Редактирование: CDK5 (раздел)

==Publications==

{{medline-entry
|title=Age-related hyperinsulinemia leads to insulin resistance in neurons and cell-cycle-induced senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31636448
|abstract=Prediabetes and Alzheimer's disease both increase in prevalence with age. The former is a risk factor for the latter, but a mechanistic linkage between them remains elusive. We show that prediabetic serum hyperinsulinemia is reflected in the cerebrospinal fluid and that this chronically elevated insulin renders neurons resistant to insulin. This leads to abnormal electrophysiological activity and other defects. In addition, neuronal insulin resistance reduces hexokinase 2, thus impairing glycolysis. This hampers the ubiquitination and degradation of p35, favoring its cleavage to p25, which hyperactivates [[CDK5]] and interferes with the GSK3β-induced degradation of β-catenin. [[CDK5]] contributes to neuronal cell death while β-catenin enters the neuronal nucleus and re-activates the cell cycle machinery. Unable to successfully divide, the neuron instead enters a senescent-like state. These findings offer a direct connection between peripheral hyperinsulinemia, as found in prediabetes, age-related neurodegeneration and cognitive decline. The implications for neurodegenerative conditions such as Alzheimer's disease are described.
|mesh-terms=* Aging
* Animals
* Cell Cycle
* Cell Death
* Cellular Senescence
* Cyclin-Dependent Kinase 5
* Excitatory Postsynaptic Potentials
* Gene Expression
* Glycolysis
* Hexokinase
* Hyperinsulinism
* Inhibitory Postsynaptic Potentials
* Insulin
* Insulin Resistance
* Liraglutide
* Male
* Maze Learning
* Metformin
* Mice
* Neurons
* Phosphotransferases
* Primary Cell Culture
* Protein-Serine-Threonine Kinases
* Ubiquitination
* beta Catenin

|full-text-url=https://sci-hub.do/10.1038/s41593-019-0505-1
}}
{{medline-entry
|title=CK2 inhibition protects white matter from ischemic injury.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30125643
|abstract=Strokes occur predominantly in the elderly and white matter (WM) is injured in most strokes, contributing to the disability associated with clinical deficits. Casein kinase 2 (CK2) is expressed in neuronal cells and was reported to be neuroprotective during cerebral ischemia. Recently, we reported that CK2 is abundantly expressed by glial cells and myelin. However, in contrast to its role in cerebral (gray matter) ischemia, CK2 activation during ischemia mediated WM injury via the [[CDK5]] and AKT/GSK3β signaling pathways (Bastian et al., 2018). Subsequently, CK2 inhibition using the small molecule inhibitor CX-4945 correlated with preservation of oligodendrocytes as well as conservation of axon structure and axonal mitochondria, leading to improved functional recovery. Notably, CK2 inhibition promoted WM function when applied before or after ischemic injury by differentially regulating the [[CDK5]] and AKT/GSK3β pathways. Specifically, blockade of the active conformation of AKT conferred post-ischemic protection to young, aging, and old WM, suggesting a common therapeutic target across age groups. CK2 inhibitors are currently being used in clinical trials for cancer patients; therefore, it is important to consider the potential benefits of CK2 inhibitors during an ischemic attack.
|mesh-terms=* Animals
* Brain Ischemia
* Casein Kinase II
* Humans
* Naphthyridines
* Neuroprotective Agents
* White Matter
|keywords=* Aging
* CK2
* Casein kinase 2
* Ischemia
* Protein kinase
* Signaling
* Stroke
|full-text-url=https://sci-hub.do/10.1016/j.neulet.2018.08.021
}}
{{medline-entry
|title=CK2 inhibition confers functional protection to young and aging axons against ischemia by differentially regulating the [[CDK5]] and AKT signaling pathways.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29944965
|abstract=White matter (WM) is injured in most strokes, which contributes to functional deficits during recovery. Casein kinase 2 (CK2) is a protein kinase that is expressed in brain, including WM. To assess the impact of CK2 inhibition on axon recovery following oxygen glucose deprivation (OGD), mouse optic nerves (MONs), which are pure WM tracts, were subjected to OGD with or without the selective CK2 inhibitor CX-4945. CX-4945 application preserved axon function during OGD and promoted axon function recovery when applied before or after OGD. This protective effect of CK2 inhibition correlated with preservation of oligodendrocytes and conservation of axon structure and axonal mitochondria. To investigate the pertinent downstream signaling pathways, siRNA targeting the CK2α subunit identified [[CDK5]] and AKT as downstream molecules. Consequently, MK-2206 and roscovitine, which are selective AKT and [[CDK5]] inhibitors, respectively, protected young and aging WM function only when applied before OGD. However, a novel pan-AKT allosteric inhibitor, ARQ-092, which targets both the inactive and active conformations of AKT, conferred protection to young and aging axons when applied before or after OGD. These results suggest that AKT and [[CDK5]] signaling contribute to the WM functional protection conferred by CK2 inhibition during ischemia, while inhibition of activated AKT signaling plays the primary role in post-ischemic protection conferred by CK2 inhibition in WM independent of age. CK2 inhibitors are currently being used in clinical trials for cancer patients; therefore, our results will provide rationale for repurposing these drugs as therapeutic options for stroke patients by adding novel targets.
|mesh-terms=* Aging
* Animals
* Axons
* Brain Ischemia
* Casein Kinase II
* Cyclin-Dependent Kinase 5
* Male
* Mice
* Mice, Inbred C57BL
* Proto-Oncogene Proteins c-akt
* Signal Transduction
|keywords=* Aging
* Myelin
* Oligodendrocyte
* Stroke
* White matter
|full-text-url=https://sci-hub.do/10.1016/j.nbd.2018.05.011
}}
{{medline-entry
|title=The pathological roles of [[NDRG2]] in Alzheimer's disease, a study using animal models and APPwt-overexpressed cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28670853
|abstract=To investigate the roles of N-myc downstream-regulated gene 2 ([[NDRG2]]) in the pathology of aging and neurodegenerative disease such as Alzheimer's disease (AD). In this study, we confirmed the upregulation of [[NDRG2]] in the brains of aging and AD animal models. To explore the role of [[NDRG2]] in the pathology of AD at molecular level, we conducted a cell-based assay of highly expressed wild-type human APP695 SK-N-SH cells (SK-N-SH APPwt). By silencing and overexpressing gene of [[NDRG2]], we demonstrated that [[NDRG2]]-mediated increase in Aβ  was through the pathways of [[BACE1]] and [[GGA3]]. NGRG2 improved tau phosphorylation via enhanced activity of [[CDK5]] and decreased Pin1, but it was not affected by GSK3β pathway. [[NDRG2]] might also induce cell apoptosis through the extrinsic (caspase 8) apoptotic pathway by interaction with [[STAT3]]. Our study confirmed the upregulation of [[NDRG2]] in AD animal models and demonstrated its important roles in AD pathology. [[NDRG2]] might be a potential target for studying and treatment of AD.
|mesh-terms=* Adaptor Proteins, Signal Transducing
* Aging
* Alzheimer Disease
* Amyloid beta-Peptides
* Amyloid beta-Protein Precursor
* Animals
* Apoptosis
* Brain
* Cell Line, Tumor
* Cell Survival
* Disease Models, Animal
* Humans
* Male
* Mice, Inbred ICR
* Mice, Transgenic
* Nerve Tissue Proteins
* Peptide Fragments
* Presenilin-1
* Proteins
* Rats, Sprague-Dawley
* Tumor Suppressor Proteins
|keywords=* Alzheimer's disease
* NDRG2
* apoptosis
* beta-amyloid
* tau phosphorylation
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6492714
}}
{{medline-entry
|title=[[APOE]]4 Induces Site-Specific Tau Phosphorylation Through Calpain-[[CDK5]] Signaling Pathway in EFAD-Tg Mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27087442
|abstract=[[APOE]]4 is the greatest genetic risk factor for Alzheimer's disease (AD), particularly associated with increased levels of amyloid-β (Aβ) and amyloid deposition. However, it remains unclear whether [[APOE]]4 is associated with greater tau phosphorylation and neurofibrillary tangle formation, a hallmark of AD leading to structural disruption of the neuronal cytoskeleton. The current study used 3 and 7 month old EFAD mice, which express human [[APOE]] and over-express specifically human Aβ42 via 5 familial-AD (FAD) mutations, to investigate [[APOE]] genotype-specific effects on site-specific tau phosphorylation. The results reveal that AD-like site-specific tau phosphorylation was increased in E4FAD mice, accompanied by disrupted cortical neuronal morphology, compared to E3FAD mice. Further analysis demonstrated that the levels of [[CDK5]], its regulatory subunits (p35 and p25) and calpain (including calpain1 and calpain2), but not GSK3β, were significantly increased in E4FAD mice compared to E3FAD mice. These results suggest that the [[APOE]]4 genotype contributes to increased site-specific tau phosphorylation via activation of the calpain-[[CDK5]] signaling pathway.
|mesh-terms=* Aging
* Amyloid beta-Peptides
* Animals
* Apolipoprotein E4
* Calpain
* Cerebral Cortex
* Cyclin-Dependent Kinase 5
* Glycogen Synthase Kinase 3 beta
* Humans
* Male
* Mice, Transgenic
* Mutation
* Neurons
* Peptide Fragments
* Phosphorylation
* Signal Transduction
* tau Proteins

|full-text-url=https://sci-hub.do/10.2174/1567205013666160415154550
}}
{{medline-entry
|title=GENETICS OF HUMAN AGE RELATED DISORDERS.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26856084
|abstract=Aging is an inevitable biological phenomenon. The incidence of age related disorders (ARDs) such as cardiovascular diseases, cancer, arthritis, dementia, osteoporosis, diabetes, neurodegenerative diseases increase rapidly with aging. ARDs are becoming a key social and economic trouble for the world's elderly population (above 60 years), which is expected to reach 2 billion by 2050. Advancement in understanding of genetic associations, particularly through genome wide association studies (GWAS), has revealed a substantial contribution of genes to human aging and ARDs. In this review, we have focused on the recent understanding of the extent to which genetic predisposition may influence the aging process. Further analysis of the genetic association studies through pathway analysis several genes associated with multiple ARDs have been highlighted such as apolipoprotein E (APOE), brain-derived neurotrophic factor (BDNF), cadherin 13 (CDH13), [[CDK5]] regulatory subunit associated protein 1 (CDKAL-1), methylenetetrahydrofolate reductase (MTHFR), disrupted in schizophrenia 1 (DISC1), nitric oxide synthase 3 (NOS3), paraoxonase 1 (PON1), indicating that these genes could play a pivotal role in ARD causation. These genes were found to be significantly enriched in Jak-STAT signalling pathway, asthma and allograft rejection. Further, interleukin-6 (IL-6), insulin (INS), vascular endothelial growth factor A (VEGFA), estrogen receptor1 (ESR1), transforming growth factor, beta 1(TGFB1) and calmodulin 1 (CALM1) were found to be highly interconnected in network analysis. We believe that extensive research on the presence of common genetic variants among various ARDs may facilitate scientists to understand the biology behind ARDs causation.
|mesh-terms=* Aged
* Aging
* Genetic Predisposition to Disease
* Genome-Wide Association Study
* Humans


}}
{{medline-entry
|title=Surgical stress induces brain-derived neurotrophic factor reduction and postoperative cognitive dysfunction via glucocorticoid receptor phosphorylation in aged mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/25611431
|abstract=This study explored whether surgical stress-induced glucocorticoid receptor (GR) phosphorylation is related to postoperative cognitive dysfunction (POCD) in aged individuals. Inhibition of GR activation could be an effective treatment for POCD. A laparotomy was given to C57/BL6 mice in POCD group both 20 and 6 months old. Animals in control group were treated in identical manners except for laparotomy. Cognitive function was evaluated by Morris water maze and elevated plus maze. Western blot and Elisa assay were used to detect related molecules. Mifepristone and roscovitine were treated as inhibitions of GR phosphorylation. The cognitive function was impaired, and brain-derived neurotrophic factor (BDNF) was found reduced in aged POCD group. GR translocation into nucleus and elevated GR phosphorylation were found in prefrontal cortex of aged POCD mice. Cyclin-dependent Kinase 5 ([[CDK5]]), kinase for GR phosphorylation also elevated in aged POCD mice. With GR antagonist and [[CDK5]] inhibitor, reduction of BDNF and cognitive dysfunction in aged mice were both rescued. These results presented a mechanism that surgical stress-induced GR phosphorylation contributes to POCD in aged individuals. Inhibition of GR activation and phosphorylation might be a potential treatment target of POCD.
|mesh-terms=* Active Transport, Cell Nucleus
* Aging
* Animals
* Brain-Derived Neurotrophic Factor
* Cognition Disorders
* Cyclin-Dependent Kinase 5
* Disease Models, Animal
* Laparotomy
* Male
* Maze Learning
* Mice, Inbred C57BL
* Phosphorylation
* Postoperative Complications
* Prefrontal Cortex
* Receptors, Glucocorticoid
* Stress, Physiological
|keywords=* Aging
* Brain-derived neurotrophic factor (BDNF)
* GR phosphorylation
* Postoperative cognitive dysfunction (POCD)
* Surgical stress
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6495659
}}
{{medline-entry
|title=Loss-of-[[SIRT1]] function during vascular ageing: hyperphosphorylation mediated by cyclin-dependent kinase 5.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23968571
|abstract=The longevity regulator [[SIRT1]] is an enzyme catalyzing the deacetylation of protein substrates, in turn modulating their biological functions. In endothelial cells, downregulation of [[SIRT1]] evokes cellular senescence. In aged arteries, [[SIRT1]] expression and activity is blunted, which contributes to the development of atherosclerosis and abnormal vascular responses. A recent study suggests that cyclin-dependent kinase 5 ([[CDK5]]) is responsible for the phosphorylation of [[SIRT1]] at the serine 47 residue. This modification blocks the anti-senescence activity of [[SIRT1]] and plays a critical role in the loss-of-[[SIRT1]] function during vascular ageing. Thus, by inhibiting [[CDK5]], [[SIRT1]] function can be improved, in turn preventing the development of atherosclerosis and slowing down the process of vascular ageing. 
|mesh-terms=* Age Factors
* Aging
* Animals
* Arteries
* Atherosclerosis
* Cyclin-Dependent Kinase 5
* Endothelial Cells
* Humans
* Phosphorylation
* Signal Transduction
* Sirtuin 1

|full-text-url=https://sci-hub.do/10.1016/j.tcm.2013.07.001
}}
{{medline-entry
|title=Neuroprotective and anti-ageing role of leptin.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/22967480
|abstract=Leptin (Lep), an adipose-derived hormone, exerts very important functions in the body mainly on energy storage and availability. The physiological effects of Lep controlling the body weight and suppressing appetite are mediated by the long form of Lep receptor in the hypothalamus. Lep receptor activates several downstream molecules involved in key pathways related to cell survival such as [[STAT3]], PI3K, MAPK, AMPK, [[CDK5]] and GSK3β. Collectively, these pathways act in a coordinated manner and form a network that is fully involved in Lep physiological response. Although the major interest in Lep is related to its role in the regulation of energy balance, and since resistance to Lep affects is the primary risk factor for obesity, the interest on their effects on brain cognition and neuroprotection is increasing. Thus, Lep and Lep mimetic compounds now await and deserve systematic exploration as the orchestrator of protective responses in the nervous system. Moreover, Lep might promote the activation of a cognitive process that may retard or even partially reverse selected aspects of Alzheimer's disease or ageing memory loss.
|mesh-terms=* Aging
* Animals
* Cognition
* Humans
* Hypothalamus
* Leptin
* Models, Biological
* Receptors, Leptin

|full-text-url=https://sci-hub.do/10.1530/JME-12-0151
}}
{{medline-entry
|title=Expression of second messenger- and cyclin-dependent protein kinases during postnatal development of rat heart.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/9620176
|abstract=During early postnatal development, cardiomyocytes, which comprise about 80% of ventricular mass and volume, become phenotypically developed to facilitate their contractile functions and terminally differentiated to grow only in size but not in cell number. These changes are due to the expression of contractile proteins as well as the regulation of intracellular signal transduction proteins. In this study, the expression patterns of several protein kinases involved in various cardiac functions and cell-cycle control were analyzed by Western blotting of ventricular extracts from 1-, 10-, 20-, 50-, and 365-day-old rats. The expression level of cAMP-dependent protein kinase was slightly decreased (20%) over the first year, whereas no change was detected in cGMP-dependent protein kinase I. Calmodulin-dependent protein kinase II, which is involved in Ca2  uptake into the sarcoplasmic reticulum, was increased as much as ten-fold. To the contrary, the expressions of protein kinase C-alpha and iota declined 77% with age. Cyclin-dependent protein kinases (CDKs) such as [[CDK1]], [[CDK2]], [[CDK4]], and [[CDK5]], which are required for cell-cycle progression, abruptly declined to almost undetectable levels after 10-20 days of age. In contrast, other CDK-related kinases, such as [[CDK8]] or Kkialre, did not change significantly or increased up to 50% with age, respectively. Protein kinases implicated in CDK regulation such as [[CDK7]] and Wee1 were either slightly increased in expression or did not change significantly. All of the proteins that were detected in ventricular extracts were also identified in isolated cardiac myocytes in equivalent amounts and analyzed for their relative expression in ten other adult rat tissues.
|mesh-terms=* Aging
* Amino Acid Sequence
* Animals
* Blotting, Western
* Calcium-Calmodulin-Dependent Protein Kinase Type 2
* Calcium-Calmodulin-Dependent Protein Kinases
* Cell Cycle Proteins
* Cell Extracts
* Cyclic Nucleotide-Regulated Protein Kinases
* Cyclin-Dependent Kinases
* Heart Ventricles
* Male
* Molecular Sequence Data
* Myocardium
* Nuclear Proteins
* Organ Specificity
* Protein Kinase C
* Protein-Tyrosine Kinases
* Rats
* Rats, Sprague-Dawley
* Second Messenger Systems

|full-text-url=https://sci-hub.do/10.1002/(sici)1097-4644(19980615)69:4<506::aid-jcb11>3.0.co;2-6
}}
{{medline-entry
|title=Expression of [[CDK5]] (PSSALRE kinase), a neural cdc2-related protein kinase, in the mature and developing mouse central and peripheral nervous systems.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/7834371
|abstract=[[CDK5]] is a cdc2-related protein kinase that is known to be highly expressed in mature brain. In this study, we obtained a mouse [[CDK5]] cDNA by screening an adult mouse cDNA library. Northern blot analysis demonstrated that the mouse [[CDK5]] mRNA was expressed especially highly in brain, and moderately in kidney, testis and ovary. In brain the expression of [[CDK5]] is already seen at embryonal 12.5 days (E12.5), and it gradually increases through the embryonal stage. After birth, the expression is maintained at a high level to adulthood. In situ hybridization demonstrated that the expression of [[CDK5]] mRNA was distributed in neurons throughout the brain, spinal cord and peripheral ganglia, especially in the hippocampal pyramidal cells, cerebellar Purkinje cells, cortical neurons, olfactory mitral cells, mesencephalic and motor trigeminal nuclei and trigeminal ganglion. In any portion, no apparent expression was observed in glia. During development, the expression of [[CDK5]] was already seen at E12.5 intensely in trigeminal and dorsal root ganglia, and moderately and diffusely in the central nervous system. The expression pattern of [[CDK5]] is quite in contrast with that of CDC2. The fact that [[CDK5]] is expressed in terminally differentiated non-dividing neurons predicts an alternative function(s) in addition to controlling the cell cycle.
|mesh-terms=* Aging
* Amino Acid Sequence
* Animals
* Base Sequence
* Blotting, Northern
* Brain
* Cerebellum
* Cyclin-Dependent Kinase 5
* Cyclin-Dependent Kinases
* DNA Primers
* DNA, Complementary
* Female
* Gene Expression
* Hippocampus
* In Situ Hybridization
* Kidney
* Male
* Mice
* Molecular Sequence Data
* Neurons
* Organ Specificity
* Ovary
* Peripheral Nerves
* Polymerase Chain Reaction
* Protein-Serine-Threonine Kinases
* RNA, Messenger
* Spinal Cord
* Testis

|full-text-url=https://sci-hub.do/10.1016/0006-8993(94)91197-5
}}