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

• Published in: Biochimica et biophysica acta Vol. 1793; no. 6; pp. 971 - 978
• Main Authors: Rong, Yi-Ping, Barr, Paul, Yee, Vivien C., Distelhorst, Clark W.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-06-2009
• Subjects: ABT-737; Amino Acid Sequence; Animals; Apoptosis; Apoptosis - physiology; Bcl-2; bcl-X Protein - chemistry; bcl-X Protein - genetics; bcl-X Protein - metabolism; BH4; Calcium; Calcium Signaling - physiology; Cell Line, Tumor; Humans; Inositol 1,4,5-trisphosphate receptor; Inositol 1,4,5-Trisphosphate Receptors - metabolism; IP3R; Models, Molecular; Molecular Sequence Data; Neoplasms - metabolism; Peptide 2; Peptides - chemistry; Peptides - genetics; Peptides - metabolism; Protein Conformation; Protein Structure, Tertiary; Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors; Proto-Oncogene Proteins c-bcl-2 - chemistry; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism; TAT-BH4; Bcl-2; Inositol 1,4,5-trisphosphate receptor; TAT-BH4; IP3R; Calcium; ABT-737; BH4; Apoptosis; Peptide 2
• ISSN: 0167-4889; 0006-3002; 1879-2596
• DOI: 10.1016/j.bbamcr.2008.10.015

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 Ca
2+ 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) Ca
2+ channel. A novel peptide inhibitor of this interaction enhances proapoptotic Ca
2+ 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.