Yao Lin
Identification of a dominant negative functional domain on DAPK-1 that degrades DAPK-1 protein and stimulates TNFR-1-mediated apoptosis.
Lin, Yao; Stevens, Craig; Hupp, Ted
Abstract
DAPK-1 is a stress-activated tumor suppressor protein that plays a role in both proapoptotic or antiapoptotic signal transduction pathways. To define mechanisms of DAPK-1 protein regulation, we have determined that DAPK-1 protein has a long half-life, and therefore its activity is primarily regulated at the protein level. Changes in DAPK-1 protein levels occur by a cathepsin B-dependent pathway, prompting us to evaluate whether cathepsin B plays positive or negative role in DAPK-1 function. The transfection of p55-TNFR-1 induced complex formation between DAPK-1 and cathepsin B. Depletion of cathepsin B protein using small interfering RNA stimulated TNFR-1 dependent apoptosis. The minimal binding region on DAPK-1 for cathepsin B was mapped to amino acids 836–947. The transfection of the DAPK-1-(836–947) miniprotein acted in a dominant negative manner inducing endogenous DAPK-1 protein degradation in a TNFR-1-dependent manner. These data suggest that DAPK-1 forms a multiprotein survival complex with cathepsin B countering the rate of TNFR-1-dependent apoptosis and highlights the importance of developing DAPK-1 inhibitors as agents to sensitize cells to stress-induced apoptosis.
Journal Article Type | Article |
---|---|
Online Publication Date | Feb 26, 2007 |
Publication Date | Jun 8, 2007 |
Deposit Date | Aug 2, 2016 |
Journal | Journal of Biological Chemistry |
Print ISSN | 0021-9258 |
Electronic ISSN | 1083-351X |
Publisher | American Society for Biochemistry and Molecular Biology |
Peer Reviewed | Peer Reviewed |
Volume | 282 |
Issue | 23 |
Pages | 16792-16802 |
DOI | https://doi.org/10.1074/jbc.M611559200 |
Keywords | DAPK-1, tumor suppressor protein, signal transduction pathways, protein regulation, |
Public URL | http://researchrepository.napier.ac.uk/Output/322308 |
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