title: The Bcl-2 proteins Noxa and Bcl-xL co-ordinately regulate oxidative stress-induced apoptosis.
abstract: Because the detailed molecular mechanisms by which oxidative stress induces apoptosis are not completely known, we investigated how the complex Bcl-2 protein network might regulate oxidative stress-induced apoptosis. Using MEFs (mouse embryonic fibroblasts), we found that the endogenous anti-apoptotic Bcl-2 protein Bcl-xL prevented apoptosis initiated by H(2)O(2). The BH3 (Bcl-2 homology 3)-only Bcl-2 protein Noxa was required for H(2)O(2)-induced cell death and was the single BH3-only Bcl-2 protein whose pro-apoptotic activity was completely antagonized by endogenous Bcl-xL. Upon H(2)O(2) treatment, Noxa mRNA displayed the greatest increase among BH3-only Bcl-2 proteins. Expression levels of the anti-apoptotic Bcl-2 protein Mcl-1 (myeloid cell leukaemia sequence 1), the primary binding target of Noxa, were reduced in H(2)O(2)-treated cells in a Noxa-dependent manner, and Mcl-1 overexpression was able to prevent H(2)O(2)-induced cell death in Bcl-xL-deficient MEF cells. Importantly, reduction of the expression of both Mcl-1 and Bcl-xL caused spontaneous cell death. These studies reveal a signalling pathway in which H(2)O(2) activates Noxa, leading to a decrease in Mcl-1 and subsequent cell death in the absence of Bcl-xL expression. The results of the present study indicate that both anti- and pro-apoptotic Bcl-2 proteins co-operate to regulate oxidative stress-induced apoptosis.
authors.affiliation: Molecular Targets Program, James Graham Brown Cancer Center, Louisville, KY 40202, USA.
authors.forename: Colins O
authors.initials: CO
authors.lastname: Eno
authors.forename: Guoping
authors.initials: G
authors.lastname: Zhao
authors.forename: Kristen E
authors.initials: KE
authors.lastname: Olberding
authors.forename: Chi
authors.initials: C
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D055786:Gene Knockout Techniques; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051379:Mice; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D018384:Oxidative Stress; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D051020:bcl-X Protein / Q000235:genetics / Q000502:physiology*
chemical_list: C494812:Bcl2l1 protein, mouse; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; C408009:Pmaip1 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D006861:Hydrogen Peroxide