TY - JOUR
T1 - Perturbation of the Bcl-2 network and an induced Noxa/Bcl-xL interaction trigger mitochondrial dysfunction after DNA damage
AU - Lopez, Hernando
AU - Zhang, Liqiang
AU - George, Nicholas M.
AU - Liu, Xiaoqiong
AU - Pang, Xiaming
AU - Evans, Jacquelynn J.D.
AU - Targy, Natalie M.
AU - Luo, Xu
PY - 2010/5/14
Y1 - 2010/5/14
N2 - How most apoptotic stimuli trigger mitochondrial dysfunction remains to be resolved. We screened the entire Bcl-2 network for its involvement inDNAdamage-induced apoptosis in HeLa cells. Although the anti-apoptotic member Bcl-xL served as a major suppressor, apoptosis initiated only when both Mcl-1 and Bcl-xL were eliminated. The pro-apoptotic members Bak, Bad, Bim, and Noxa were required for apoptosis induced by DNA damaging agents camptothecin and UV. We, therefore, used a His-tagged Bcl-xL expression system to capture the relevant BH3-only proteins that bind to Bcl-xL in response to DNA damage. Surprisingly, unlike Bad and Bim, which bound Bcl-xL constitutively, Noxa became "Mcl-1-free" and interacted with Bcl-xL after DNA damage but not after death receptor engagement. Similar observations were also made in A431 cells. Importantly, this induced interaction caused cytochrome c release and apoptosis and was directly inhibited by Mcl-1, a protein eliminated or inactivated after DNA damage. These results suggest that the loss/inactivation of Mcl-1 in conjunction with an induced Noxa/Bcl-xL interaction may serve as a trigger for mitochondrial dysfunction during DNA damage-induced apoptosis.
AB - How most apoptotic stimuli trigger mitochondrial dysfunction remains to be resolved. We screened the entire Bcl-2 network for its involvement inDNAdamage-induced apoptosis in HeLa cells. Although the anti-apoptotic member Bcl-xL served as a major suppressor, apoptosis initiated only when both Mcl-1 and Bcl-xL were eliminated. The pro-apoptotic members Bak, Bad, Bim, and Noxa were required for apoptosis induced by DNA damaging agents camptothecin and UV. We, therefore, used a His-tagged Bcl-xL expression system to capture the relevant BH3-only proteins that bind to Bcl-xL in response to DNA damage. Surprisingly, unlike Bad and Bim, which bound Bcl-xL constitutively, Noxa became "Mcl-1-free" and interacted with Bcl-xL after DNA damage but not after death receptor engagement. Similar observations were also made in A431 cells. Importantly, this induced interaction caused cytochrome c release and apoptosis and was directly inhibited by Mcl-1, a protein eliminated or inactivated after DNA damage. These results suggest that the loss/inactivation of Mcl-1 in conjunction with an induced Noxa/Bcl-xL interaction may serve as a trigger for mitochondrial dysfunction during DNA damage-induced apoptosis.
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U2 - 10.1074/jbc.M109.086231
DO - 10.1074/jbc.M109.086231
M3 - Article
C2 - 20223826
AN - SCOPUS:77952029788
SN - 0021-9258
VL - 285
SP - 15016
EP - 15026
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 20
ER -