BIK, the founding member of the BH3-only family proteins: mechanisms of cell death and role in cancer and pathogenic processes

Abstract

BIK is the founding member of the BH3-only family pro-apoptotic proteins. BIK is predominantly localized in the ER and induces apoptosis through the mitochondrial pathway by mobilizing calcium from the ER to the mitochondria and remodeling the mitochondrial cristae. BIK-mediated apoptosis is mediated by selective activation of BAX. BIK also induces non-apoptotic cell death in certain cell types by unknown mechanisms. BIK is non-essential for animal development, but appears to be functionally redundant for certain developmental functions with BIM. BIK is implicated in the selection of mature B cells in humans. BIK is a pro-apoptotic tumor suppressor in several human tissues and its expression in cancers is prevented by chromosomal deletions encompassing the Bik locus or by epigenetic silencing. BIK appears to be a critical effector in apoptosis induced by toxins, cytokines and virus infection. Several anti-cancer drugs transcriptionally activate Bik gene expression through transcriptional pathways dependent on factors such as E2F and p53 or by removal of epigenetic marks on the chromatin. BIK appears to be a prominent target for anti-cancer drugs that inhibit proteasomal functions. BIK has also been used as a therapeutic molecule in gene therapy-based approaches to treat difficult cancers.

Figure 1. Domain structure of BIK protein

Three domains of human BIK and their homologies to BIK proteins from different animal species are shown. The predicted secondary structure of hBIK (shown on the top) is based on McDonnell et al. (McDonnell et al., 1999). The α3 region encompassing the BH3 domain is highly conserved and the sequences of the α3 region of human, murine, equine and bovine BIK are indicated. The C-terminal domain (aa 121 to 135) that is required for maximal pro-apoptotic activity of hBIK is conserved only in mBIK. The phosphorylation sites at Thr33 and Ser35 and the RHBDD1 cleavage site (G₁₅₃G₁₅₄) in the transmembrane (TM) domain are indicated.

Figure 2. Model for BIK-induced apoptosis in epithelial cancer cells

In the boxed area, various stimuli that transcriptionally activate the expression of endogenous Bik gene are indicated. The mode of BAX activation through interaction of BIK with BCL-xL and BCL-2 is also shown in the boxed panel. The mode of mitochondrial cristae remodeling, mitochondrial fission and the release of cytochrome c mediated by ER-associated BIK is illustrated and is based on Germain et al. (Germain et al., 2005). The mitochondrial uptake of Ca²⁺ released from the ER is depicted to recruit the cytosolic GTPase, DRP-1 to the mitochondria to mediate mitochondrial fission.