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https://www.readbyqxmd.com/read/29758318/proteome-and-behavioral-alternations-in-phosphorylation-deficient-mutant-collapsin-response-mediator-protein2-knock-in-mice
#1
Haruko Nakamura, Aoi Takahashi-Jitsuki, Hiroko Makihara, Tetsuya Asano, Yayoi Kimura, Jun Nakabayashi, Naoya Yamashita, Yuko Kawamoto, Fumio Nakamura, Toshio Ohshima, Hisashi Hirano, Fumiaki Tanaka, Yoshio Goshima
CRMP2, alternatively designated as DPYSL2, was the first CRMP family member to be identified as an intracellular molecule mediating the signaling of the axon guidance molecule Semaphorin 3A (Sema3A). In Sema3A signaling, cyclin-dependent kinase 5 (Cdk5) primarily phosphorylates CRMP2 at Ser522. Glycogen synthase kinase-3β (GSK-3β) subsequently phosphorylates the residues of Thr509 and Thr514 of CRMP2. Previous studies showed that CRMP2 is involved in pathogenesis of neurological disorders such as Alzheimer's disease...
May 11, 2018: Neurochemistry International
https://www.readbyqxmd.com/read/29742423/cdk5-inhibition-resolves-pka-camp-independent-activation-of-creb1-signaling-in-glioma-stem-cells
#2
Subhas Mukherjee, Carol Tucker-Burden, Emily Kaissi, Austin Newsam, Hithardhi Duggireddy, Monica Chau, Changming Zhang, Bhakti Diwedi, Manali Rupji, Sandra Seby, Jeanne Kowalski, Jun Kong, Renee Read, Daniel J Brat
Cancer stem cells promote neoplastic growth, in part by deregulating asymmetric cell division and enhancing self-renewal. To uncover mechanisms and potential therapeutic targets in glioma stem cell (GSC) self-renewal, we performed a genetic suppressor screen for kinases to reverse the tumor phenotype of our Drosophila brain tumor model and identified dCdk5 as a critical regulator. CDK5, the human ortholog of dCdk5 (79% identity), is aberrantly activated in GBMs and tightly aligned with both chromosome 7 gains and stem cell markers affecting tumor-propagation...
May 8, 2018: Cell Reports
https://www.readbyqxmd.com/read/29729246/oligodendrocyte-specific-loss-of-cdk5-disrupts-the-architecture-of-nodes-of-ranvier-as-well-as-learning-and-memory
#3
Fucheng Luo, Jessie Zhang, Kathryn Burke, Rita R Romito-DiGiacomo, Robert H Miller, Yan Yang
Myelination of the central nervous system is important for normal motor and sensory neuronal function and recent studies also link it to efficient learning and memory. Cyclin-dependent kinase 5 (Cdk5) is required for normal oligodendrocyte development, myelination and myelin repair. Here we show that conditional deletion of Cdk5 by targeting with CNP (CNP;Cdk5 CKO) results in hypomyelination and disruption of the structural integrity of Nodes of Ranvier. In addition, CNP;Cdk5 CKO mice exhibited a severe impairment of learning and memory compared to controls that may reflect perturbed neuron-glial interactions...
May 2, 2018: Experimental Neurology
https://www.readbyqxmd.com/read/29728702/elevated-levels-of-brain-homocysteine-directly-modulate-the-pathological-phenotype-of-a-mouse-model-of-tauopathy
#4
Antonio Di Meco, Jian-Guo Li, Carlos Barrero, Salim Merali, Domenico Praticò
A high circulating level of homocysteine (Hcy), also known as hyperhomocysteinemia, is a risk factor for Alzheimer's disease (AD). Previous studies show that elevated Hcy promotes brain amyloidosis and behavioral deficits in mouse models of AD. However, whether it directly modulates the development of tau neuropathology independently of amyloid beta in vivo is unknown. Herein, we investigate the effect of diet-induced elevated levels of brain Hcy on the phenotype of a relevant mouse model of human tauopathy...
May 4, 2018: Molecular Psychiatry
https://www.readbyqxmd.com/read/29705343/cdk5-mediated-tau-accumulation-triggers-methamphetamine-induced-neuronal-apoptosis-via-endoplasmic-reticulum-associated-degradation-pathway
#5
Ning Xiao, Fu Zhang, Bofeng Zhu, Chao Liu, Zhoumeng Lin, Huijun Wang, Wei-Bing Xie
Overexposure to methamphetamine (METH) causes apoptosis in a number of cell types, particularly neuronal cells. However, the underlying mechanisms of METH-induced neuronal apoptosis remain to be elucidated. Accumulation of microtubule-associated protein Tau can lead to activation of multiple neurotoxic pathways, which is closely correlated with neuronal apoptosis. The aim of this study was to determine the role of Tau in METH-induced neuronal apoptosis. We determined the expression of two phosphorylated Tau proteins (serine 396 and threonine 231) in the human neuroblastoma SH-SY5Y cells and in the hippocampus of Sprague-Dawley rats treated with vehicle or METH using western blotting, immunohistochemical staining and immunofluorescence staining...
April 26, 2018: Toxicology Letters
https://www.readbyqxmd.com/read/29704550/tau-hyperphosphorylation-and-p-creb-reduction-are-involved-in-acrylamide-induced-spatial-memory-impairment-suppression-by-curcumin
#6
Dandan Yan, Jianling Yao, Ying Liu, Xing Zhang, Yiqi Wang, Xiaoyi Chen, Liegang Liu, Nian Shi, Hong Yan
Acrylamide (ACR) is an axonal toxicant that produces peripheral neuropathy in laboratory animals and humans. Epidemiological study found that diet ACR exposure was associated with a mild cognitive decline in men. However, limited information is available as regards its potential and underlying mechanism to cause memory alterations. Curcumin is a polyphenol with neuroprotective and cognitive-enhancing properties. In this study, we aimed to investigate the mechanism of ACR-induced spatial memory impairment and the beneficial effect of curcumin...
April 26, 2018: Brain, Behavior, and Immunity
https://www.readbyqxmd.com/read/29697001/nestin-is-highly-expressed-in-fetal-spinal-cord-isolated-from-placenta-previa-patients-and-promotes-inflammation-by-enhancing-nf-%C3%AE%C2%BAb-activity
#7
Ling Li, Jing Zhang, Huahe Gao, Yuyan Ma
Purpose Nestin is expressed in various tissues of the embryo in patients with placenta previa, while the regulatory mechanism still unknown. Materials and methods All participants terminated pregnancy. Among them, 75 patients with placenta previa were assigned to the case group and 80 healthy pregnant women with normal placenta were assigned to the control group. Expression of nestin and CDK5 in fetal spinal cord tissues was detected by Western Blot and RT-qPCR methods. The enzyme-linked immunosorbent assay (ELISA) was used to determine the serum expression of some pro-inflammatory cytokines in placenta previa patients...
April 26, 2018: Biomarkers: Biochemical Indicators of Exposure, Response, and Susceptibility to Chemicals
https://www.readbyqxmd.com/read/29689548/nestin-improves-preeclampsia-like-symptoms-by-inhibiting-activity-of-cyclin-dependent-kinase-5
#8
Xu Yang, Yiling Ding, Mengyuan Yang, Ling Yu, Yun Hu, Yali Deng
BACKGROUND/AIMS: Preeclampsia (PE) is a pregnancy-specific hypertensive disorder that is characterised by a high incidence of hypertension and proteinuria. Podocytes are involved in the formation of a split membrane, which is the last barrier preventing the leakage of protein into the urine. Nestin, a cytoskeleton protein, is expressed stably in podocytes. However, the association between the Nestin concentration in urine and the progression of PE and the role of Nestin in PE remains unclear...
April 19, 2018: Kidney & Blood Pressure Research
https://www.readbyqxmd.com/read/29651006/cyclin-dependent-kinase-5-mediates-pleiotrophin-induced-endothelial-cell-migration
#9
Evgenia Lampropoulou, Ioanna Logoviti, Marina Koutsioumpa, Maria Hatziapostolou, Christos Polytarchou, Spyros S Skandalis, Ulf Hellman, Manolis Fousteris, Sotirios Nikolaropoulos, Efrosini Choleva, Margarita Lamprou, Angeliki Skoura, Vasileios Megalooikonomou, Evangelia Papadimitriou
Pleiotrophin (PTN) stimulates endothelial cell migration through binding to receptor protein tyrosine phosphatase beta/zeta (RPTPβ/ζ) and αν β3 integrin. Screening for proteins that interact with RPTPβ/ζ and potentially regulate PTN signaling, through mass spectrometry analysis, identified cyclin-dependent kinase 5 (CDK5) activator p35 among the proteins displaying high sequence coverage. Interaction of p35 with the serine/threonine kinase CDK5 leads to CDK5 activation, known to be implicated in cell migration...
April 12, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29621559/neurotrophins-and-cholinergic-enzyme-regulated-by-calpain-2-new-insights-into-neuronal-apoptosis-induced-by-polybrominated-diphenyl-ether-153
#10
Hongmei Zhang, Xiaorong Yang, Huajun Zhang, Xin Li, Zhihong Zhang, Lifang Hou, Zemin Wang, Qiao Niu, Tong Wang
Polybrominated diphenyl ether-153 (BDE-153) has been demonstrated to induce neuronal apoptosis in rat cerebral cortex and primary neurons. Neurotrophins and cholinergic enzymes play critical roles in the neuronal survival, maintenance, synaptic plasticity and learning memory, however, their roles in neuronal apoptosis following the BDE-153 treatment remain unclear. In this study, we firstly explored the possible predominant pathway underlying the neuronal apoptotic induced by the BDE-153 treatment in rat cerebral cortex, by measuring expression levels (protein and mRNA) of p53, caspase-3, 8, 9, calpain-1, and calpain-2, detected the expression levels (protein and mRNA) of neurotrophins including brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4), and measured acetylcholinesterase (AchE) and choline acetyltransferase (ChaT) activities in rat cerebral cortex and primary neurons following BDE-153 treatment with or without pretreatment with inhibitors...
April 2, 2018: Toxicology Letters
https://www.readbyqxmd.com/read/29607621/antileukotriene-therapy-by-reducing-tau-phosphorylation-improves-synaptic-integrity-and-cognition-of-p301s-transgenic-mice
#11
Phillip F Giannopoulos, Jian Chiu, Domenico Praticò
The 5-lipoxygenase (5LO) is a source of inflammatory leukotrienes and is upregulated in Alzheimer's disease and related tauopathies. However, whether it directly modulates tau phosphorylation and the development of its typical neuropathology in the absence of Aβ or is a secondary event during the course of the disease pathogenesis remains to be fully elucidated. The goal of this study was to evaluate the effect that pharmacologic blockade of this inflammatory pathway has on the phenotype of a transgenic mouse model of tauopathy, the P301S mice...
April 1, 2018: Aging Cell
https://www.readbyqxmd.com/read/29572554/multibacmam-bimolecular-fluorescence-complementation-bifc-tool-kit-identifies-new-small-molecule-inhibitors-of-the-cdk5-p25-protein-protein-interaction-ppi
#12
Itxaso Bellón-Echeverría, Jean-Philippe Carralot, Andrea Araujo Del Rosario, Stephanie Kueng, Harald Mauser, Georg Schmid, Ralf Thoma, Imre Berger
Protein-protein interactions (PPIs) are at the core of virtually all biological processes in cells. Consequently, targeting PPIs is emerging at the forefront of drug discovery. Cellular assays which closely recapitulate native conditions in vivo are instrumental to understand how small molecule drugs can modulate such interactions. We have integrated MultiBacMam, a baculovirus-based mammalian gene delivery tool we developed, with bimolecular fluorescence complementation (BiFC), giving rise to a highly efficient system for assay development, identification and characterization of PPI modulators...
March 23, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29571747/cdk5-suppression-blocks-sirt1-degradation-via-the-ubiquitin-proteasome-pathway-in-parkinson-s-disease-models
#13
Qian Zhang, Pei Zhang, Guang-Jian Qi, Zheng Zhang, Feng He, Ze-Xi Lv, Xiang Peng, Hong-Wei Cai, Tong-Xia Li, Xue-Min Wang, Bo Tian
The NAD+ -dependent protein deacetylase sirtuin 1 (SIRT1), a member of the sirtuin family, may have a neuroprotective effect in multiple neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD) and Amyotrophic lateral sclerosis (ALS). Many studies have suggested that overexpression-induced or resveratrol-treated activation of SIRT1 could significantly ameliorate several neurodegenerative diseases in mouse models. However, the type of SIRT1, protein expression levels and underlying mechanisms remain unclear, especially in PD...
March 20, 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29564811/recovery-of-neurovascular-unit-integrity-by-cdk5-kd-astrocyte-transplantation-in-a-global-cerebral-ischemia-model
#14
Andrea Becerra-Calixto, Rafael Posada-Duque, Gloria Patricia Cardona-Gómez
Astrocytes play metabolic and structural support roles and contribute to the integrity of the blood-brain barrier (BBB), linking communication between neurons and the endothelium. Cyclin-dependent kinase 5 (CDK5) likely exerts a dual effect on the endothelium and astrocytes due to its involvement in migration and angiogenesis; the overactivation of CDK5 is associated with dysfunction in glutamate recapture and hypoxia. Recently, we proposed that CDK5-targeted astrocytes facilitate the recovery of neurological and motor function in transplanted ischemic rats...
March 22, 2018: Molecular Neurobiology
https://www.readbyqxmd.com/read/29552116/cdk5rap1-targeting-nf-%C3%AE%C2%BAb-signaling-pathway-in-human-malignant-melanoma-a375-cell-apoptosis
#15
Jikui Xiong, Yan Wang, Yanli Gu, Yadong Xue, Lin Dang, Yuzhen Li
Malignant melanoma is characterized by rapid deterioration, early metastasis and high mortality. Cdk5 regulatory subunit-associated protein 1 (CDK5RAP1), which catalyzes 2-methylthio (ms2 ) modification of mitochondrial transfer RNAs, has been reported to induce cancer cell apoptosis, by a phospho-c-Jun N-terminal kinase (p-JNK) signaling pathway. The present study was the first to report on the association between CDK5RAP1 deficiency and nuclear factor-κB (NF-κB) signaling pathway during the apoptosis process in human malignant melanoma (A375) cells...
April 2018: Oncology Letters
https://www.readbyqxmd.com/read/29545334/icec0942-an-orally-bioavailable-selective-inhibitor-of-cdk7-for-cancer-treatment
#16
Hetal Patel, Manikandan Periyasamy, Georgina P Sava, Alexander Bondke, Brian W Slafer, Sebastian H B Kroll, Marion Barbazanges, Richard Starkey, Silvia Ottaviani, Alison Harrod, Eric O Aboagye, Laki Buluwela, Matthew J Fuchter, Anthony G M Barrett, Charles Coombes, Simak Ali
Recent reports indicate that some cancer types are especially sensitive to transcription inhibition, suggesting that targeting the transcriptional machinery provides new approaches to cancer treatment. Cyclin-dependent kinase (CDK)7 is necessary for transcription, and acts by phosphorylating the C-terminal domain (CTD) of RNA polymerase II (PolII) to enable transcription initiation. CDK7 additionally regulates the activities of a number of transcription factors, including Estrogen receptor-α (ER). Here we describe a new, orally bioavailable CDK7 inhibitor, ICEC0942...
March 15, 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29540196/cdk5rap3-suppresses-wnt-%C3%AE-catenin-signaling-by-inhibiting-akt-phosphorylation-in-gastric-cancer
#17
Chao-Hui Zheng, Jia-Bin Wang, Man-Qiang Lin, Peng-Yang Zhang, Li-Chao Liu, Jian-Xian Lin, Jun Lu, Qi-Yue Chen, Long-Long Cao, Mi Lin, Ru-Hong Tu, Jian-Wei Xie, Ping Li, Chang-Ming Huang
BACKGROUND: CDK5RAP3 was initially isolated as a binding protein of the CDK5 activator p35. Although CDK5RAP3 has been shown to negatively regulate the Wnt/β-catenin signaling pathway in gastric cancer by repressing GSK-3β phosphorylation, its in-depth mechanism has not been determined. METHODS: Following CDK5RAP3 overexpression or knock down, CDK5RAP3 signaling pathways were investigated in gastric cancer cells by Western Blotting. Cell growth, invasion and migration were also evaluated in gastric cancer cell lines...
March 14, 2018: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/29535807/the-non-neuronal-cyclin-dependent-kinase-5-is-a-fibrotic-mediator-potentially-implicated-in-systemic-sclerosis-and-a-novel-therapeutic-target
#18
Jun Wei, Roberta G Marangoni, Feng Fang, Wenxia Wang, Jingang Huang, Joerg H W Distler, John Varga
The mechanisms underlying persistent fibroblast activation and myofibroblast phenoconversion in underlying multi-organ fibrosis in systemic sclerosis (SSc) remain incompletely understood, hindering effective therapies to slow or reverse the process. Cyclin-dependent kinase 5 (CDK5) is a pleiotropic member of the CDK family originally identified in neuronal cells. In contrast to other CDKs, CDK5 activity depends on its CDK5R1 subunit p35. Here we demonstrate that expression of p35 and CDK5 activity are induced by TGF-ß in fibroblasts and adipocytic cell types...
February 13, 2018: Oncotarget
https://www.readbyqxmd.com/read/29511352/regulation-of-inside-out-%C3%AE-1-integrin-activation-by-cdcp1
#19
Sara G Pollan, Fangjin Huang, Jamie M Sperger, Joshua M Lang, Colm Morrissey, Anne E Cress, C Y Chu, Neil A Bhowmick, Sungyong You, Michael R Freeman, Danislav S Spassov, Mark M Moasser, William G Carter, Shakti Ranjan Satapathy, Kavita Shah, Beatrice S Knudsen
Tumor metastasis depends on the dynamic regulation of cell adhesion through β1-integrin. The Cub-Domain Containing Protein-1, CDCP1, is a transmembrane glycoprotein which regulates cell adhesion. Overexpression and loss of CDCP1 have been observed in the same cancer types to promote metastatic progression. Here, we demonstrate reduced CDCP1 expression in high-grade, primary prostate cancers, circulating tumor cells and tumor metastases of patients with castrate-resistant prostate cancer. CDCP1 is expressed in epithelial and not mesenchymal cells, and its cell surface and mRNA expression declines upon stimulation with TGFβ1 and epithelial-to-mesenchymal transition...
March 7, 2018: Oncogene
https://www.readbyqxmd.com/read/29469033/altered-expression-of-the-cdk5-activator-like-protein-cdk5%C3%AE-causes-neurodegeneration-in-part-by-accelerating-the-rate-of-aging
#20
Joshua Spurrier, Arvind Kumar Shukla, Kristina McLinden, Kory Johnson, Edward Giniger
Aging is the greatest risk factor for neurodegeneration, but the connection between the two processes remains opaque. This is in part for want of a rigorous way to define physiological age, as opposed to chronological age. Here, we develop a comprehensive metric for physiological age in Drosophila , based on genome-wide expression profiling. We applied this metric to a model of adult-onset neurodegeneration, increased or decreased expression of the activating subunit of the Cdk5 protein kinase, encoded by the gene Cdk5α , the ortholog of mammalian p35...
March 8, 2018: Disease Models & Mechanisms
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