Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The objective of this study was examine whether the inducible isoform of the enzyme cyclooxygenase (COX-2) was expressed in dying oligodendrocytes in the Theiler's murine encephalomyelitis virus (TMEV) induced demyelinating disease (TMEV-IDD), an experimental animal model for multiple sclerosis (MS). COX-2 is an enzyme that is tightly coupled to neuronal excitotoxic death. Since neuronal expression of COX-2 contributes to the susceptibility of neurons to excitotoxic death, we asked whether COX-2 was expressed in oligodendrocytes in MS plaques and in lesions during TMEV-IDD. COX-2 was expressed in oligodendrocytes in chronic active lesions from two MS patients. Similar pathology was present in TMEV-IDD spinal cord lesions. COX-2 was expressed in oligodendrocytes four weeks after infection with TMEV coincident with the onset of demyelination. A marker for apoptotic death, activated caspase 3, was present in a subset of oligodendrocytes that expressed COX-2. Oligodendrocyte expression of COX-2 in TMEV-IDD and MS lesions is consistent with a pathological role for this enzyme in demyelination. The presence of the cell death marker (activated caspase 3) with COX-2 in oligodendrocytes is direct evidence linking COX-2 with cell death of oligodendrocytes in these demyelinating diseases.
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PMID:The pathologic role for COX-2 in apoptotic oligodendrocytes in virus induced demyelinating disease: implications for multiple sclerosis. 1651 8

Cellular apoptosis induced by viral genes can play a critical role in determining virulence as well as viral persistence. This form of cell death has been of interest with respect to Theiler's murine encephalomyelitis virus (TMEV) because the GDVII strain and members of the GDVII subgroup are highly neurovirulent, while the DA strain and members of the TO subgroup induce a chronic progressive inflammatory demyelination with persistence of the virus in the central nervous system. The TMEV L protein has been identified as important in the pathogenesis of Theiler's virus-induced demyelinating disease (TMEV-IDD). We now show that DA L is apoptotic following transfection of L expression constructs or following DA virus infection of HeLa cells; the apoptotic activity depends on the presence of the serine/threonine domain of L, especially a serine at amino acid 57. In contrast, GDVII L has little apoptotic activity following transfection of L expression constructs in HeLa cells and is antiapoptotic following GDVII infection of HeLa cells. Of note, both DA and GDVII L cleave caspase-3 in BHK-21 cells, although neither implements the full apoptotic machinery in this cell type as manifested by the induction of terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) staining. The differences in apoptotic activities of DA and GDVII L in varied cell types may play an important role in TMEV subgroup-specific disease phenotypes.
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PMID:Apoptotic and antiapoptotic activity of L protein of Theiler's murine encephalomyelitis virus. 2156 11

Back pain is a leading cause of global disability and is strongly associated with intervertebral disc (IVD) degeneration (IDD). Hallmarks of IDD include progressive cell loss and matrix degradation. The Akt signaling pathway regulates cellularity and matrix production in IVDs and its inactivation is known to contribute to a catabolic shift and increased cell loss via apoptosis. The PH domain leucine-rich repeat protein phosphatase (Phlpp1) directly regulates Akt signaling and therefore may play a role in regulating IDD, yet this has not been investigated. The aim of this study was to investigate if Phlpp1 has a role in Akt dysregulation during IDD. In human IVDs, Phlpp1 expression was positively correlated with IDD and the apoptosis marker cleaved Caspase-3, suggesting a key role of Phlpp1 in the progression of IDD. In mice, 3 days after IVD needle puncture injury, Phlpp1 knockout (KO) promoted Akt phosphorylation and cell proliferation, with less apoptosis. At 2 and 8 months after injury, Phlpp1 deficiency also had protective effects on IVD cellularity, matrix production, and collagen structure as measured with histological and immunohistochemical analyses. Specifically, Phlpp1-deletion resulted in enhanced nucleus pulposus matrix production and more chondrocytic cells at 2 months, and increased IVD height, nucleus pulposus cellularity, and extracellular matrix deposition 8 months after injury. In conclusion, Phlpp1 has a role in limiting cell survival and matrix degradation in IDD and research targeting its suppression could identify a potential therapeutic target for IDD.
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PMID:Phlpp1 is associated with human intervertebral disc degeneration and its deficiency promotes healing after needle puncture injury in mice. 3158 30