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https://www.readbyqxmd.com/read/28179579/designing-of-dual-inhibitors-for-gsk-3%C3%AE-and-cdk5-virtual-screening-and-in-vitro-biological-activities-study
#1
Hongbo Xie, Haixia Wen, Denan Zhang, Lei Liu, Bo Liu, Qiuqi Liu, Qing Jin, Kehui Ke, Ming Hu, Xiujie Chen
Alzheimer's disease is a multifactorial neurodegenerative disorder with many drug targets contributing to its etiology. Despite the devastating effects of this disease, therapeutic methods for treating Alzheimer's disease remain limited. The multifactorial nature of Alzheimer's disease strongly supports a multi-target rationale as a drug design strategy. Glycogen synthase kinase-3 beta and cyclin-dependent kinase 5 have been identified as being involved in the pathological hyperphosphorylation of tau proteins, which leads to the formation of neurofibrillary tangles and causes Alzheimer's disease...
February 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28179473/dynamic-regulation-of-homer-binding-to-group-i-mglurs-by-preso1-and-converging-kinase-cascades
#2
Jia-Hua Hu, Paul F Worley, Paul Kammermeier
In rat sympathetic neurons from the superior cervical ganglia (SCG) expressing metabotropic glutamate receptors (mGluRs) 1 or 5, overexpression of scaffolding Homer proteins, which bind to a Homer ligand in their C-termini, cause receptor clustering and uncoupling from ion channel modulation. In the absence of recombinant Homer protein overexpression, uncoupling of mGluRs from voltage dependent channels can be induced by expression of Preso1, an adaptor of proline directed kinases that phosphorylates the Homer ligand and recruits binding of endogenous Homer proteins...
February 8, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28157684/cdk5-foxo3-axis-initially-neuroprotective-eventually-neurodegenerative-in-alzheimer-s-disease-models
#3
Chun Shi, Keith Viccaro, Hyoung-Gon Lee, Kavita Shah
Deregulated Cdk5 causes neurotoxic amyloid beta peptide (Aβ) processing and cell death, two hallmarks of Alzheimer's disease, through the Foxo3 transcriptional factor in hippocampal cells, primary neurons and an Alzheimer's disease mouse model. Using an innovative chemical genetic screen, we identified Foxo3 as a direct substrate of Cdk5 in brain lysates. Cdk5 directly phosphorylates Foxo3, which increased its levels and nuclear translocation. Nuclear Foxo3 initially rescued cells from ensuing oxidative stress by upregulating MnSOD (also known as SOD2)...
May 1, 2016: Journal of Cell Science
https://www.readbyqxmd.com/read/28153522/cdk5-inhibitors-prevent-astroglial-apoptosis-and-reactive-astrogliosis-by-regulating-pka-and-drp1-phosphorylations-in-the-rat-hippocampus
#4
Hye-Won Hyun, Su-Ji Min, Ji-Eun Kim
Status epilepticus (SE) results in the unique pattern of dynamin-related protein 1 (DRP1)-mediated mitochondrial dynamics, which is associated with astroglial apoptosis and reactive astrogliosis in the regional-specific pattern representing the differential astroglial properties. However, less defined are the epiphenomena/upstream effecters for DRP1 phosphorylation in this process. Since cyclin-dependent kinase 5 (CDK5) is involved in reactive astrogliosis, CDK5 is one of the possible upstream regulators for DRP1 phosphorylation...
January 30, 2017: Neuroscience Research
https://www.readbyqxmd.com/read/28129593/multi-step-virtual-screening-to-develop-selective-dyrk1a-inhibitors
#5
Tomoko Koyama, Noriyuki Yamaotsu, Izumi Nakagome, Shin-Ichiro Ozawa, Tomoki Yoshida, Daichi Hayakawa, Shuichi Hirono
Developing selective inhibitors for a particular kinase remains a major challenge in kinase-targeted drug discovery. Here we performed a multi-step virtual screening for dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) inhibitors by focusing on the selectivity for DYRK1A over cyclin-dependent kinase 5 (CDK5). To examine the key factors contributing to the selectivity, we constructed logistic regression models to discriminate between actives and inactives for DYRK1A and CDK5, respectively, using residue-based binding free energies...
January 15, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/28123545/increased-expression-of-s100a6-promotes-cell-proliferation-in-gastric-cancer-cells
#6
Xiao-Hong Wang, Hong Du, Lin Li, Duan-Fang Shao, Xi-Yao Zhong, Ying Hu, Yi-Qiang Liu, Xiao-Fang Xing, Xiao-Jing Cheng, Ting Guo, Shen Li, Zi-Yu Li, Zhao-De Bu, Xian-Zi Wen, Lian-Hai Zhang, Jia-Fu Ji
S100A6 is involved in regulating the progression of cancer. S100A6 can regulate the dynamics of cytoskeletal constituents, cell growth and differentiation by interacting with binding or target proteins. The present study investigated whether S100A6 affects cell proliferation in gastric cancer cells by stimulating several downstream factors. Firstly, the expression and localization of S100A6 were investigated using immunohistochemical staining, an immunoelectron microscopy and laser confocal scanning. A ChIP-Chip assay was performed to determine the downstream factors of S100A6 using promoter Chip analysis, including approximately the -800 to +200 regions around the transcription starting point...
January 2017: Oncology Letters
https://www.readbyqxmd.com/read/28123016/cdk5-regulation-of-the-grab-mediated-rab8-rab11-cascade-in-axon-outgrowth
#7
Kotaro Furusawa, Akiko Asada, Pamela Urrutia, Christian Gonzalez-Billault, Mitsunori Fukuda, Shin-Ichi Hisanaga
: Neurons communicate with each other through their axons and dendrites. However, a full characterization of the molecular mechanisms involved in axon and dendrite formation is still incomplete. Neurite outgrowth requires the supply of membrane components for surface expansion. Two membrane sources for axon outgrowth are suggested: Golgi secretary vesicles and endocytic recycling endosomes. In non-neuronal cells, trafficking of secretary vesicles from Golgi is regulated by Rab8, a member of Rab small GTPases, and that of recycling endosomes is by Rab11, another member of Rabs...
January 25, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28122114/serotonin-5-ht7-receptor-increases-the-density-of-dendritic-spines-and-facilitates-synaptogenesis-in-forebrain-neurons
#8
Luisa Speranza, Josephine Labus, Floriana Volpicelli, Daria Guseva, Enza Lacivita, Marcello Leopoldo, Gian Carlo Bellenchi, Umberto di Porzio, Monika Bijata, Carla Perrone-Capano, Evgeni Ponimaskin
Precise control of dendritic spine density and synapse formation is critical for normal and pathological brain functions. Therefore, signaling pathways influencing dendrite outgrowth and remodeling remain a subject of extensive investigations. Here we report that prolonged activation of the serotonin 5-HT7 receptor (5-HT7R) with selective agonist LP-211 promotes formation of dendritic spines and facilitates synaptogenesis in postnatal cortical and striatal neurons. Critical role of 5-HT7R in neuronal morphogenesis was confirmed by analysis of neurons isolated from 5-HT7R-deficient mice and by pharmacological inactivation of the receptor...
January 25, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28119482/the-emerging-role-of-cables1-in-cancer-and-other-diseases
#9
Jia-Rong Huang, Guang-Mou Tan, Yong Li, Zhi Shi
Cdk5 and Abl enzyme substrate (Cables) 1 is adaptor protein to link cyclin-dependent kinase (Cdks) with nonreceptor tyrosine kinases and regulate the activity of Cdks by enhancing their Y15 phosphorylation. The emerging evidences also show Cables1 can interact with p53 family proteins, 14-3-3, β-catenin and so on, suggesting Cables1 may be a signaling hub to regulate cell growth. Abnormal expression of Cables1 has been observed in multiple types of cancers and other disease. In this review, we summarize the characteristics of Cables1, and highlight the molecular mechanisms through which Cables1 regulates the development of cancer and other disease...
January 24, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28118639/cables1-inhibits-proliferation-and-induces-senescence-by-angiotensin-ii-via-a-p21-dependent-pathway-in-human-umbilical-vein-endothelial-cells
#10
Zhongyue Pu, Yongshun Wang, Xinxin Liu, Jingjin Liu, Jinjin Cui, Yan Wang, Bo Lv, Bo Yu
Cables1 (Cdk5 and Abl enzyme substrate 1) is a vital cell cycle regulator and a candidate tumor suppressor that negatively regulates cell growth by inhibiting cyclin-dependent kinases. Here, we report on the critical role of the Cables1/p21 pathway, which inhibits cell proliferation and induces cell senescence in human umbilical vein endothelial cells. Moreover, we confirmed that silencing of Cables1 promoted cell proliferation as well as increased resistance to angiotensin II-induced senescence, at least in part, by altering Cables1 activation...
January 25, 2017: Journal of Vascular Research
https://www.readbyqxmd.com/read/28115704/wave1-in-neurons-expressing-the-d1-dopamine-receptor-regulates-cellular-and-behavioral-actions-of-cocaine
#11
Ilaria Ceglia, Ko-Woon Lee, Michael E Cahill, Steven M Graves, David Dietz, Dalton J Surmeier, Eric J Nestler, Angus C Nairn, Paul Greengard, Yong Kim
Wiskott-Aldrich syndrome protein (WASP) family verprolin homologous protein 1 (WAVE1) regulates actin-related protein 2/3 (Arp2/3) complex-mediated actin polymerization. Our previous studies have found WAVE1 to be inhibited by Cdk5-mediated phosphorylation in brain and to play a role in the regulation of dendritic spine morphology. Here we report that mice in which WAVE1 was knocked out (KO) in neurons expressing the D1 dopamine receptor (D1-KO), but not mice where WAVE1 was knocked out in neurons expressing the D2 dopamine receptor (D2-KO), exhibited a significant decrease in place preference associated with cocaine...
February 7, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28112194/cyclin-i-like-ccni2-is-a-cyclin-dependent-kinase-5-cdk5-activator-and-is-involved-in-cell-cycle-regulation
#12
Chengcheng Liu, Xiaoyan Zhai, Bin Zhao, Yanfei Wang, Zhigang Xu
In contrast to conventional cyclin-dependent kinases that are important for mitotic cell division, cyclin-dependent kinase 5 (CDK5) is predominantly activated in post-mitotic cells and is involved in various cellular events. The kinase activity of CDK5 is tightly regulated by specific activators including p35, p39, and cyclin I (CCNI). Here we show that cyclin I-like (CCNI2), a homolog of CCNI, interacts with CDK5 and activates the kinase activity of CDK5. Different from CCNI, which colocalizes with CDK5 in the nuclei in transfected cells, CCNI2 mainly retains CDK5 in the cytoplasm as well as on the cell membrane...
January 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28107387/neuronal-cell-death-and-degeneration-through-increased-nitroxidative-stress-and-tau-phosphorylation-in-hiv-1-transgenic-rats
#13
Young-Eun Cho, Myoung-Hwa Lee, Byoung-Joon Song
The underlying mechanisms for increased neurodegeneration and neurocognitive deficits in HIV-infected people are unclear. Therefore, this study was aimed to investigate the mechanisms of increased neurodegeneration in 5-month old male HIV-1 Transgenic (Tg) rats compared to the age- and gender-matched wild-type (WT) by evaluating histological changes and biochemical parameters of the key proteins involved in the cell death signaling and apoptosis. Histological and immunohistochemical analyses revealed decreased neuronal cells with elevated astrogliosis in HIV-1 Tg rats compared to WT...
2017: PloS One
https://www.readbyqxmd.com/read/28105557/the-anticancer-drug-sunitinib-promotes-autophagyand-protects-from-neurotoxicity-in-an-hiv-1-tat-model-of-neurodegeneration
#14
Jerel A Fields, Jeff Metcalf, Cassia Overk, Anthony Adame, Brian Spencer, Wolfgang Wrasidlo, Jazmin Florio, Edward Rockenstein, Johnny J He, Eliezer Masliah
Despite the success of antiretroviral therapies to control systemic HIV-1 infection, the prevalence of HIV-associated neurocognitive disorders (HANDs) has not decreased among aging patients with HIV. Autophagy pathway alterations, triggered by HIV-1 proteins including gp120, Tat, and Nef, might contribute to the neurodegenerative process in aging patients with HAND. Although no treatments are currently available to manage HAND, we have previously shown that sunitinib, an anticancer drug that blocks receptor tyrosine-kinase and cyclin kinase pathways, might be of interest...
January 19, 2017: Journal of Neurovirology
https://www.readbyqxmd.com/read/28078567/the-c-abl-inhibitor-in-parkinson-disease
#15
REVIEW
Zhi-Hua Zhou, Yun-Fan Wu, Xue-Min Wang, Yong-Zhu Han
Parkinson's disease (PD) is an insidious onset neurodegenerative disease affecting approximately 1% of the population over the age of 65. So far available therapies for PD have only aimed at improving or alleviating symptoms, but not at slowing, preventing, and reversing the course of PD. Recently, some studies have indicated that the levels and activation of Abelson non-receptor tyrosine kinase (c-Abl, Abl1) were up-regulated in the brain tissue of patients with PD and demonstrated that c-Abl inhibitors could improve motor behavior, prevent the loss of dopamine neurons, inhibit phosphorylation of Cdk5, regulate α-synuclein phosphorylation and clearance, inhibit the tyrosine phosphorylation of parkin and decrease parkin substrate, for example, PARIS (zinc finger protein 746), AIMP2 (aminoacyl-tRNA synthetase-interacting multifunctional protein type2), FBP1 (fuse-binding protein 1), and synphilin-1...
January 11, 2017: Neurological Sciences
https://www.readbyqxmd.com/read/28077789/biological-functions-of-cdk5-and-potential-cdk5-targeted-clinical-treatments
#16
REVIEW
Alison Shupp, Mathew C Casimiro, Richard G Pestell
Cyclin dependent kinases are proline-directed serine/threonine protein kinases that are traditionally activated upon association with a regulatory subunit. For most CDKs, activation by a cyclin occurs through association and phosphorylation of the CDK's T-loop. CDK5 is unusual because it is not typically activated upon binding with a cyclin and does not require T-loop phosphorylation for activation, even though it has high amino acid sequence homology with other CDKs. While it was previously thought that CDK5 only interacted with p35 or p39 and their cleaved counterparts, Recent evidence suggests that CDK5 can interact with certain cylins, amongst other proteins, which modulate CDK5 activity levels...
January 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/28064242/cyclin-dependent-kinase-5-activity-is-required-for-allogeneic-t-cell-responses-after-hematopoietic-cell-transplantation-in-mice
#17
David Askew, Tej K Pareek, Saada Eid, Sudipto Ganguly, Megan Tyler, Alex Y Huang, John J Letterio, Kenneth R Cooke
Molecular intermediates in T-cell activation pathways are crucial targets for the therapy and prevention of graft-versus-host disease (GVHD) following allogeneic hematopoietic cell transplantation (allo-HCT). We recently identified an essential role for cyclin-dependent kinase 5 (Cdk5) in T-cell activation and effector function, but the contribution of Cdk5 activity to the development of GVHD has not been explored. Using an established, preclinical, murine, GVHD model, we reveal that Cdk5 activity is increased in key target organs early after allo-HCT...
January 12, 2017: Blood
https://www.readbyqxmd.com/read/28052097/the-natural-flavonoid-fisetin-inhibits-cellular-proliferation-of-hepatic-colorectal-and-pancreatic-cancer-cells-through-modulation-of-multiple-signaling-pathways
#18
Mаhmoud Youns, Wael Abdel Halim Hegazy
Digestive cancers are major causes of mortality and morbidity worldwide. Fisetin, a naturally occurring flavonoid, has been previously shown anti-proliferative, anti-cancer, neuroprotective, and antioxidant activities. In our study, the anti-tumor activities in addition to regulatory effects of fisetin on some cancer cell lines were investigated. Data presented here showed that fisetin induces growth inhibition, and apoptosis in hepatic (HepG-2), colorectal (Caco-2) and pancreatic (Suit-2) cancer cell lines...
2017: PloS One
https://www.readbyqxmd.com/read/28045138/tfp5-peptide-derived-from-cdk5-activating-cofactor-p35-provides-neuroprotection-in-early-stage-of-adult-ischemic-stroke
#19
Ya-Bin Ji, Pei-Pei Zhuang, Zhong Ji, Yong-Ming Wu, Yong Gu, Xiao-Ya Gao, Su-Yue Pan, Ya-Fang Hu
Cyclin-dependent kinase 5 (CDK5) is a multifaceted protein shown to play important roles in the central nervous system. Abundant evidence indicates that CDK5 hyperactivities associated with neuronal apoptosis and death following ischemic stroke. CDK5 activity increases when its cofactor p35 cleaves into p25 during ischemia. Theoretically, inhibition of CDK5/p25 activity or reduction of p25 would be neuroprotective. TFP5, a modified 24-aa peptide (Lys254-Ala277) derived from p35, was found to effectively inhibit CDK5 hyperactivity and improve the outcomes of Alzheimer's disease and Parkinson's disease in vivo...
January 3, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28024901/cyclin-dependent-kinase-5-contributes-to-endoplasmic-reticulum-stress-induced-podocyte-apoptosis-via-promoting-mekk1-phosphorylation-at-ser280-in-diabetic-nephropathy
#20
Yue Zhang, Xiang Gao, Shuanggang Chen, Min Zhao, Jing Chen, Rui Liu, Shengyang Cheng, Mengyuan Qi, Shuo Wang, Wei Liu
Endoplasmic reticulum (ER) stress has been reported to be associated with podocyte apoptosis in diabetic nephropathy, but the mechanism of ER signaling in podocyte apoptosis hasn't been fully understood. Our previous studies have demonstrated that Cyclin-dependent kinase 5 (Cdk5) was associated with podocyte apoptosis in diabetic nephropathy. The present study was designed to examine whether and how Cdk5 activity plays a role in ER stress induced podocyte apoptosis in diabetic nephropathy. The results showed that along with induction of Cdk5 and apoptosis, GRP78 and its two sensors as well as CHOP and cleaved caspase-12 were induced in high glucose treated podocytes...
February 2017: Cellular Signalling
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