The BIM gene spans 47,532 bases, centromere to telomere orientation. Three major isoforms are produced by alternative splicing of 6 exons. These isoforms differ in size and have different apoptotic activity. The three major BIM isoforms are BIMEL (BCL2L11 isoform 1), BIML (BCL2L11 isoform 6) and BIMS (BCL2L11 isoform 9). More than 12 minor BIM isoforms have been cloned from human tissues, and involve exons contained within the large introns. The physiological relevance of these minor isoforms is undetermined.

Based on studies using the mouse BIM gene, it was found that the 800-bp region immediately upstream of exon 1 contains the important elements for control of BIM expression. The BIM promoter does not contain a TATA or CAAT box and has the characteristics of a TATA-less promoter. It is very GC-rich and contains six GGGCGG motifs, the recognition site for the transcription factor SP1. There are alternative promoters located in intron 1.

There are no known pseudogenes for BIM.

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.

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.

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.

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 BIMs 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.

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.

The BIM gene is located at chromosome 2q13, a region where alterations (mainly deletions) have been reported for 14 cases of human malignancy, mostly hematopoietic in origin. Although loss of Bim by itself does not elevate tumor incidence in mice within the first 12 months of life, it was found that deletion of even a single allele of BIM dramatically accelerates tumor formation in mice expressing the Eµ-myc transgene (which causes myc over-expression in the B cell compartment). These results suggest that, at least in B cells, BIM is an important tumor suppressor.