The Bcl-2 family in cancer development and cancer treatment


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Suzanne Cory
The Walter and Eliza Hall Institute of Medical Research, University of Melbourne, Australia

Abstract

<p>Impaired apoptosis is a critical step in the development of cancer and a major impediment to effective therapy.  Bcl-2, the oncoprotein activated by chromosome translocation in human follicular lymphoma, inhibits cells from undergoing apoptosis in response to many cytotoxic agents. A score or so Bcl-2 relatives have been identified in mammalian cells.  The closest homologs (Bcl-x<sub>L</sub>, Bcl-w, Mcl-1 and A1) are also anti-apoptotic but others are instead pro-apoptotic. While the pro-apoptotic proteins Bax and Bak are very similar to Bcl-2 in sequence and structure, the ‘BH3-only proteins’ are largely unrelated, apart from the signature BH3 (Bcl-2 homology region 3) domain that is essential for their killing function. Collectively, the Bcl-2 family functions as a ‘life/death switch’ that arbitrates whether or not a cell should activate the caspase-driven proteolytic cascade responsible for cellular demolition. We have determined the impact of over-expression of Bcl-2 and Mcl-1 and loss of key BH3-proteins on normal hematopoiesis, tumour development and tumour treatment. Our recent <i>in vivo </i>studies suggest that small molecules mimicking BH3 domains will be effective cancer therapeutics. </p><br>