Differential involvement of MEK kinase 1 (MEKK1) in the induction of apoptosis in response to microtubule-targeted drugs versus DNA damaging agents.

Details

Serval ID
serval:BIB_ABA986090DC3
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Differential involvement of MEK kinase 1 (MEKK1) in the induction of apoptosis in response to microtubule-targeted drugs versus DNA damaging agents.
Journal
The Journal of biological chemistry
Author(s)
Gibson S., Widmann C., Johnson G.L.
ISSN
0021-9258
Publication state
Published
Issued date
1999
Peer-reviewed
Oui
Volume
274
Number
16
Pages
10916-22
Language
english
Notes
Publication types: Journal Article ; Research Support, U.S. Gov't, P.H.S. - Publication Status: ppublish
Abstract
MEK kinase 1 (MEKK1) is a 196-kDa enzyme that is involved in the regulation of the c-Jun N-terminal kinase (JNK) pathway and apoptosis. In cells exposed to genotoxic agents including etoposide and cytosine arabinoside, MEKK1 is cleaved at Asp874 by caspases. The cleaved kinase domain of MEKK1, itself, stimulates caspase activity leading to apoptosis. Kinase-inactive MEKK1 expressed in HEK293 cells effectively blocks genotoxin-induced apoptosis. Treatment of cells with taxol, a microtubule stabilizing agent, did not induce MEKK1 cleavage in cells, and kinase-inactive MEKK1 expression failed to block taxol-induced apoptosis. MEKK1 became activated in HEK293 cells exposed to taxol, but in contrast to etoposide-treatment, taxol failed to increase JNK activity. Taxol treatment of cells, therefore, dissociates MEKK1 activation from the regulation of the JNK pathway. Overexpression of anti-apoptotic Bcl2 blocked MEKK1 and taxol-induced apoptosis but did not block the caspase-dependent cleavage of MEKK1 in response to etoposide. This indicates Bcl2 inhibition of apoptosis is, therefore, downstream of caspase-dependent MEKK1 cleavage. The results define the involvement of MEKK1 in the induction of apoptosis by genotoxins but not microtubule altering drugs.
Keywords
Apoptosis, Cell Line, Cytarabine, DNA Damage, Enzyme Activation, Etoposide, Humans, Hydrolysis, MAP Kinase Kinase Kinase 1, Microtubules, Mutagens, Paclitaxel, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins c-bcl-2, Vinblastine
Pubmed
Web of science
Open Access
Yes
Create date
24/01/2008 15:43
Last modification date
20/08/2019 16:15
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