| Description | There are three major isoforms of BIM. BIMEL is the longest (198 amino acids and 22.0kDa), followed by BIML (138 amino acids long and 15.8kDa), and BIMS (112 amino acids and 12.3kDa). All three isoforms contain a BH3 domain (but not the BH1, BH2 and BH4 domains found in other members of the family). They have different pro-apoptotic potencies suspected to be due at least in part to differences in interaction with the dynein motor complex. |
| Expression | BIM is found in many organs and cell types including brain, heart, kidney, liver, lung, ovary, testis, spleen, thymus and trachea. It is also present in hematopoietic, epithelial, neuronal, and germ cells. BIML and BIMEL were found to be co-expressed at similar levels in many cell types, but BIMS is sometimes not detected. |
| Localisation | In healthy cells, most BIM molecules (BIML and BIMEL) are either bound to DLC1 cytoplasmic dynein light chain and sequestered to the microtubule-associated dynein motor complex or associated with the pro-survival proteins on the mitochondria. A C-terminal hydrophobic domain present in all three major isoforms of BIM localizes the protein to intracytoplasmic membranes. |
| Function | BIM is a pro-apoptotic member of the Bcl-2 family important in mediating apoptosis in response to various intrinsic stimuli. Studies using BIM knockout mice showed that it plays a large part in maintaining hematopoietic homeostasis. BIM-deficient mice have high numbers of B cells, CD4 and CD8 single-positive T cells, macrophages and granulocytes in their periphery. BIM is also needed for the deletion of auto-reactive B and T cells and on a mixed C57BL/6/129Sv genetic background, BIM-deficient mice developed a fatal systemic lupus erythematosus (SLE)-like disease. Lymphocytes lacking BIM are refractory to a number of stimuli including cytokine deprivation, deregulated calcium ion flux. BIM is also important in turning off immune responses following acute viral infection. BIM cooperates with the death ligand Fas (which triggers the extrinsic pathway) to shut down immune responses following chronic viral infection and to prevent autoimmunity. Experiments using mice deficient for both BIM and pro-survival Bcl-2 demonstrated that Bcl-2 is an essential guardian of BIM. Indeed, removal of just one allele of BIM prevented polycystic kidney disease and restored normal growth of Bcl-2-deficient mice. Loss of both alleles restored a robust hematopoietic system and prevented graying. Regulation:
BIM is regulated by transcriptional control which differs with cell types by transcription factors including FOXO-3a and c-JUN . BIM is also controlled via alternative splicing that produces many different isoforms. BIM is regulated as well by post-translational modifications such as phosphorylation by ERK1, ERK2 and JNK. Phosphorylation-dependant ubiquitylation is thought to regulates BIM's half life. Interactions:
Unlike some BH3-only proteins, BIM is a promiscuous binder of pro-survival proteins and can bind BCL2, BCLX, BCLW , MCL1 and BCL2A1 with high affinity. There are also some reports that BIMS is able to bind BAX (multidomain pro-apoptotic effector of the pathway) and activate it directly, but whether this binding occurs physiologically is unclear. |
| Homology | BIM belongs to the Bcl-2 family of proteins and contains the BH3 domain which is homologous to the BH3 domains of:
The pro-survival proteins: BCL2, BCLX, BCLW, MCL1, BCL2A1/BFL1, Bcl-B/BOO.
The multidomain pro-apoptotic proteins: BAX, BAK, BOK.
The other BH3-only proteins: PUMA, NOXA, BAD, HRK, BMF, BIK, BID. |
| Bim: a novel member of the Bcl-2 family that promotes apoptosis. |
| O'Connor L, Strasser A, O'Reilly LA, Hausmann G, Adams JM, Cory S, Huang DC. |
| EMBO J. 1998 Jan 15;17(2):384-95. |
| PMID 9430630 |
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| Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity. |
| Bouillet P, Metcalf D, Huang DC, Tarlinton DM, Kay TW, Kontgen F, Adams JM, Strasser A. |
| Science. 1999 Nov 26;286(5445):1735-8. |
| PMID 10576740 |
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| The pro-apoptotic activity of the Bcl-2 family member Bim is regulated by interaction with the dynein motor complex. |
| Puthalakath H, Huang DC, O'Reilly LA, King SM, Strasser A. |
| Mol Cell. 1999 Mar;3(3):287-96. |
| PMID 10198631 |
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| The proapoptotic BH3-only protein bim is expressed in hematopoietic, epithelial, neuronal, and germ cells. |
| O'Reilly LA, Cullen L, Visvader J, Lindeman GJ, Print C, Bath ML, Huang DC, Strasser A. |
| Am J Pathol. 2000 Aug;157(2):449-61. |
| PMID 10934149 |
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| Gene structure alternative splicing, and chromosomal localization of pro-apoptotic Bcl-2 relative Bim. |
| Bouillet P, Zhang LC, Huang DC, Webb GC, Bottema CD, Shore P, Eyre HJ, Sutherland GR, Adams JM. |
| Mamm Genome. 2001 Feb;12(2):163-8. |
| PMID 11210187 |
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| BH3-only Bcl-2 family member Bim is required for apoptosis of autoreactive thymocytes. |
| Bouillet P, Purton JF, Godfrey DI, Zhang LC, Coultas L, Puthalakath H, Pellegrini M, Cory S, Adams JM, Strasser A. |
| Nature. 2002 Feb 21;415(6874):922-6. |
| PMID 11859372 |
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| Bim is a suppressor of Myc-induced mouse B cell leukemia. |
| Egle A, Harris AW, Bouillet P, Cory S. |
| Proc Natl Acad Sci U S A. 2004 Apr 20;101(16):6164-9. Epub 2004 Apr 12. |
| PMID 15079075 |
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| Constitutive association of the proapoptotic protein Bim with Bcl-2-related proteins on mitochondria in T cells. |
| Zhu Y, Swanson BJ, Wang M, Hildeman DA, Schaefer BC, Liu X, Suzuki H, Mihara K, Kappler J, Marrack P. |
| Proc Natl Acad Sci U S A. 2004 May 18;101(20):7681-6. Epub 2004 May 10. |
| PMID 15136728 |
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| Nomenclature of dynein light chain-linked BH3-only protein Bim isoforms. |
| Adachi M, Zhao X, Imai K. |
| Cell Death Differ. 2005 Feb;12(2):192-3. Erratum in: Cell Death Differ. 2005 Jun;12(6):690. |
| PMID 15592437 |
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| Genome-wide array-based CGH for mantle cell lymphoma: identification of homozygous deletions of the proapoptotic gene BIM. |
| Tagawa H, Karnan S, Suzuki R, Matsuo K, Zhang X, Ota A, Morishima Y, Nakamura S, Seto M. |
| Oncogene. 2005 Feb 17;24(8):1348-58. |
| PMID 15608680 |
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| Bim is elevated in Alzheimer's disease neurons and is required for beta-amyloid-induced neuronal apoptosis. |
| Biswas SC, Shi Y, Vonsattel JP, Leung CL, Troy CM, Greene LA. |
| J Neurosci. 2007 Jan 24;27(4):893-900. |
| PMID 17251431 |
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| Homozygous deletions localize novel tumor suppressor genes in B-cell lymphomas. |
| Mestre-Escorihuela C, Rubio-Moscardo F, Richter JA, Siebert R, Climent J, Fresquet V, Beltran E, Agirre X, Marugan I, Marin M, Rosenwald A, Sugimoto KJ, Wheat LM, Karran EL, Garcia JF, Sanchez L, Prosper F, Staudt LM, Pinkel D, Dyer MJ, Martinez-Climent JA. |
| Blood. 2007 Jan 1;109(1):271-80. Epub 2006 Sep 7. |
| PMID 16960149 |
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| Identification of a candidate alternative promoter region of the human Bcl2L11 (Bim) gene. |
| Gaviraghi M, Caricasole A, Costanzo C, Diamanti D, Dandrea M, Donadelli M, Scarpa A, Palmieri M. |
| BMC Mol Biol. 2008 Jun 12;9:56. |
| PMID 18549468 |
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