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Apoptosis

New strategies to tip the BCL-2 balance

Nature Reviews Drug Discovery volume 7, page 977 (2008)Cite this article

The central players of the BCL-2 family are the pro-survival proteins such as BCL-2 and BCL-XL, the apoptotic effector proteins BAX and BAK, and the BH3-domain only proteins, which transmit pro-death signals from various stimuli. Once deployed, the BH3-only proteins are either neutralized by pro-survival family members such as BCL-2 — which contain an anti-apoptotic binding groove that can bind and sequester BH3-only proteins — or delivered to the mitochondrial executioners BAK and BAX.

BCL-2 is a particularly attractive anticancer target, as it is frequently overexpressed in cancer cells, and can confer resistance to chemotherapy and radiotherapy. Identifying compounds that bind to its anti-apoptotic binding groove, thereby neutralizing its ability to sequester BH3-only proteins, is a popular therapeutic strategy. In their paper, Zhang and colleagues describe an alternative approach, based on previous findings from the group showing that the nuclear receptor NUR77 can induce a phenotypic conversion that turns BCL-2 into a pro-apoptotic protein, by binding to a large unstructured loop between the BCL-2 BH3 and BH4 domains.

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ORIGINAL RESEARCH PAPERS

  1. Kolluri, S. K. et al. A short Nur77-derived peptide converts Bcl-2 from a protector to a killer. Cancer Cell 14, 285–298 (2008)

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  2. Gavathiotis, E. et al. BAX activation is initiated at a novel interaction site. Nature 455, 1076–1081 (2008)

    Article  CAS  Google Scholar 

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Authors
  1. Alexandra Flemming
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Flemming, A. New strategies to tip the BCL-2 balance. Nat Rev Drug Discov 7, 977 (2008). https://doi.org/10.1038/nrd2773

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