BCL2L11

BCL2L11 Background

The BCL2L11 gene encodes Bcl-2-like protein 11, commonly called BIM (Bcl-2 Interacting Mediator of cell death) ^[1]. BIM possesses a single BH3 domain and a hydrophobic C‐terminus that contributes to its localization to intracytoplasmic membranes ^[1]. BH3-only proteins can displace BAK or BAX from their antiapoptotic counterparts, thereby facilitating their oligomerization and subsequent mitochondrial outer membrane permeability (MOMP) ^[2]. A competing direct activation model proposes that effector function is triggered by activator BH3-only proteins such as BIM and truncated BID (tBID) ^[3][4][5]. The ability to oligomerize did not correlate with cell death, and the formation of a MOMP-inducing pore required association with the direct activator BIM. Consistently, BIM synergized with the BAK proapoptotic function as coexpression of both proteins enhanced, and a decrease of BIM levels reduced cell death. Direct activator BIM is required to convert oligomerized pre-pore into a membrane-permeabilizing pore. BIM's oligomerization with BAK subsequently promotes its conversion to a membrane-inserted pore ^[6]. Reduced expression of BIM was associated with tumor promotion and autoimmunity, while its overexpression inhibited tumor growth and drug resistance as cancer cells suppress BIM expression and stability. Apart from its role in normal homeostasis, BIM has emerged as a central player in the regulation of tumorigenesis. It, therefore, gains attention as a potential target for chemotherapy. Furthermore, controlling overexpression and stability of BIM may enhance chemotherapeutic efficacy, overcome drug resistance, and select anticancer drug regimens since various chemotherapeutic agents regard BIM as an executioner of cell death. It is more likely that strategies commanding BIM expression and stability ultimately leads to a BIM-based therapeutic regimen for cancer treatment soon ^[7]. Measurement of BIM levels may be a useful marker to monitor objective responses to anti-PD-1 therapy, especially in patients who might have radiographic pseudoprogression of disease ^[8].

[1] O'Connor L, Strasser A, et al. Bim: a novel member of the Bcl-2 family that promotes apoptosis [J]. EMBO J. 17, 1998, (2): 384-;95.
[2] S.N. Willis, L. Chen, G. et al. Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins [J]. Genes Dev., 19 ,2005, pp. 1294-1305.
[3] M.C. Wei, T. Lindsten, et al. tBID, a membrane-targeted death ligand, oligomerizes BAK to release cytochrome c [J]. Genes Dev., 14, 2000, pp. 2060-2071.
[4] S.C. Ruffolo, G.C. Shore. BCL-2 selectively interacts with the BID-induced open conformer of BAK, inhibiting BAK auto-oligomerization [J]. J. Biol. Chem., 278, 2003, pp. 25039-25045.
[5] H. Kim, H.C. Tu, D., et al. Stepwise activation of BAX and BAK by tBID, BIM, and PUMA initiates mitochondrial apoptosis [J]. Mol. Cell, 36, 2009, pp. 487-499.
[6] Kathrin Weber, Nicholas Harper, et al. BIM-Mediated Membrane Insertion of the BAK Pore Domain Is an Essential Requirement for Apoptosis [J]. Volume 5, Issue 2, 31 October 2013, Pages 409-420.
[7] Shatrunajay Shukla, Sugandh Saxena, et al. BH3-only protein BIM: An emerging target in chemotherapy [J]. Volume 96, Issue 8, December 2017, Pages 728-738.
[8] Roxana S Dronca, Aaron S Mansfield, et al. BCL-2-interacting Mediator of Cell Death (Bim) Is a Novel Biomarker for Response to anti-PD-1 Therapy in Patients With Advanced Melanoma [J]. Immunotherapy, 8 (12), 2016, 1351-1353.