Targeting Bcl-2 based on the interaction of its BH4 domain with the inositol 1,4,5-trisphosphate receptor

Department of Medicine, Comprehensive Cancer Center and University Hospital of Cleveland, Case Western Reserve University, Cleveland, OH 44106, USA.
Biochimica et Biophysica Acta (Impact Factor: 4.66). 12/2008; 1793(6):971-8. DOI: 10.1016/j.bbamcr.2008.10.015
Source: PubMed


Bcl-2 is the founding member of a large family of apoptosis regulating proteins. Bcl-2 is a prime target for novel therapeutics because it is elevated in many forms of cancer and contributes to cancer progression and therapy resistance based on its ability to inhibit apoptosis. Bcl-2 interacts with proapoptotic members of the Bcl-2 family to inhibit apoptosis and small molecules that disrupt this interaction have already entered the cancer therapy arena. A separate function of Bcl-2 is to inhibit Ca2+ signals that promote apoptosis. This function is mediated through interaction of the Bcl-2 BH4 domain with the inositol 1,4,5-trisphosphate receptor (IP3R) Ca2+ channel. A novel peptide inhibitor of this interaction enhances proapoptotic Ca2+ signals. In preliminary experiments this peptide enhanced ABT-737 induced apoptosis in chronic lymphocytic leukemia cells. These findings draw attention to the BH4 domain as a potential therapeutic target. This review summarizes what is currently known about the BH4 domain of Bcl-2, its interaction with the IP3R and other proteins, and the part it plays in Bcl-2's anti-apoptotic function. In addition, we speculate on how the BH4 domain of Bcl-2 can be targeted therapeutically not only for diseases associated with apoptosis resistance, but also for diseases associated with accelerated cell death.

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Available from: Yiping Rong, Nov 10, 2014
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    • "erload . Consistent with this al - ternate model a peptide derived from IP3R has been shown to disrupt the BCL - 2 / IP3R inter - action and reverse the inhibitory effect of BCL - 2 on IP3R ( Rong et al . 2008 ) . The inhibitory effect of BCL - 2 was attributed to the BH4 do - main of BCL - 2 that binds the regulatory and coupling domain of IP3R ( Rong et al . 2009 ) ."
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    • "Bcl-2 family proteins are involved in this process, as several members, including Mcl-1, have been shown to interact with e.g. inositol 1,4,5-triphosphate receptor [34]–[38]. The precise mechanisms how the 9.2.27PE+ABT-737 drug combination causes calcium release and synergistic cell death in melanoma cells is under investigation. "
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