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Ji-Eun Kim, Tae-Cheon Kang
Parvalbumin (PV) is one of the calcium-binding proteins, which plays an important role in the responsiveness of inhibitory neurons to an adaptation to repetitive spikes. Furthermore, PV neurons are highly vulnerable to status epilepticus (SE, prolonged seizure activity), although the underlining mechanism remains to be clarified. In the present study, we found that p47Phox expression was transiently and selectively increased in PV neurons 6 h after SE. This up-regulated p47Phox expression was accompanied by excessive mitochondrial fission...
2017: Frontiers in Cellular Neuroscience
Jinsoo Seo, Oleg Kritskiy, L Ashley Watson, Scarlett J Barker, Dilip Dey, Waseem K Raja, Yuan-Ta Lin, Tak Ko, Sukhee Cho, Jay Penney, M Catarina Silva, Steven D Sheridan, Diane Lucente, James F Gusella, Bradford C Dickerson, Stephen J Haggarty, Li-Huei Tsai
Increased p25, a proteolytic fragment of the regulatory subunit p35, is known to induce aberrant activity of cyclin-dependent kinase 5 (Cdk5), which is associated with neurodegenerative disorders including Alzheimer's disease (AD). Previously, we showed that replacing endogenous p35 with the non-cleavable mutant p35 (Δp35) attenuated amyloidosis and improved cognitive function in a familial AD mouse model. Here, to address the role of p25/Cdk5 in tauopathy, we generated double transgenic mice by crossing mice overexpressing mutant human tau (P301S) with Δp35KI mice...
September 14, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Yanwei Lu, Jia Ma, Yan Li, Jing Huang, Sheng Zhang, Zhongyuan Yin, Jinghua Ren, Kai Huang, Gang Wu, Kunyu Yang, Shuangbing Xu
CDP138, a CDK5 binding partner, regulates cell proliferation and migration. However, the mechanisms by which CDP138 functions in these processes remain unclear. In this study, we show that CDP138 is frequently overexpressed and that high levels of CDP138 are correlated with lymph node metastasis in lung cancer. Furthermore, we provide evidence that CDP138-depleted lung cancer cells exhibit enhanced radiosensitivity as well as reduced migration and invasion. Mechanistically, we identify GDF15, a member of the TGF-β superfamily, as a key downstream effector of CDP138...
September 7, 2017: Cell Death & Disease
Henning Hagmann, Nicole Mangold, Markus M Rinschen, Tim Koenig, Karl Kunzelmann, Bernhard Schermer, Thomas Benzing, Paul T Brinkkoetter
Signaling via the transient receptor potential (TRP) ion channel C6 plays a pivotal role in hereditary and sporadic glomerular kidney disease. Several studies have identified gain-of-function mutations of TRPC6 and report induced expression and enhanced channel activity of TRPC6 in association with glomerular diseases. Interfering with TRPC6 activity may open novel therapeutic pathways. TRPC6 channel activity is controlled by protein expression and stability as well as intracellular trafficking. Identification of regulatory phosphorylation sites in TRPC6 and corresponding protein kinases is essential to understand the regulation of TRPC6 activity and may result in future therapeutic strategies...
September 6, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Andrew N Bankston, Li Ku, Yue Feng
Cdk5 activity is regulated by the amounts of two activator proteins, p35 and p39 (Tsai et al., 1994; Zheng et al., 1998; Humbert et al., 2000). The p35-Cdk5 and p39-Cdk5 complexes have differing sensitivity to salt and detergent concentrations (Hisanaga and Saito, 2003; Sato et al., 2007; Yamada et al., 2007; Asada et al., 2008). Cdk5 activation can be directly measured by immunoprecipitation of Cdk5 with its bound activator, followed by a Cdk5 kinase assay. In this protocol, buffers for cell lysis and immunoprecipitation are intended to preserve both p35- and p39-Cdk5 complexes to assess total Cdk5 activity...
July 5, 2017: Bio-protocol
Yohei Shinmyo, Yukari Terashita, Tung Anh Dinh Duong, Toshihide Horiike, Muneo Kawasumi, Kazuyoshi Hosomichi, Atsushi Tajima, Hiroshi Kawasaki
Folds in the cerebral cortex in mammals are believed to be key structures for accommodating increased cortical neurons in the cranial cavity. However, the mechanisms underlying cortical folding remain largely unknown, mainly because genetic manipulations for the gyrencephalic brain have been unavailable. By combining in utero electroporation and the CRISPR/Cas9 system, we succeeded in efficient gene knockout of Cdk5, which is mutated in some patients with classical lissencephaly, in the gyrencephalic brains of ferrets...
August 29, 2017: Cell Reports
Ningning Cui, Hui Lu, Meng Li, Qiuyue Yan
PTPN21, a cytosolic non-receptor tyrosine phosphatase isolated from human skeletal muscle, was reported to promote neuronal survival. Nevertheless, it is not clear whether PTPN21 plays a role in hypoxia ischemia-induced neuronal injury. A proper understanding of the PTPN21 mechanism in neuron growth regulation is limited. In this study, we investigated the neuroprotective effects and potential mechanism of PTPN21 on oxygen glucose deprivation (OGD)-injured PC12 cells. The ischemic stroke model of PC12 cells was made by OGD for 2h, after transfection of the PTPN21 siRNA and pcDNA 3...
August 24, 2017: European Journal of Pharmacology
Xiaoshu Zhou, Runxia Gu, Xiaoming Han, Gang Wu, Junli Liu
Vasculogenic mimicry (VM), an endothelial-independent tumor vascularization phenomenon representing functional tumor plasticity, might be the culprit behind the poor clinical outcome in classic antiangiogenesis treatment. However, the mechanism underlying VM needs to be elucidated. Cyclin-dependent kinase 5 (CDK5) has been recognized as a key factor in regulating migration and neuronal plasticity. Recently, CDK5 was associated with tumor migration and invasion and its expression levels correlated with poor clinical prognosis, indicating its important role in tumor cell plasticity...
August 24, 2017: Biochemical and Biophysical Research Communications
Fatma Asli Erdem, Isabella Salzer, Seok Heo, Wei-Qiang Chen, Gangsoo Jung, Gert Lubec, Stefan Boehm, Jae-Won Yang
Voltage-gated Kv7.2 potassium channels regulate neuronal excitability. The gating of these channels is tightly controlled by various mediators and neurotransmitters acting via G protein-coupled receptors (GPCRs); the underlying signalling cascades involve phosphatidylinositol-4,5-bisphosphate (PIP2 ), Ca(2+) /Calmodulin and phosphorylation. Recent studies found that the PIP2 sensitivity of Kv7.2 channels is affected by two post-translational modifications, phosphorylation and methylation, harboured within putative PIP2 binding domains...
August 18, 2017: Proteomics
Inyoung Lee, Gwang Su Kim, June Sung Bae, Jaeyoun Kim, Kunsoo Rhee, Deog Su Hwang
The centrosome serves as a major microtubule-organizing center (MTOC). The Cdc6 protein is a component of the pre-replicative complex and a licensing factor for the initiation of chromosome replication and localizes to centrosomes during the S- and G2-phases of the cell cycle of human cells. This cell cycle-dependent localization of Cdc6 to the centrosome motivated us to investigate whether Cdc6 negatively regulates MTOC activity and to determine the integral proteins that comprise the pericentriolar material (PCM)...
August 21, 2017: Journal of Biological Chemistry
Sun Jun Park, Eunjin Kim, Miyoun Yoo, Joo-Youn Lee, Chi Hoon Park, Jong Yeon Hwang, Jae Du Ha
A novel 6-aminopurine scaffold bearing an N9-cis-cyclobutyl moiety was designed using structure-based molecular design based on two known CDK inhibitors, dinaciclib and Cmpd-27. A series of novel 6-aminopurine compounds was prepared for structure-activity relationship (SAR) studies of CDK2 and CDK5 inhibitors. Among the compounds synthesized, compound 8l displayed potent CDK2 and CDK5 inhibitory activities with low nanomolar ranges (IC50=2.1 and 4.8nM, respectively) and showed moderate cytotoxicity in HCT116 colon cancer and MCF7 breast cancer cell lines...
September 15, 2017: Bioorganic & Medicinal Chemistry Letters
Claudio Coddou, Rodrigo Sandoval, Patricio Castro, Pablo Lazcano, Maria José Hevia, Milos Rokic, Bradford Hall, Anita Terse, Christian Gonzalez-Billault, Ashok B Kulkarni, Stanko S Stojilkovic, Elias Utreras
The purinergic P2X2 receptor (P2X2R) is an adenosine triphosphate-gated ion channel widely expressed in the nervous system. Here, we identified a putative cyclin-dependent kinase 5 (Cdk5) phosphorylation site in the full-size variant P2X2aR (TPKH), which is absent in the splice variant P2X2bR. We therefore investigated the effects of Cdk5 and its neuronal activator, p35, on P2X2aR function. We found an interaction between P2X2aR and Cdk5/p35 by co-immunofluorescence and co-immunoprecipitation in HEK293 cells...
July 17, 2017: Pain
Mengbing Huang, Lingpin Kong, Lihua Yang, Xiang Li, Xiaoshuang Zhou, Ye Li, Jie Bai
Methamphetamine (METH) is a highly addictive drug of abuse which induces behavioral sensitization and rewarding effects. Thioredoxin-1 (Trx-1) is a redox protein and plays role in regulating activity of transcription factor, such as cAMP responsive element-binding protein (CREB), AP-1, p53, is emerging as an important modulator of neuronal function. It has been reported that Trx-1 is involved in morphine dependence. In this study, we examined the rewarding effect after METH administration by conditioned place preference (CPP) of mice, and detected the levels of dopamine and the activity of cAMP responsive element-binding protein (CREB), the expressions of ΔFosB and cyclin-dependent kinase 5 (CDK5) in the ventral tegmental area (VTA) and nucleus accumbens (NAc) in mice...
August 4, 2017: Behavioural Brain Research
Syed Waseem Bihaqi, Aseel Eid, Nasser H Zawia
The presence of fibrillary lesions, which are mainly composed of the microtubule associated protein tau (MAPT) in neurons, has gained immense recognition due to their presence in numerous neurodegenerative diseases, including Alzheimer's disease (AD). Dysregulation of tau is related with its altered site-specific phosphorylation which is followed by tau polymerization, neuronal dysfunction and death. Previous reports by us suggest that molecular alterations favor abundant tau phosphorylation and immunoreactivity in the frontal cortex of aged primates and rodents with past exposure to lead (Pb)...
July 29, 2017: Neurotoxicology
Huiqian Huang, Xiaochen Lin, Zhuoyi Liang, Teng Zhao, Shengwang Du, Michael M T Loy, Kwok-On Lai, Amy K Y Fu, Nancy Y Ip
The experience-dependent modulation of brain circuitry depends on dynamic changes in synaptic connections that are guided by neuronal activity. In particular, postsynaptic maturation requires changes in dendritic spine morphology, the targeting of postsynaptic proteins, and the insertion of synaptic neurotransmitter receptors. Thus, it is critical to understand how neuronal activity controls postsynaptic maturation. Here we report that the scaffold protein liprinα1 and its phosphorylation by cyclin-dependent kinase 5 (Cdk5) are critical for the maturation of excitatory synapses through regulation of the synaptic localization of the major postsynaptic organizer postsynaptic density (PSD)-95...
August 15, 2017: Proceedings of the National Academy of Sciences of the United States of America
Subhamita Maitra, Mahasweta Chatterjee, Swagata Sinha, Kanchan Mukhopadhyay
Cortical neuronal migration and formation of filamentous actin cytoskeleton, needed for development, normal cell growth and differentiation, are regulated by the cyclin-dependent kinase 5 (Cdk5). Attention deficit hyperactivity disorder (ADHD) is associated with delayed maturation of the brain and hence we hypothesized that cdk5 may have a role in ADHD. Eight functional CDK5 gene variants were analyzed in 848 Indo-Caucasoid individuals including 217 families with ADHD probands and 250 healthy volunteers. Only three variants, rs2069454, rs2069456 and rs2069459, predicted to affect transcription, were found to be bimorphic...
July 28, 2017: Scientific Reports
Kumar Nikhil, Kavita Shah
Cdk5 deregulation is highly neurotoxic in AD. We identified Mcl-1 as a direct Cdk5 substrate using an innovative chemical screen in mouse brain lysates. Our data demonstrate that Mcl-1 levels determine the threshold for cellular damage in response to neurotoxic insults. Mcl-1 is a disease-specific target of Cdk5, which associates with Cdk5 under basal conditions, however, is not regulated by it. Neurotoxic insults hyperactivate Cdk5 causing Mcl-1 phosphorylation at T92. This phosphorylation event triggers Mcl-1 ubiquitylation, which directly correlates with mitochondrial dysfunction...
July 27, 2017: Journal of Cell Science
Julia Lindqvist, Elin Torvaldson, Josef Gullmets, Henok Karvonen, Andras Nagy, Pekka Taimen, John E Eriksson
Nestin, a member of the cytoskeletal family of intermediate filaments, regulates the onset of myogenic differentiation through bidirectional signaling with the Cdk5-kinase. Here we show that these effects are also reflected at the organism level, as there is a loss of skeletal muscle mass in nestin(-/-) (NesKO) mice, reflected as reduced lean mass in the mice. Further examination of muscles in male mice revealed that these effects stemmed from nestin-deficient muscles being more prone to spontaneous regeneration...
July 21, 2017: Journal of Cell Science
Meng Lian, Haizhou Wang, Jugao Fang, Jie Zhai, Ru Wang, Xixi Shen, Yifan Yang, Zhihong Ma, Honggang Liu
OBJECTIVE: To screen out a set of candidate genes which could help to determine whether patients with hypopharyngeal squamous cell carcinoma (HSCC) could benefit from docetaxel, cisplatin and 5-fluorouracil (TPF) induction chemotherapy. METHODS: Gene-expression profiles in 12 TPF-sensitive patients were compared to 9 resistant controls by microarray analysis. Subsequently, expression levels of potential biomarkers in chemosensitive cell line FaDu after TPF treatment were observed by quantitative real-time polymerase chain reaction (qRT-PCR)...
June 2017: Chinese Journal of Cancer Research, Chung-kuo Yen Cheng Yen Chiu
Manali Dimri, Cassandra Bilogan, Lain X Pierce, Gregory Naegele, Amit Vasanji, Isabel Gibson, Allyson McClendon, Kevin Tae, Takuya F Sakaguchi
The intrahepatic biliary network is a highly branched three-dimensional network lined by biliary epithelial cells, but how its branching patterns are precisely established is not clear. We designed a new computer-based algorithm that quantitatively computes the structural differences of the three-dimensional networks. Utilizing the algorithm, we showed that inhibition of Cyclin-dependent kinase 5 (Cdk5) led to reduced branching in the intrahepatic biliary network in zebrafish. Further, we identified a previously unappreciated downstream kinase cascade regulated by Cdk5...
July 15, 2017: Development
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