RGD Reference Report - Proapoptotic effects of NARC 1 (= PCSK9), the gene encoding a novel serine proteinase. - Rat Genome Database

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Proapoptotic effects of NARC 1 (= PCSK9), the gene encoding a novel serine proteinase.

Authors: Bingham, B  Shen, R  Kotnis, S  Lo, CF  Ozenberger, BA  Ghosh, N  Kennedy, JD  Jacobsen, JS  Grenier, JM  DiStefano, PS  Chiang, LW  Wood, A 
Citation: Bingham B, etal., Cytometry A. 2006 Nov 1;69(11):1123-31.
RGD ID: 1599462
Pubmed: PMID:17051583   (View Abstract at PubMed)
DOI: DOI:10.1002/cyto.a.20346   (Journal Full-text)

BACKGROUND: NARC 1/PCSK9 encodes a novel serine proteinase known to play a role in cholesterol homeostasis. NARC 1 mRNA expression in cerebellar granule neurons (CGNs) was discovered to be induced following an apoptotic injury. Coregulation of known apoptotic mediators (caspase-3 and death receptor 6) raises the possibility that NARC 1 might be involved in the propagation of apoptotic signaling in neurons. METHODS: CGNs were transfected with EGFP-fusion constructs of wild-type and mutant NARC 1, and a laser scanning cytometry-based method of scoring cell death in transfectants was applied. Use of the poly-caspase inhibitor BAF allowed assessment of the caspase-dependence of the NARC 1 proapoptotic effect. RESULTS: Wild-type NARC 1 was found to have substantial proapoptotic effects that were only partially reversible by BAF. Mutation of the active site serine or deletion of the catalytic domain resulted in a reduced level of cell death, consistent with loss of the BAF-sensitive component of cell death. NH(2)-terminal deletion constructs of NARC 1 had effects similar to wild-type, both in the absence and presence of BAF, whereas expression of COOH-terminal deletion mutants produced a rate of cell death similar to wild-type in the absence of BAF treatment, but which lacked the capacity to be reduced by treatment with BAF. CONCLUSION: The mechanism by which NARC 1-EGFP over-expression induces cell death in cultured CGNs remains unclear. Mutation analysis established a positive correlation between the presence of the Narc 1 active site serine in the transiently expressed protein and induction of the BAF-sensitive component of the cell death phenotype. A caspase-independent component proved sufficiently complex to map discretely within the Narc 1 protein.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
positive regulation of neuron apoptotic process involved_inIDA 1599462PMID:17051583HGNC-UCL 

Objects Annotated

Genes (Rattus norvegicus)
Pcsk9  (proprotein convertase subtilisin/kexin type 9)


Additional Information