Noxa is a BH3-only protein involved in regulating cell death decisions. Noxa is a primary p53-response gene and is upregulated in response to p53 overexpression or DNA damage. Noxa can also be induced by alternative mechanisms including through a hypoxia-response element found in its promoter. Noxa localizes to mitochondria where it binds to Mcl1, an anti-apoptotic Bcl2 family member. Binding of Mcl1 by Noxa not only neutralizes its pro-survival effects but can also lead to proteasomal degradation of Mcl1 to further enhance apoptosis. While Noxa is important for induction of cell death in some cellular contexts, overexpression of Noxa does not always lead to a strong apoptotic response. This suggests Noxa-induced cell death may depend on the levels of other Bcl2-like and BH3-only proteins within the cell. While the relevance of Noxa in tumor suppression is unclear insight into the regulation of Mcl1 levels by Noxa may offer strategies to overcome Mcl1 mediated drug resistance in tumors.
Noxa antibodies have been used in studies of apoptosis mechanisms and in research on drug resistance mechanisms of cancer cell lines. Given the importance of Noxa in regulating the proteasomal degradation of Mcl1, researchers at the University of Nebraska investigated the mechanism of Noxa degradation (1). Using the Noxa antibody for western blotting they identified a short sequence near the C-terminus that mediates Noxa stability and is also needed for the degradation of Noxa and Mcl1. The Hersey group at the University of Newcastle used the Noxa antibody in their investigation of two BH3 mimetic cancer drugs, Obatoclax and ABT-737 (2). Through western blotting with the Noxa antibody they demonstrated ABT-737 and Obatoclax treatment both induced Noxa expression. However Noxa was only necessary for Obatoclax-induced apoptosis. In a separate study of the ABT-737 BH3 mimetic Tromp et al. from the University of Amsterdam showed ABT-737 resistance can be overcome by manipulating levels of Noxa and Mcl1 (3). They used the Noxa antibody to examine protein levels in chronic lymphocytic leukemia cells through western blotting. Cells with a high ration of Noxa:Mcl1 showed enhanced sensitivity to ABT-737 treatment.
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