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

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive, fatal neurodegenerative disease characterised by the death of upper and lower motor neurons. Approximately 10% of cases have a known family history of ALS and disease-linked mutations in multiple genes have been identified. ALS-linked mutations in CCNF were recently reported, however the pathogenic mechanisms associated with these mutations are yet to be established. To investigate possible disease mechanisms, we developed in vitro and in vivo models based on an ALS-linked missense mutation in CCNF. Proteomic analysis of the in vitro models identified the disruption of several cellular pathways in the mutant model, including caspase-3 mediated cell death. Transient overexpression of human CCNF in zebrafish embryos supported this finding, with fish expressing the mutant protein found to have increased levels of cleaved (activated) caspase-3 and increased cell death in the spinal cord. The mutant CCNF fish also developed a motor neuron axonopathy consisting of shortened primary motor axons and increased frequency of aberrant axonal branching. Importantly, we demonstrated a significant correlation between the severity of the CCNF-induced axonopathy and a reduced motor response to a light stimulus (photomotor response). This is the first report of an ALS-linked CCNF mutation in vivo and taken together with the in vitro model identifies the disruption of cell death pathways as a significant consequence of this mutation. Additionally, this study presents a valuable new tool for use in ongoing studies investigating the pathobiology of ALS-linked CCNF mutations.
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PMID:Expression of ALS/FTD-linked mutant CCNF in zebrafish leads to increased cell death in the spinal cord and an aberrant motor phenotype. 3037 81

The aim of the current study was to investigate the underlying mechanism of S-phase kinase associated protein 2 (Skp2) gene inhibition by lentivirus-mediated RNA interference (RNAi) on the cell cycle, apoptosis and proliferation of endometrial carcinoma HEC-1-A cells. A lentivirus shRNA vector targeting Skp2 was constructed and transfected into HEC-1-A cells. HEC-1-A cells transfected with a scramble sequence were used as negative controls. The mRNA and protein expression of Skp2, p27, cyclin D1 and caspase-3 were detected via reverse transcription-quantitative polymerase chain reaction and western blotting, respectively. The effects of Skp2 inhibition on the cell cycle, apoptosis and proliferation of HEC-1-A cells were detected using flow cytometry and a cell counting kit-8. Skp2 co-expression data was analyzed using Oncomine and TCGA databases. The positive recombinant viral clones were identified via PCR and confirmed via sequencing. The mRNA and protein expression of Skp2 were significantly decreased in HEC-1-A cells transfected with the lentiviral vectors compared with the negative control. In addition, there were no significant changes in the mRNA expression of p27 and cyclin D1; however, the protein levels of p27 and cyclin D1 were upregulated and downregulated, respectively, in HEC-1-A cells transfected with lentiviral vectors compared with negative controls. RNAi-induced Skp2 inhibition exerted an anti-proliferative effect by inducing cell cycle arrest, however cell apoptosis was not significantly affected. In the TCGA database, Skp2 expression positively associated with IGF2R, IGF2BP3, IGFBP1 and CCNF, while Skp2 expression negatively associated with IGF2, IGFBP6, IGFBP7 and IGFBP3. RNAi-induced Skp2 inhibition upregulated the protein expression of p27 and downregulated the protein expression of cyclin D1. The expression of Skp2 in endometrial cancer may therefore be regulated by the insulin-like growth factor 1 receptor signaling pathway.
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PMID:Effects of RNAi-induced Skp2 inhibition on cell cycle, apoptosis and proliferation of endometrial carcinoma cells. 3098 23