenay-aux-Roses, France.

The production of neurons from neural stem cells (NSCs) persists throughout life in the mouse ventricular-subventricular zone (V-SVZ). We have previously reported that NSCs from adult V-SVZ are contained in cell populations expressing the carbohydrate SSEA-1/LeX, which exhibit either characteristics of quiescent NSCs (qNSCs) or of actively dividing NSCs (aNSCs) based on the absence or the presence of EGF-receptor, respectively. Using the fluorescence ubiquitination cell cycle indicator-Cdt1 transgenic mice to mark cells in G/G phase of the cell cycle, we uncovered a subpopulation of qNSCs which were primed to enter the cell cycle . Read More

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December 2020

Importance of Cullin4 Ubiquitin Ligase in Malignant Pleural Mesothelioma.

Cancers (Basel) 2020 Nov 20;12(11). Epub 2020 Nov 20.

Department of Thoracic Surgery, University Hospital Zürich, 8091 Zürich, Switzerland.

Neurofibromatosis type 2 (NF2), the tumor suppressor frequently lost in malignant pleural mesothelioma (MPM), suppresses tumorigenesis in part by inhibiting the Cullin4 ubiquitin ligase (CUL4) complex in the nucleus. Here, we evaluated the importance of CUL4 in MPM progression and tested the efficacy of cullin inhibition by pevonedistat, a small molecule inhibiting cullin neddylation. CUL4 paralogs (CUL4A and CUL4B) were upregulated in MPM tumor specimens compared to nonmalignant pleural tissues. Read More

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November 2020

Efficient production of large deletion and gene fragment knock-in mice mediated by genome editing with Cas9-mouse Cdt1 in mouse zygotes.

Methods 2021 07 22;191:23-31. Epub 2020 Apr 22.

Laborarory Animal Resource Center, Transborder Medical Research Center, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.

Genetically modified mouse models are essential for in vivo investigation of gene function and human disease research. Targeted mutations can be introduced into mouse embryos using genome editing technology such as CRISPR-Cas. Although mice with small indel mutations can be produced, the production of mice carrying large deletions or gene fragment knock-in alleles remains inefficient. Read More

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Both BRCA1-wild type and -mutant triple-negative breast cancers show sensitivity to the NAE inhibitor MLN4924 which is enhanced upon MLN4924 and cisplatin combination treatment.

Oncotarget 2020 Feb 25;11(8):784-800. Epub 2020 Feb 25.

Department of Pathology, The Ohio State University, Columbus, OH, USA.

Triple-negative breast cancer (TNBC) shows limited therapeutic efficacy. PARP inhibitor has been approved to treat advanced BRCA-mutant breast cancer but shows high resistance. Therefore, the development of new therapeutics that sensitize TNBC irrespective of BRCA status is urgently needed. Read More

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February 2020

TAS4464, A Highly Potent and Selective Inhibitor of NEDD8-Activating Enzyme, Suppresses Neddylation and Shows Antitumor Activity in Diverse Cancer Models.

Mol Cancer Ther 2019 07 15;18(7):1205-1216. Epub 2019 May 15.

Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd, Tsukuba, Japan.

NEDD8-activating enzyme (NAE) is an essential E1 enzyme of the NEDD8 conjugation (neddylation) pathway, which controls cancer cell growth and survival through activation of cullin-RING ubiquitin ligase complexes (CRL). In this study, we describe the preclinical profile of a novel, highly potent, and selective NAE inhibitor, TAS4464. TAS4464 selectively inhibited NAE relative to the other E1s UAE and SAE. Read More

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G1/S cell cycle regulators mediate effects of circadian dysregulation on tumor growth and provide targets for timed anticancer treatment.

PLoS Biol 2019 04 30;17(4):e3000228. Epub 2019 Apr 30.

Penn Chronobiology, Howard Hughes Medical Institute, Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.

Circadian disruption has multiple pathological consequences, but the underlying mechanisms are largely unknown. To address such mechanisms, we subjected transformed cultured cells to chronic circadian desynchrony (CCD), mimicking a chronic jet-lag scheme, and assayed a range of cellular functions. The results indicated a specific circadian clock-dependent increase in cell proliferation. Read More

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Visualization of Hepatocellular Regeneration in Mice After Partial Hepatectomy.

J Surg Res 2019 03 26;235:494-500. Epub 2018 Nov 26.

Department of Transplantation, Mayo Clinic, Jacksonville, Florida. Electronic address:

Background: Although hepatocellular regeneration is the cornerstone of liver homeostasis, current techniques for assessing such regeneration are limited. A method for visualizing the regeneration process would provide a means for advanced studies. Therefore, we examined the possibility of using fluorescence ubiquination-based cell cycle indicator (Fucci) mice for direct visualization of hepatocellular regeneration. Read More

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Targeting ubiquitin-activating enzyme induces ER stress-mediated apoptosis in B-cell lymphoma cells.

Blood Adv 2019 01;3(1):51-62

Knight Cancer Institute, Oregon Health & Science University, Portland, OR; and.

Alterations in the ubiquitin proteasome system (UPS) leave malignant cells in heightened cellular stress, making them susceptible to proteasome inhibition. However, given the limited efficacy of proteasome inhibitors in non-Hodgkin lymphoma (NHL), novel approaches to target the UPS are needed. Here, we show that TAK-243, the first small-molecule inhibitor of the ubiquitin activating enzyme (UAE) to enter clinical development, disrupts all ubiquitin signaling and global protein ubiquitination in diffuse large B-cell lymphoma (DLBCL) cells, thereby inducing endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). Read More

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January 2019

TGFβ1 Cell Cycle Arrest Is Mediated by Inhibition of MCM Assembly in Rb-Deficient Conditions.

Mol Cancer Res 2019 01 26;17(1):277-288. Epub 2018 Sep 26.

Department of Molecular Oncology, Moffitt Cancer Center and Research Institute, Tampa, Florida.

Transforming growth factor β1 (TGFβ1) is a potent inhibitor of cell growth that targets gene-regulatory events, but also inhibits the function of CDC45-MCM-GINS helicases (CMG; MCM, Mini-Chromosome Maintenance; GINS, Go-Ichi-Ni-San) through multiple mechanisms to achieve cell-cycle arrest. Early in G, TGFβ1 blocks MCM subunit expression and suppresses Myc and Cyclin E/Cdk2 activity required for CMG assembly, should MCMs be expressed. Once CMGs are assembled in late-G, TGFβ1 blocks CMG activation using a direct mechanism involving the retinoblastoma (Rb) tumor suppressor. Read More

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January 2019

Proteomic and immunomic analysis of Schistosoma mekongi egg proteins.

Exp Parasitol 2018 Aug 17;191:88-96. Epub 2018 Jul 17.

Department of Molecular Tropical Medicine and Genetics, Faculty of Tropical Medicine, Mahidol University, Bangkok, 10400, Thailand. Electronic address:

Schistosomiasis remains a global health problem. In the Mekong river basin, approximately 80,000 people are at risk of infection by Schistosoma mekongi. The parasite's eggs become entrapped in the host's organs and induce massive inflammation, contributing to the pathogenesis of schistosomiasis. Read More

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Genetically Encoded Tools for Optical Dissection of the Mammalian Cell Cycle.

Mol Cell 2017 11 26;68(3):626-640.e5. Epub 2017 Oct 26.

Laboratory for Cell Function Dynamics, BSI, RIKEN, 2-1 Hirosawa, Wako-city, Saitama 351-0198, Japan; Biotechnological Optics Research Team, Center for Advanced Photonics, RIKEN, 2-1 Hirosawa, Wako-city, Saitama 351-0198, Japan. Electronic address:

Eukaryotic cells spend most of their life in interphase of the cell cycle. Understanding the rich diversity of metabolic and genomic regulation that occurs in interphase requires the demarcation of precise phase boundaries in situ. Here, we report the properties of two genetically encoded fluorescence sensors, Fucci(CA) and Fucci(SCA), which enable real-time monitoring of interphase and cell-cycle biology. Read More

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November 2017

The Neddylation Inhibitor Pevonedistat (MLN4924) Suppresses and Radiosensitizes Head and Neck Squamous Carcinoma Cells and Tumors.

Mol Cancer Ther 2018 02 24;17(2):368-380. Epub 2017 Aug 24.

Department of Radiation Oncology, University of Virginia, Charlottesville, Virginia.

The cullin RING E3 ubiquitin ligase 4 (CRL4) with its substrate receptor CDT2 (CRL4-CDT2) is emerging as a critical regulator of DNA replication through targeting CDT1, SET8, and p21 for ubiquitin-dependent proteolysis. The aberrant increased stability of these proteins in cells with inactivated CRL4-CDT2 results in DNA rereplication, which is deleterious to cells due to the accumulation of replication intermediates and stalled replication forks. Here, we demonstrate that CDT2 is overexpressed in head and neck squamous cell carcinoma (HNSCC), and its depletion by siRNA inhibits the proliferation of human papilloma virus-negative (HPV-ve) HNSCC cells primarily through the induction of rereplication. Read More

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February 2018

Geminin deletion in pre-meiotic DNA replication stage causes spermatogenesis defect and infertility.

J Reprod Dev 2017 Oct 9;63(5):481-488. Epub 2017 Jul 9.

State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.

Geminin plays a critical role in cell cycle regulation by regulating DNA replication and serves as a transcriptional molecular switch that directs cell fate decisions. Spermatogonia lacking Geminin disappear during the initial wave of mitotic proliferation, while geminin is not required for meiotic progression of spermatocytes. It is unclear whether geminin plays a role in pre-meiotic DNA replication in later-stage spermatogonia and their subsequent differentiation. Read More

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October 2017

In Vivo DNA Re-replication Elicits Lethal Tissue Dysplasias.

Cell Rep 2017 05;19(5):928-938

DNA Replication Group, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), 3 Melchor Fernández Almagro, 28029 Madrid, Spain. Electronic address:

Mammalian DNA replication origins are "licensed" by the loading of DNA helicases, a reaction that is mediated by CDC6 and CDT1 proteins. After initiation of DNA synthesis, CDC6 and CDT1 are inhibited to prevent origin reactivation and DNA overreplication before cell division. CDC6 and CDT1 are highly expressed in many types of cancer cells, but the impact of their deregulated expression had not been investigated in vivo. Read More

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The prognostic significance of Cdc6 and Cdt1 in breast cancer.

Sci Rep 2017 04 20;7(1):985. Epub 2017 Apr 20.

Faculty of Health Sciences, University of Macau, Avenida de Universidade, Taipa, Macau SAR, China.

DNA replication is a critical step in cell proliferation. Overexpression of MCM2-7 genes correlated with poor prognosis in breast cancer patients. However, the roles of Cdc6 and Cdt1, which work with MCMs to regulate DNA replication, in breast cancers are largely unknown. Read More

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Geminin is an indispensable inhibitor of Cdt1 in mouse embryonic stem cells.

Genes Cells 2017 Apr 14;22(4):360-375. Epub 2017 Mar 14.

Department of Cell Proliferation, United Center for Advanced Research and Translational Medicine, Graduate School of Medicine, Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan.

Geminin is implicated in regulation of the cell cycle and differentiation. Although loss of Geminin triggers unscheduled DNA rereplication as a result of interruption of its interaction with Cdt1 in some somatic cancer cells, whether such cell cycle regulation also operates in embryonic stem cells (ESCs) has remained unclear. To characterize the Geminin-Cdt1 axis in ESCs and compare it with that in somatic cells, we established conditional knockout (KO) of Geminin in mouse ESCs and mouse embryonic fibroblasts (MEFs). Read More

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The protein phosphatase 2A regulatory subunit PR70 is a gonosomal melanoma tumor suppressor gene.

Sci Transl Med 2016 12;8(369):369ra177

Department of Pathology, McGill University, Montreal, Quebec, Canada.

Male gender is independently and significantly associated with poor prognosis in melanoma of all clinical stages. The biological underpinnings of this sex difference remain largely unknown, but we hypothesized that gene expression from gonosomes (sex chromosomes) might play an important role. We demonstrate that loss of the inactivated X chromosome in melanomas arising in females is strongly associated with poor distant metastasis-free survival, suggesting a dosage benefit from two X chromosomes. Read More

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December 2016

Inactivation of the CRL4-CDT2-SET8/p21 ubiquitylation and degradation axis underlies the therapeutic efficacy of pevonedistat in melanoma.

EBioMedicine 2016 Aug 16;10:85-100. Epub 2016 Jun 16.

Department of Radiation Oncology, University of Virginia, Charlottesville, VA 22908, USA; Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22908, USA; Center for Cell Signaling, University of Virginia, Charlottesville, VA 22908, USA. Electronic address:

Unlabelled: The cullin-based CRL4-CDT2 ubiquitin ligase is emerging as a master regulator of cell proliferation. CRL4-CDT2 prevents re-initiation of DNA replication during the same cell cycle "rereplication" through targeted degradation of CDT1, SET8 and p21 during S-phase of the cell cycle. We show that CDT2 is overexpressed in cutaneous melanoma and predicts poor overall and disease-free survival. Read More

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MLN4924 suppresses neddylation and induces cell cycle arrest, senescence, and apoptosis in human osteosarcoma.

Oncotarget 2016 Jul;7(29):45263-45274

Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.

Neddylation is a post-translational protein modification process associated with carcinogenesis and cancer development. MLN4924, a pharmaceutical neddylation inhibitor, induces potent anti-cancer effects in multiple types of cancers. In this study, we investigated the effects of MLN4924 on human osteosarcoma (OS). Read More

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Manipulation of Cell Cycle and Chromatin Configuration by Means of Cell-Penetrating Geminin.

PLoS One 2016 19;11(5):e0155558. Epub 2016 May 19.

Department of Stem Cell Biology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Kasumi, Minami-ku, Hiroshima, Japan.

Geminin regulates chromatin remodeling and DNA replication licensing which play an important role in regulating cellular proliferation and differentiation. Transcription of the Geminin gene is regulated via an E2F-responsive region, while the protein is being closely regulated by the ubiquitin-proteasome system. Our objective was to directly transduce Geminin protein into cells. Read More

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Characterization of conserved arginine residues on Cdt1 that affect licensing activity and interaction with Geminin or Mcm complex.

Cell Cycle 2016 05;15(9):1213-26

a Department of Genome Medicine , Tokyo Metropolitan Institute of Medical Science , Tokyo , Japan.

All organisms ensure once and only once replication during S phase through a process called replication licensing. Cdt1 is a key component and crucial loading factor of Mcm complex, which is a central component for the eukaryotic replicative helicase. In higher eukaryotes, timely inhibition of Cdt1 by Geminin is essential to prevent rereplication. Read More

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Geminin deletion in mouse oocytes results in impaired embryo development and reduced fertility.

Mol Biol Cell 2016 Mar 13;27(5):768-75. Epub 2016 Jan 13.

State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China

Geminin controls proper centrosome duplication, cell division, and differentiation. We investigated the function of geminin in oogenesis, fertilization, and early embryo development by deleting the geminin gene in oocytes from the primordial follicle stage. Oocyte-specific disruption of geminin results in low fertility in mice. Read More

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Cell Sorting of Neural Stem and Progenitor Cells from the Adult Mouse Subventricular Zone and Live-imaging of their Cell Cycle Dynamics.

J Vis Exp 2015 Sep 14(103). Epub 2015 Sep 14.

CEA DSV iRCM SCSR, Laboratoire de Radiopathologie, UMR 967; INSERM, UMR 967; Université Paris Diderot, Sorbonne Paris Cité, UMR 967; Université Paris Sud, UMR 967;

Neural stem cells (NSCs) in the subventricular zone of the lateral ventricles (SVZ) sustain olfactory neurogenesis throughout life in the mammalian brain. They successively generate transit amplifying cells (TACs) and neuroblasts that differentiate into neurons once they integrate the olfactory bulbs. Emerging fluorescent activated cell sorting (FACS) techniques have allowed the isolation of NSCs as well as their progeny and have started to shed light on gene regulatory networks in adult neurogenic niches. Read More

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September 2015

The NEDD8-activating enzyme inhibitor MLN4924 disrupts nucleotide metabolism and augments the efficacy of cytarabine.

Clin Cancer Res 2015 Jan 11;21(2):439-47. Epub 2014 Nov 11.

Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.

Purpose: New therapies are urgently needed for patients with acute myelogenous leukemia (AML). The novel NEDDylation inhibitor MLN4924 (pevonedistat) has demonstrated significant preclinical antileukemic activity and preliminary efficacy in patients with AML in a phase I trial. On the basis of its antimyeloid and DNA-damaging properties, we investigated the ability of MLN4924 to augment conventional cytarabine (ara-C) therapy. Read More

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January 2015