Perturbation of the Bcl-2 network and an induced Noxa/Bcl-xL interaction trigger mitochondrial dysfunction after DNA damage

Hernando Lopez, Liqiang Zhang, Nicholas M. George, Xiaoqiong Liu, Xiaming Pang, Jacquelynn J D Evans, Natalie M. Targy, Xu Luo

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)15016-15026
Number of pages11
JournalJournal of Biological Chemistry
Volume285
Issue number20
DOIs
StatePublished - May 14 2010

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Noxae
DNA Damage
Apoptosis
DNA
Camptothecin
Death Domain Receptors
Cytochromes c
HeLa Cells
Proteins

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Perturbation of the Bcl-2 network and an induced Noxa/Bcl-xL interaction trigger mitochondrial dysfunction after DNA damage. / Lopez, Hernando; Zhang, Liqiang; George, Nicholas M.; Liu, Xiaoqiong; Pang, Xiaming; Evans, Jacquelynn J D; Targy, Natalie M.; Luo, Xu.

In: Journal of Biological Chemistry, Vol. 285, No. 20, 14.05.2010, p. 15016-15026.

Research output: Contribution to journalArticle

Lopez, Hernando ; Zhang, Liqiang ; George, Nicholas M. ; Liu, Xiaoqiong ; Pang, Xiaming ; Evans, Jacquelynn J D ; Targy, Natalie M. ; Luo, Xu. / Perturbation of the Bcl-2 network and an induced Noxa/Bcl-xL interaction trigger mitochondrial dysfunction after DNA damage. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 20. pp. 15016-15026.
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