Pro-Survival Bcl-2 Family Antibody Sampler Kit II

The Bcl-2 family consists of a number of evolutionarily conserved proteins containing Bcl-2 homology domains (BH) that regulate apoptosis through control of mitochondrial membrane permeability and release of cytochrome c (1-3). Four BH domains have been identified (BH1-4) that mediate protein interactions. The family can be separated into three groups based upon function and sequence homology: pro-survival members include Bcl-2, Bcl-xL, Mcl-1, A1 and Bcl-w; pro-apoptotic proteins include Bax, Bak and Bok; and "BH3 only" proteins Bad, Bik, Bid, Puma, Bim, Bmf, Noxa and Hrk. Interactions between death-promoting and death-suppressing Bcl-2 family members has led to a rheostat model in which the ratio of pro-apoptotic and anti-apoptotic proteins controls cell fate (4). Thus, pro-survival members exert their behavior by binding to and antagonizing death-promoting members. In general, the "BH3-only members" can bind to and antagonize the pro-survival proteins leading to increased apoptosis (5). While some redundancy of this system likely exists, tissue specificity, transcriptional and post-translational regulation of many of these family members can account for distinct physiological roles.Several phosphorylation sites have been identified within Bcl-2 including Thr56, Ser70, Thr74 and Ser87 (6). These phosphorylation sites may be targets of the ASK1/MKK7/JNK1 pathway, and phosphorylation of Bcl-2 may be a marker for mitotic events (7,8). Mutation of Bcl-2 at Thr56 or Ser87 inhibits its anti-apoptotic activity during glucocorticoid-induced apoptosis of T lymphocytes (9). Interleukin 3 and JNK-induced Bcl-2 phosphorylation at Ser70 may be required for its enhanced antiapoptotic functions (10).Mcl-1 is phosphorylated in response to treatment with phorbol ester, microtubule-damaging agents, oxidative stress, and cytokine withdrawal (11-14). Phosphorylation at Thr163, the conserved MAP kinase/ERK site located within the PEST region, slows Mcl-1 protein turnover (13) but may prime the GSK-3 mediated phosphorylation at Ser159 that leads to Mcl-1 destabilization (14). 1.Cory, S. et al. (2003) Oncogene 22, 8590-607. 2.Antonsson, B. and Martinou, J.C. (2000) Exp Cell Res 256, 50-7. 3.Sharpe, J.C. et al. (2004) Biochim Biophys Acta 1644, 107-13. 4.Korsmeyer, S.J. et al. (1993) Semin Cancer Biol 4, 327-32. 5.Bouillet, P. and Strasser, A. (2002) J Cell Sci 115, 1567-74. 6.Maundrell, K. et al. (1997) J Biol Chem 272, 25238-42. 7.Yamamoto, K. et al. (1999) Mol Cell Biol 19, 8469-78. 8.Ling, Y.H. et al. (1998) J Biol Chem 273, 18984-91. 9.Huang, S.T. and Cidlowski, J.A. (2002) FASEB J 16, 825-32. 10.Deng, X. et al. (2001) J Biol Chem 276, 23681-8. 11.Domina, A.M. et al. (2000) J Biol Chem 275, 21688-94. 12.Inoshita, S. et al. (2002) J Biol Chem 277, 43730-4. 13.Domina, A.M. et al. (2004) Oncogene 23, 5301-15. 14.Maurer, U. et al. (2006) Mol Cell 21, 749-60.