Bcl 2 Family Proteins


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 Bcl 2 Family Proteins Background

The B cell lymphoma 2 (BCL‑2) gene family encodes more than 20 proteins that have a central role in regulating programmed cell death by controlling pro-apoptotic and anti-apoptotic intracellular signals, and are fundamental to the balance between cell survival and death [1-3].

BCL2 was initially discovered as part of the t(14;18) chromosomal translocation, which occurs in patients with follicular lymphoma and diffuse large B cell lymphoma (DLBCL), and leads to elevated BCL2 transcription [4-5]. Although originally believed to act as a classical growth-driving oncogene, it was later shown that BCL2 instead promotes malignant cell survival by attenuating apoptosis [6-7]. Members of the BCL‑2 family are grouped together, as they contain up to four con­served BCL‑2 homology (BH) regions. The multi-region (BH1–4) anti-apoptotic proteins BCL‑2, BCL‑XL (also known as BCL‑2L1), BCL‑W (also known as BCL‑2L2), myeloid cell leukaemia 1 (MCL1) and A1 (also known as BCL‑2A1) antagonize pro-apoptotic BH3‑only proteins, and they inhibit the essential apoptosis effectors BCL‑2 antagonist killer [7] (BAK) and BCL‑2‑associated X protein (BAX) [8]. BCL2 dysregulation results in the overexpression of the anti-apoptotic protein BCL‑2, which alters the bal­ance between pro-apoptotic and anti-apoptotic mem­bers of the BCL‑2 family [9].

Fig1. The intrinsic apoptosis pathway. [17]

Programmed cell death, or apoptosis, is critical to both development and maintenance of tissues, as well as to the destruction of the cell when injured. The BCL-2 family proteins and the inhibitors of apoptosis proteins (AIPs) are the major regulators of the apoptotic process, whereas caspases, a family of cysteine proteases, are the major executioners of this process [16]. Following activation of the intrinsic pathway by cellular stress, pro-apoptotic BCL‑2 homology 3 (BH3) ‑only proteins inhibit the anti-apoptotic proteins B cell lymphoma 2 (BCL‑2), BCL‑XL, BCL‑W and myeloid cell leukaemia 1 (MCL1). The subsequent activation and oligomerization of the pro-apoptotic proteins BCL‑2 antagonist killer 1 (BAK) and BCL‑2‑associated X protein (BAX) results in mitochondrial outer membrane permeabilization (MOMP). This results in the release of cytochrome c and second mitochondria-derived activator of caspase (SMAC; also known as DIABLO) from the mitochondria. Cytochrome c forms a complex with procaspase 9 and apoptosis protease-activating factor 1 (APAF1), which leads to the activation of caspase 9. Caspase 9 then activates procaspase 3 and procaspase 7, resulting in cell death. Inhibition of this process by anti-apoptotic BCL‑2 proteins occurs via sequestration of pro-apoptotic proteins through binding to their BH3 motifs. BIM, BCL‑2‑interacting mediator of cell death; XIAP, X‑linked inhibitor of apoptosis. [15, 17]

Nowadays, studies showed that the inhibition of apoptosis related Bcl-2 family proteins is thought to lead to chemoresistance [10] and has been identified in many cancers, including haematological malignancies [11] (such as multiple myeloma, chronic lymphocytic leukaemia (CLL), acute lymphocytic leu­kaemia (ALL), acute myeloid leukaemia (AML), myelodysplastic syndrome and myeloproliferative neoplasms) and solid tumours (such as breast cancer [12], lung cancer [13], melanoma [14] and mesothelioma [15]. Therefore, as BCL‑2‑mediated resistance to intrinsic apoptosis is a hallmark of malignancy, targeting the anti-apoptotic BCL‑2 proteins is an attractive therapeutic strategy in cancer.

Ref:

  1. Shamas-Din, A., Brahmbhatt, H., Leber, B. & Andrews, D. W. BH3‑only proteins: orchestrators of apoptosis. Biochim. Biophys. Acta 1813, 508–520 (2011).
  2. Chipuk, J. E., Moldoveanu, T., Llambi, F., Parsons, M. J. & Green, D. R. The BCL‑2 family reunion. Mol. Cell 37, 299–310 (2010).
  3. Czabotar, P. E., Lessene, G., Strasser, A. & Adams, J. M. Control of apoptosis by the BCL‑2 protein family: implications for physiology and therapy. Nat. Rev. Mol. Cell Biol. 15, 49–63 (2014).
  4. Tsujimoto, Y., Finger, L. R., Yunis, J., Nowell, P. C. & Croce, C. M. Cloning of the chromosome breakpoint of neoplastic B cells with the t(14;18) chromosome translocation. Science 226, 1097–1099 (1984).
  5. Tsujimoto, Y. et al. Molecular cloning of the chromosomal breakpoint of B‑cell lymphomas and leukemias with the t(11;14) chromosome translocation. Science 224, 1403–1406 (1984).
  6. Vaux, D. L., Cory, S. & Adams, J. M. Bcl‑2 gene promotes haemopoietic cell survival and cooperates with c‑myc to immortalize pre‑B cells. Nature 335, 440–442 (1988).
  7. McDonnell, T. J. et al. bcl‑2‑immunoglobulin transgenic mice demonstrate extended B cell survival and follicular lymphoproliferation. Cell 57, 79–88 (1989).
  8. O’Neill, K. L., Huang, K., Zhang, J., Chen, Y. & Luo, X. Inactivation of prosurvival Bcl‑2 proteins activates Bax/Bak through the outer mitochondrial membrane. Genes Dev. 30, 973–988 (2016).
  9. Kang, M. H. & Reynolds, C. P. Bcl‑2 inhibitors: targeting mitochondrial apoptotic pathways in cancer therapy. Clin. Cancer Res. 15, 1126–1132 (2009).
  10. Amundson, S. A. et al. An informatics approach identifying markers of chemosensitivity in human cancer cell lines. Cancer Res. 60, 6101–6110 (2000).
  11. Kitada, S., Pedersen, I. M., Schimmer, A. D. & Reed, J. C. Dysregulation of apoptosis genes in hematopoietic malignancies. Oncogene 21, 3459–3474 (2002).
  12. Vaillant, F. et al. Targeting BCL‑2 with the BH3 mimetic ABT‑199 in estrogen receptor-positive breast cancer. Cancer Cell 24, 120–129 (2013).
  13. Gandhi, L. et al. Phase I study of navitoclax (ABT‑263), a novel Bcl‑2 family inhibitor, in patients with small cell lung cancer and other solid tumors. J. Clin. Oncol. 29, 909–916 (2011).
  14. Bedikian, A. Y. et al. Bcl‑2 antisense (oblimersen sodium) plus dacarbazine in patients with advanced melanoma: the Oblimersen Melanoma Study Group. J. Clin. Oncol. 24, 4738–4745 (2006).
  15. Cao, X. X., Mohuiddin, I., Ece, F., McConkey, D. J. & Smythe, W. R. Histone deacetylase inhibitor downregulation of bcl‑xl gene expression leads to apoptotic cell death in mesothelioma. Am. J. Respir. Cell Mol. Biol. 25, 562–568 (2001).
  16. J.C. Martinou, R.J. Youle, Mitochondria in apoptosis: Bcl-2 family members and mitochondrial dynamics, Developmental cell, 21 (2011) 92-101.
  17. Avi Ashkenazi1, Wayne J. Fairbrother1, Joel D. Leverson2 and Andrew J. Souers. From basic apoptosis discoveries to advanced selective BCL‑2 family inhibitors. NATURE REVIEWS. DRUG DISCOVERY 2017