Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.22.61 (caspase-8)
 6,833 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fas-induced death of motoneurons in vitro has been shown to involve two signaling cascades that act together to execute the death program: a Fas-Daxx-ASK-1-p38 kinase-nNOS branch, which controls transcriptional and post-translational events, and the second classical Fas-FADD-caspase-8 branch. To analyze the role of Daxx in the developmental motoneuron cell death, we studied Fas-dependent cell death in motoneurons from transgenic mice that overexpress a dominant-negative form of Daxx. Motoneurons purified from these transgenic mice are resistant to Fas-induced death. This protective effect is specific to Fas because ultraviolet irradiation-triggered death is not affected by the transgene. The Daxx and the FADD pathways work in parallel because only Daxx, but not FADD, is involved in the transcriptional control of neuronal nitric oxide synthase and nitric oxide production. Nevertheless, we do not observe involvement of Daxx in developmental motoneuronal cell death, as the pattern of naturally occurring programmed cell death in vivo is normal in transgenic mice overexpressing the dominant negative form of Daxx, suggesting that Daxx-independent pathways are used during development.
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PMID:Expression of a dominant negative form of Daxx in vivo rescues motoneurons from Fas (CD95)-induced cell death. 1545 96

A growing body of evidence suggests oxidative stress involvement in neurodegenerative diseases; however, it remains to be determined whether oxidative stress is a cause, result, or epiphenomenon of the pathological processes. This review concerns the current issue, focusing on Alzheimer disease (AD), Parkinson disease (PD), and amyotrophic lateral sclerosis (ALS). Several studies have indicated that oxidative stress initially occurs in the disease-specific, site-restricted sources such as amyloid-beta in the cerebral cortex of AD brain, alpha-synuclein in the brain stem of PD brain, and glutamate receptor-coupled Ca2+ channel in the motor system of ALS spinal cord. Subsequent events in the neurons common to these diseases are glutamate-induced neurotoxicity and increased cytosolic Ca2+ levels, resulting in activation of Ca2+ -dependent enzymes including NADPH oxidase, cytosolic phospholipase A2, xanthine oxidase, and neuronal nitric oxide synthase (NOS). These enzymes produce reactive oxygen and nitrogen species (ROS/RNS), which oxidatively modify nucleic acid, lipid, sugar, and protein, leading to nuclear damage, mitochondrial damage, proteasome inhibition, and endoplasmic reticulum (ER) stress. Mitochondrial damage results in both ROS leakage from the electron transport system and Ca2+ release. Nuclear damage induces p53 activation, and proteasome inhibition reduces p53 degradation. The resultant increased p53 levels in the nucleus induce Bax activation and Bcl-2 inhibition, followed by a release of cytochrome c into the cytosol that truncates procaspase-9. ER stress triggers activation of caspase-12 as well as caspase-9 via the tumor necrosis factor (TNF) receptor-associated factor-2 / apoptosis-signaling kinase-1 / c-Jun N-terminal kinase pathway. Oxidative stress also stimulates astrocytes and microglia to yield and secrete cytokines such as TNFa and FasL that cause not only neuronal caspase-8 activation but also glial inflammatory response through induction of nuclear factor-kappaB-mediated, proinflammatory gene products including cytokines, chemokines, growth factors, cell adhesion molecules, and ROS/RNS-producing enzymes. The activated caspases truncate procaspase-3 to exert classical apoptosis. Moreover, oxidative DNA damage leads to the release and nuclear truncation of mitochondrial apoptosis-inducing kinase, which triggers apoptosis-like programmed cell death via cyclophilin A. These observations could indicate crucial implications for oxidative stress in several steps of the pathomechanisms of neurodegenerative diseases.
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PMID:[The role for oxidative stress in neurodegenerative diseases]. 1830 64

The work studied vasopressinergic neurons of hypothalamic supraoptic and paravenricular nuclei of the wild type mice and the neuronal nitric oxide synthase (nNOS) gene knockouted mice at a decrease of the brain catecholamine (CA) level caused by administration of the blocker of activity of tyrosine hydroxylase alpha-methyl-paratyrosine (alpha-MPT) and at the CA level decrease on the background of functional activity of the vasopressinergic neurons caused by dehydration of animals. There were analyzed changes in the number of neurons in both magnocellular hypothalamic nuclei expressing proapoptotic proteins caspase-8 and caspase-9, p53, and antiapoptotic protein Bcl-2. The disturbance of the CA-ergic innervation was shown to be a strong damaging factor leading to apoptosis of neurons regardless of the presence of nNOS in the cells. However, at disturbance of the CA-ergic innervation due to the 5-day mouse dehydration, no death of neurons by apoptosis was revealed. Thus, it is possible that functional activation prevents the hypothalamic vasopressinergic neurons from death at a decrease of the CA level in brain. The main difference of the nNOS gene knockouts is the absence of activation of the Bcl-2 expression under all used actions. This confirms our suggestion about interaction of CA and NO in triggering of expression of the antiapoptotic protein Bcl-2.
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PMID:[Interaction of neuronal NOS and catecholamines in regulation of expression of proteins of apoptosis by vasopressinergic hypothalamic neurons]. 2178 Jun 43