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Identification of SNF1/AMP kinase-related kinase as an NF-kappaB-regulated anti-apoptotic kinase involved in CD95-induced motility and invasiveness.

Authors: Legembre, P  Schickel, R  Barnhart, BC  Peter, ME 
Citation: Legembre P, etal., J Biol Chem 2004 Nov 5;279(45):46742-7. Epub 2004 Sep 3.
Pubmed: (View Article at PubMed) PMID:15345718
DOI: Full-text: DOI:10.1074/jbc.M404334200

The death receptor CD95 (APO-1/Fas) induces apoptosis in many tissues. However, in apoptosis-resistant tumor cells, stimulation of CD95 induces up-regulation of a defined number of mostly anti-apoptotic genes, resulting in increased motility and invasiveness of tumor cells. The majority of these genes are known NF-kappaB target genes. We have identified one of the CD95-regulated genes as the serine/threonine kinase (SNF1/AMP kinase-related kinase (SNARK)), which is induced in response to various forms of metabolic stress. We demonstrate that up-regulation of SNARK in response to CD95 ligand and tumor necrosis factor alpha depends on activation of NF-kappaB. Overexpression of SNARK rendered tumor cells more resistant, whereas a kinase-inactive mutant of SNARK sensitized cells to CD95-mediated apoptosis. Furthermore, small interfering RNA-mediated knockdown of SNARK increased the sensitivity of tumor cells to CD95 ligand- and TRAIL-induced apoptosis. Importantly, cells with reduced expression of SNARK also showed reduced motility and invasiveness in response to CD95 engagement. SNARK therefore represents an NF-kappaB-regulated anti-apoptotic gene that contributes to the tumor-promoting activity of CD95 in apoptosis-resistant tumor cells.


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RGD Object Information
RGD ID: 1554324
Created: 2005-10-19
Species: All species
Last Modified: 2005-10-19
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.