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Gene Review

BCL2L11  -  BCL2-like 11 (apoptosis facilitator)

Homo sapiens

Synonyms: BAM, BIM, BOD, Bcl-2-like protein 11, Bcl2-L-11, ...
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Disease relevance of BCL2L11


High impact information on BCL2L11


Chemical compound and disease context of BCL2L11

  • Regulation of the proapoptotic BH3-only protein BIM by glucocorticoids, survival signals and proteasome in chronic lymphocytic leukemia cells [9].
  • Cell hybrids (BIM) were produced between human neuroblastoma cells (IMR-32) and thymidine auxotrophs (B3T) of rat nerve-like cells (B103) in order to obtain cell lines undergoing stable neuronal differentiation [10].
  • This study was carried out to compare the effects of two GnRH analogs (the agonist Decapeptyl and the antagonist BIM 21009C) and the antiestrogen 4-hydroxy-tamoxifen (OH-TAM) on proliferation in antiestrogen-responsive or antiestrogen-resistant human breast cancer cell lines (MCF-7, MCF-7 LY2) [11].
  • Analogues of ACTH-(4-9) (Org 2766) and ACTH-(4-10) (BIM 22015) are capable of sustaining neurite outgrowth from cultured dorsal root ganglion and spinal cord cells in the absence of nerve growth factor [12].
  • Each age group of rats was subdivided in three group (i) acute heat stress - subjected to a single exposure for 4 h in the BOD (Biological Oxygen Demand) incubator at 38 degrees C; (ii) chronic heat stress - exposed for 21 days daily for 1 h in the incubator at 38 degrees C, and (iii) handling control groups [13].

Biological context of BCL2L11


Anatomical context of BCL2L11

  • Interestingly, Bimgamma mRNA, similar to the BimEL protein, is up-regulated in the majority of the prostate cancer cell lines studied, whereas several other proapoptotic Bcl-2 proteins, including Bax, Bak, and Bad, are down-regulated in prostate cancer cells [2].
  • Interestingly, native Bax is attached loosely on the surface of isolated mitochondria, which undergoes conformational change and insertion into mitochondrial membrane upon stimulation by BimEL, Bak-BH3 peptide, or freeze/thaw damage [17].
  • Taken together, these findings indicate that BimEL may activate Bax by damaging the mitochondrial membrane structure directly, in addition to its binding and antagonizing Bcl-2/Bcl-XL function [17].
  • Subcellular fractionation experiments show that the Bim mutant M1DeltaC is localized in the cytosol, indicating that both the C-terminal hydrophobic region and the BH3 domain are required for the mitochondrial targeting and pro-apoptotic activity of BimEL [17].
  • JNK inhibitory kinase is up-regulated in retinal ganglion cells after axotomy and enhances BimEL expression level in neuronal cells [18].

Associations of BCL2L11 with chemical compounds

  • The activation of Raf was increased either by the phorbol ester-induced activation of protein kinase C (PKC) or by the addition of the PKC inhibitor bisindolylmaleimide I (BIM) [19].
  • Treatment of cells with the garlic compound diallyl disulphide had similar effects on BimEL [20].
  • The EGF receptor expression was reduced by 30% in cells treated with PYY/5-FU/leucovorin and by 45% in cells treated with BIM/5-FU/leucovorin as compared with control cells without treatment [21].
  • We found that activation of p75NTR induced the JNK-dependent phosphorylation of endogenous BimEL at serine 65 in cells [22].
  • The expression of MEX promoted apoptosis that was induced through Fas, DR (death receptor) 3 and DR4 signalling, but not that mediated by the BH3 (Bcl-2 homology 3)-only protein BimEL or the chemotherapeutic drug adriamycin [23].
  • Upon paclitaxel treatment, RACK1, DLC1, and CIS mediated the degradation of BimEL through the ElonginB/C-Cullin2-CIS ubiquitin-protein isopeptide ligase complex [24].

Enzymatic interactions of BCL2L11


Regulatory relationships of BCL2L11

  • Either the activation of PKC with phorbol ester or the addition of BIM to cells growing in serum induced a rapid but transient increase of p53 levels, which preceded growth inhibition [19].
  • The JNK-induced phosphorylation of BimEL at serine 65 promoted the apoptotic effect of BimEL in primary cerebellar granule neurons [22].
  • BimEL is an important determinant for induction of anoikis sensitivity by mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitors [5].
  • MEK inhibitors also induced the electrophoretic mobility shift of BimEL, indicative of reduced phosphorylation [5].
  • Together, these results support the notion that BIM and tBID follow different strategies to trigger BAX-driven mitochondrial outer membrane permeabilization with strong potency [25].

Other interactions of BCL2L11

  • OSU-03012 lethality as a single agent or when combined with signaling modulators was not modified in cells lacking expression of BIM or of BAX/BAK [26].
  • Characterization of the c-Jun N-terminal kinase-BimEL signaling pathway in neuronal apoptosis [22].
  • p38 MAP kinase mediates apoptosis through phosphorylation of BimEL at Ser-65 [27].
  • On the other hand, only a weak association of BimEL and L with the dynein LC8 chain has been found [28].
  • On treatment with MEK inhibitors, BimEL in MDA-MB231 and HBC4 cells rapidly increased, irrespective of the state of anchorage [5].

Analytical, diagnostic and therapeutic context of BCL2L11

  • The cell-killing activity of BOD is also antagonized in cells cotransfected with the antiapoptotic Bcl-w protein, which showed high affinity for BOD in the two-hybrid assay [29].
  • In unstimulated cells, BimL protein was complexed with Bcl-x(L) and changed the partner to associate with Bax on the mitochondrial membrane after ligation of BCR, leading to initiation of apoptotic processes [4].
  • Using in vitro protein binding, immunoprecipitation, and coimmunolocalization assays, we demonstrated that HN binds directly to the extra long isoform of Bim (BimEL) but not the long (BimL) or short (BimS) isoforms [30].
  • By Southern blot analysis, BIM cells had both human and rat types of N-myc genes [10].
  • Verapamil or nifedipine (at 50 microM) or 25 nM BIM, but not 25 microM adenosine 3',5'-cyclic monophosphorothioate, Rp-isomer, a PKA inhibitor, abolished the PTHrP (107-139)-induced increase in interleukin 6 messenger RNA (assessed by RT, followed by PCR) in UMR 106 cells [31].


  1. Chronic lymphocytic leukemia requires BCL2 to sequester prodeath BIM, explaining sensitivity to BCL2 antagonist ABT-737. Del Gaizo Moore, V., Brown, J.R., Certo, M., Love, T.M., Novina, C.D., Letai, A. J. Clin. Invest. (2007) [Pubmed]
  2. Identification and characterization of Bimgamma, a novel proapoptotic BH3-only splice variant of Bim. Liu, J.W., Chandra, D., Tang, S.H., Chopra, D., Tang, D.G. Cancer Res. (2002) [Pubmed]
  3. Inhibition of glucocorticoid-induced apoptosis by targeting the major splice variants of BIM mRNA with small interfering RNA and short hairpin RNA. Abrams, M.T., Robertson, N.M., Yoon, K., Wickstrom, E. J. Biol. Chem. (2004) [Pubmed]
  4. Requirement for JNK-dependent upregulation of BimL in anti-IgM-induced apoptosis in murine B lymphoma cell lines WEHI-231 and CH31. Takada, E., Hata, K., Mizuguchi, J. Exp. Cell Res. (2006) [Pubmed]
  5. BimEL is an important determinant for induction of anoikis sensitivity by mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitors. Fukazawa, H., Noguchi, K., Masumi, A., Murakami, Y., Uehara, Y. Mol. Cancer Ther. (2004) [Pubmed]
  6. JNK-mediated BIM phosphorylation potentiates BAX-dependent apoptosis. Putcha, G.V., Le, S., Frank, S., Besirli, C.G., Clark, K., Chu, B., Alix, S., Youle, R.J., LaMarche, A., Maroney, A.C., Johnson, E.M. Neuron (2003) [Pubmed]
  7. Induction of BIM, a proapoptotic BH3-only BCL-2 family member, is critical for neuronal apoptosis. Putcha, G.V., Moulder, K.L., Golden, J.P., Bouillet, P., Adams, J.A., Strasser, A., Johnson, E.M. Neuron (2001) [Pubmed]
  8. TAp63alpha induces apoptosis by activating signaling via death receptors and mitochondria. Gressner, O., Schilling, T., Lorenz, K., Schulze Schleithoff, E., Koch, A., Schulze-Bergkamen, H., Maria Lena, A., Candi, E., Terrinoni, A., Valeria Catani, M., Oren, M., Melino, G., Krammer, P.H., Stremmel, W., Müller, M. EMBO J. (2005) [Pubmed]
  9. Regulation of the proapoptotic BH3-only protein BIM by glucocorticoids, survival signals and proteasome in chronic lymphocytic leukemia cells. Iglesias-Serret, D., de Frias, M., Santidrián, A.F., Coll-Mulet, L., Cosialls, A.M., Barragán, M., Domingo, A., Gil, J., Pons, G. Leukemia (2007) [Pubmed]
  10. Spontaneous and cAMP-dependent induction of a resting phase and neurite formation in cell hybrids between human neuroblastoma cells and thymidine auxotrophs of rat nerve-like cells. Ishii, K., Adachi, Y., Hatanaka, M., Sakamoto, H., Furuyama, J. J. Cell. Physiol. (1990) [Pubmed]
  11. Compared effects of GnRH analogs and 4-hydroxytamoxifen on growth and steroid receptors in antiestrogen sensitive and resistant MCF-7 breast cancer cell sublines. Néri, C., Berthois, Y., Schatz, B., Drieu, K., Martin, P.M. Breast Cancer Res. Treat. (1990) [Pubmed]
  12. Melanotropins as growth factors. Strand, F.L., Zuccarelli, L.A., Williams, K.A., Lee, S.J., Lee, T.S., Antonawich, F.J., Alves, S.E. Ann. N. Y. Acad. Sci. (1993) [Pubmed]
  13. Sleep-wake study in an animal model of acute and chronic heat stress. Sinha, R.K., Ray, A.K. Physiol. Behav. (2006) [Pubmed]
  14. Assignment of BCL2L11 to human chromosome band 2p13 with somatic cell and radiation hybrids. Murray, S., Halford, S., Ebenezer, N.D., Gregory-Evans, C.Y., Bhattacharya, S.S. Cytogenet. Cell Genet. (2001) [Pubmed]
  15. Autosomal dominant acute necrotizing encephalopathy maps to 2q12.1-2q13. Neilson, D.E., Feiler, H.S., Wilhelmsen, K.C., Lynn, A., Eiben, R.M., Kerr, D.S., Warman, M.L. Ann. Neurol. (2004) [Pubmed]
  16. Melphalan-induced apoptosis in multiple myeloma cells is associated with a cleavage of Mcl-1 and Bim and a decrease in the Mcl-1/Bim complex. Gomez-Bougie, P., Oliver, L., Le Gouill, S., Bataille, R., Amiot, M. Oncogene (2005) [Pubmed]
  17. Bcl-XL protects BimEL-induced Bax conformational change and cytochrome C release independent of interacting with Bax or BimEL. Yamaguchi, H., Wang, H.G. J. Biol. Chem. (2002) [Pubmed]
  18. JNK inhibitory kinase is up-regulated in retinal ganglion cells after axotomy and enhances BimEL expression level in neuronal cells. Wakabayashi, T., Kosaka, J., Oshika, T. J. Neurochem. (2005) [Pubmed]
  19. Activation of Erk1/Erk2 and transiently increased p53 levels together may account for p21 expression associated with phorbol ester-induced transient growth inhibition in HepG2 cells. Sipeki, S., Bander, E., Ways, D.K., Faragó, A. Cell. Signal. (2002) [Pubmed]
  20. Garlic arrests MDA-MB-435 cancer cells in mitosis, phosphorylates the proapoptotic BH3-only protein BimEL and induces apoptosis. Lund, T., Stokke, T., Olsen, Ø.E., Fodstad, Ø. Br. J. Cancer (2005) [Pubmed]
  21. Adjuvant hormonal treatment with peptide YY or its analog decreases human pancreatic carcinoma growth. Liu, C.D., Rongione, A.J., Garvey, L., Balasubramaniam, A., McFadden, D.W. Am. J. Surg. (1996) [Pubmed]
  22. Characterization of the c-Jun N-terminal kinase-BimEL signaling pathway in neuronal apoptosis. Becker, E.B., Howell, J., Kodama, Y., Barker, P.A., Bonni, A. J. Neurosci. (2004) [Pubmed]
  23. MEX is a testis-specific E3 ubiquitin ligase that promotes death receptor-induced apoptosis. Nishito, Y., Hasegawa, M., Inohara, N., Núñez, G. Biochem. J. (2006) [Pubmed]
  24. RACK1 and CIS mediate the degradation of BimEL in cancer cells. Zhang, W., Cheng, G.Z., Gong, J., Hermanto, U., Zong, C.S., Chan, J., Cheng, J.Q., Wang, L.H. J. Biol. Chem. (2008) [Pubmed]
  25. BIM and tBID are not mechanistically equivalent when assisting BAX to permeabilize bilayer membranes. Terrones, O., Etxebarria, A., Landajuela, A., Landeta, O., Antonsson, B., Basañez, G. J. Biol. Chem. (2008) [Pubmed]
  26. OSU-03012 promotes caspase-independent but PERK-, cathepsin B-, BID-, and AIF-dependent killing of transformed cells. Yacoub, A., Park, M.A., Hanna, D., Hong, Y., Mitchell, C., Pandya, A.P., Harada, H., Powis, G., Chen, C.S., Koumenis, C., Grant, S., Dent, P. Mol. Pharmacol. (2006) [Pubmed]
  27. p38 MAP kinase mediates apoptosis through phosphorylation of BimEL at Ser-65. Cai, B., Chang, S.H., Becker, E.B., Bonni, A., Xia, Z. J. Biol. Chem. (2006) [Pubmed]
  28. Endogenous association of Bim BH3-only protein with Mcl-1, Bcl-xL and Bcl-2 on mitochondria in human B cells. Gomez-Bougie, P., Bataille, R., Amiot, M. Eur. J. Immunol. (2005) [Pubmed]
  29. BOD (Bcl-2-related ovarian death gene) is an ovarian BH3 domain-containing proapoptotic Bcl-2 protein capable of dimerization with diverse antiapoptotic Bcl-2 members. Hsu, S.Y., Lin, P., Hsueh, A.J. Mol. Endocrinol. (1998) [Pubmed]
  30. Cytoprotective peptide humanin binds and inhibits proapoptotic Bcl-2/Bax family protein BimEL. Luciano, F., Zhai, D., Zhu, X., Bailly-Maitre, B., Ricci, J.E., Satterthwait, A.C., Reed, J.C. J. Biol. Chem. (2005) [Pubmed]
  31. C-terminal parathyroid hormone-related protein (PTHrP) (107-139) stimulates intracellular Ca(2+) through a receptor different from the type 1 PTH/PTHrP receptor in osteoblastic osteosarcoma UMR 106 cells. Valín, A., Guillén, C., Esbrit, P. Endocrinology (2001) [Pubmed]
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