Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.22 (cdc2)
 8,319 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

TDP-43 (for TAR DNA binding protein) is a highly conserved heterogeneous nuclear ribonucleoprotein (hnRNP) involved in specific pre-mRNA splicing and transcription events. TDP-43 recently has been identified as the main component of cytoplasmic inclusions in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS), two neurodegenerative disorders. The cellular role of this protein remains to be identified. Here, we show that loss of TDP-43 results in dysmorphic nuclear shape, misregulation of the cell cycle, and apoptosis. Removal of TDP-43 in human cells significantly increases cyclin-dependent kinase 6 (Cdk6) protein and transcript levels. The control of Cdk6 expression mediated by TDP-43 involves GT repeats in the target gene sequence. Cdk6 up-regulation in TDP-43-depleted cells is accompanied by an increase in phosphorylation of two of its major targets, the retinoblastoma protein pRb and pRb-related protein pRb2/p130. TDP-43 silencing also is followed by changes in the expression levels of several factors that control cell proliferation. Morphological nuclear defects and increased apoptosis upon TDP-43 loss are mediated via the pRb pathway because pRb-negative cells (Saos-2) do not undergo programmed cell death or nuclear shape deformation upon TDP-43 removal. Our results identify a regulatory target of TDP-43 and show that TDP-43 depletion has important consequences in essential metabolic processes in human cells.
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PMID:TDP-43 regulates retinoblastoma protein phosphorylation through the repression of cyclin-dependent kinase 6 expression. 1830 52

Amyotrophic lateral sclerosis (ALS) is primarily a motor neuron disorder. Intriguingly, early muscle denervation preceding motor neuron loss is observed in mouse models of ALS. Enhanced muscle vulnerability to denervation process has been suggested by accelerated muscle deterioration following peripheral nerve injury in an ALS mouse model. Here we provide evidence of biochemical changes in the hindlimb muscle of young, presymptomatic G93A hSOD1 transgenic mice. In this report, we demonstrate that cdk5 activity is reduced in hindlimb muscle of 27-day-old G93A hSOD1 transgenic mice. In vitro analysis revealed mutant hSOD1-mediated suppression of cdk5 activity. Furthermore, the decrease in muscle cdk5 activity was accompanied by a significant reduction in MyoD and cyclin D1 levels. These early muscle changes raise the possibility that the progressive deterioration of muscle function is potentiated by altered muscle biochemistry in these mice at a very young, presymptomatic age.
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PMID:Presymptomatic biochemical changes in hindlimb muscle of G93A human Cu/Zn superoxide dismutase 1 transgenic mouse model of amyotrophic lateral sclerosis. 1848 20

Cyclin-dependent kinase 5 (Cdk5) was identified almost two decades ago as a Tau kinase specific to the nervous system. Shortly after its discovery, it was revealed that this atypical member of the CDK family does not partner with cyclins but with two other proteins, p35 and p39. P35 is predominantly expressed in post-mitotic neurons, whereas p39 is expressed in many different tissues including the brain, pancreas, muscle cells, neutrophils, and many other cell types. A proline-directed serine/threonine (S/T) kinase, predominantly active in the nervous system, Cdk5 regulates a multitude of functions including nervous system development, neuronal migration, cytoskeletal dynamics, axonal guidance, synaptic plasticity, neurotransmission, neuronal survival and death, to mention a few. In association with its ubiquitous expression in other tissues, Cdk5 is implicated in a wide range of functions, such as gene transcription, vesicular transport, apoptosis, cell adhesion, migration, exocytosis, etc. A focal point of investigation surrounding Cdk5 is its deregulation in pathogenic processes of neurodegenerative disorders, which has emphasized on its hyperactivation by p25, a calpain-cleaved product of p35 leading to Tau and neurofilament hyperphosphorylation followed by neuronal death. What has intrigued researchers about Cdk5 is its tight regulation in carrying out many normal physiological functions while its deregulation under pathological conditions, is linked to neurodegenerative diseases like amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Neiman Pick's Type C disease and others. Between these two so-called 'good Cdk5 (Cdk5/p35)' and 'bad Cdk5 (Cdk5/p25)', the latter has become the target for therapeutic intervention in neurodegenerative disorders.
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PMID:Special Issue on "Cdk5 and Brain Disorders": Prologue. 2806 92


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