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BH3-Only Proteins in Apoptosis and Beyond: an Overview

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BH3-Only Proteins in Apoptosis and Beyond: an Overview Oncogene (2009) 27, S2–S19 & 2009 Macmillan Publishers Limited All rights reserved 0950-9232/09 $32.00 www.nature.com/onc REVIEW BH3-only proteins in apoptosis and beyond: an overview E Lomonosova1 and G Chinnadurai Institute for Molecular Virology, Saint Louis University School of Medicine, Doisy Research Center, St Louis, MO, USA BH3-only BCL-2 family proteins are effectors of groups are pro-apoptotic proteins possessing three BH canonical mitochondrial apoptosis. They discharge their (BH1–3) domains represented by BAX, BAK and BOK pro-apoptotic functions through BH1–3 pro-apoptotic and BH3-only proteins that as their name implies, are proteins such as BAX and BAK, while their activity is characterized by the presence of only the BH3 domain. suppressed by BH1–4 anti-apoptotic BCL-2 family BCL-2 family proteins form a complex regulatory members. The precise mechanism by which BH3-only network that controls cell survival and death in response proteins mediate apoptosis remains unresolved. The to different physiological and pathological stimuli. Our existing data are consistent with three mutually non- current understanding of the canonical apoptotic path- exclusive models (1) displacement of BH1–3 proteins from way in animal cells is that various cell death stimuli complexes with BH1–4 proteins; (2) direct interaction either transcriptionally or post-transcriptionally activate with and conformational activation of BH1–3 proteins; one or more of BH3-only effectors that integrate and and (3) membrane insertion and membrane remodeling. transmit the death signal through the multi-domain The BH3-only proteins appear to play critical roles in BH1–3 pro-apoptotic proteins, BAX and BAK. The restraining cancer and inflammatory diseases such as BH1–3 pro-apoptotic proteins undergo conformational rheumatoid arthritis. Molecules that mimic the effect of activation leading to oligomerization and insertion in BH3-only proteins are being used in treatments against the outer mitochondrial membrane. This process is these diseases. The cell death activity of a subclass of presumed to result in permeabilization of outer mito- BH3-only members (BNIP3 and BNIP3L) is linked to chondrial membrane and egress of apoptogenic factors cardiomyocyte loss during heart failure. In addition to such as cytochrome c that activate the caspase cascade their established role in apoptosis, several BH3-only leading to cellular demise. This process is actively members also regulate diverse cellular functions in cell- opposed by the BH1–4 anti-apoptotic members. The cycle regulation, DNA repair and metabolism. Several general mechanisms by which the BCL-2 family proteins members are implicated in the induction of autophagy and regulate cell survival and death have been reviewed in a autophagic cell death, possibly through unleashing of the number of review articles. Since the discovery of the first BH3-only autophagic effector Beclin 1 from complexes member of the BH3-only family proteins (Boyd et al., with BCL-2/BCL-xL. The Chapters included in the 1995), a large number of this family’s members have current Oncogene Review issues provide in-depth discus- been identified and their roles in physiological and sions on various aspects of major BH3-only proteins. pathological cell elimination have been documented. Oncogene (2009) 27, S2–S19; doi:10.1038/onc.2009.39 Surprisingly, several members of this family, in addition to their function as the effectors of cell death, also Keywords: BH3-only; apoptosis; autophagy; non-apop- play other non-cell death functions. This article provides totic functions; cancer an overview of the known BH3-only proteins and their functions. Comprehensive reviews on major BH3- only members, namely BIK, EGl-1, BIM, BMF, NOXA, BID, BAD, BNIP3 and Beclin-1 and their Introduction physiological and pathological functions are reviewed in the articles included in the present Oncogene Review The BCL-2 family proteins are well-characterized Issue. regulators of apoptosis and are grouped into three subfamilies based on the number of BH (BCL-2 Homology) domains they share (Figure 1). The first Discovery of the BH3 domain and the first BH3-only subfamily includes the anti-apoptotic proteins BCL-2, BCL-2 family member BCL-xL, BCL-w, MCL-1 and A1/BFL-1. These pro- teins possess four BH domains—BH1–4. The next two In 1995, a collaborative study between Tom Chittenden and Bob Lutz at Immunogen Inc. and the laboratory of Correspondence: Professor G Chinnadurai, Institute for Molecular G Chinnadurai (Saint Louis University School of Virology, Saint Louis University School of Medicine, Doisy Research Medicine) that involved functional dissection of BAK Center, 1100 South Grand Blvd, St Louis, MO 63104, USA. E-mail: [email protected] (Chittenden et al., 1995) and the identification and 1Current address: Department of Molecular Microbiology and cloning of the pro-apoptotic protein BIK (Bcl-2 Inter- Immunology, Saint Louis University School of Medicine acting Killer) that shared a conserved domain with other BH3-only BCL-2 family proteins E Lomonosova and G Chinnadurai S3 1. Anti-apoptotic proteins, BH1-4 –BCL-2, BCL-xL, MCL-1, A1, BCL-w BH4 BH3 BH1 BH2 TM BCL-2 2. Pro-apoptotic proteins, BH1-3 –BAX, BAK, BOK BH3 BH1 BH2 TM BAX 3. Pro-apoptotic proteins, BH3-only –BIK, BID, BIM, BAD, PUMA, NOXA, HRK etc BH3 TM BIK Figure 1 BCL-2 family proteins. Domain structures of representative members of each subfamily are shown. BCL-2 family proteins (Boyd et al., 1995) resulted in the The BH3-only subfamily and siblings first identification of the functions of the BH3 domain and the BH3-only proteins. These studies showed that: After the discovery of BIK, the list of BH3-only (1) the cell death activities of BAK and BIK were members has increased substantially (Figure 2). The dependent on the conserved BH3 domain; (2) the BH3 well known members of this family, such as BID domain of BAK was required and sufficient for (Wang et al., 1996), HRK/DP5 (Imaizumi et al., 1997; heterodimerization with BCL-xL; and (3) the BH3 Inohara et al., 1997) and BIM/BOD (Hsu et al., 1998; domain of BIK mediated an interaction with cellular O’Connor et al., 1998) were discovered in interaction (BCL-2, BCL-xL) and viral (E1B-19K and EBV- cloning with cellular anti-apoptosis proteins BCL-2, BHRF1) anti-apoptosis proteins. In subsequent pub- BCL-xL and MCL-1. BIK was also identified in lications, the function of the BH3 domain was also interaction cloning with adenovirus E1B-19K (Han identified by mutational analysis of BAX (Hunter et al., et al., 1996). Proteins, such as BNIP1, BNIP3 1996; Zha et al., 1996a). The physiological relevance of (Boyd et al., 1994) and BAD (Yang et al., 1995) were the BH3-only members as death effector molecules in subsequently included in the BH3-only list. Other whole animal models was demonstrated by genetic members such as NOXA (Oda et al., 2000), PUMA/ studies in Caenorhabditis elegans (Conradt and Horvitz, BBC3 (Han et al., 2001; Nakano and Vousden, 2001; Yu 1998). This study identified the worm BH3-only member et al., 2001) and BMF (Puthalakath et al., 2001) were EGL-1 and demonstrated that it acted at the point of identified on the basis of differential mRNA expression the cell death pathway where signals of cell death were in cells exposed to apoptotic stress or by interaction integrated to activate the process of programmed cell cloning. The autophagy effector Beclin 1, which was death. The egl-1 gene was shown to be required for most originally identified as a BCL-2-interacting protein somatic and genotoxic stress-induced cell death in the (Liang et al., 1998) was also identified as a BH3-only worm (Gumienny et al., 1999; Gartner et al., 2000). member (Feng et al., 2007; Oberstein et al., 2007) (see The cell death activity of EGL-1 was linked to its accompanying article by Sinha and Levine, in this issue interaction with CED-9, the worm ortholog of BCL-2 on page S137). Certain splice variants of multi-domain (Conradt and Horvitz, 1998) (see accompanying article BCL-2 family members have also gained entry into this by Nehme and Conradt, in this issue on page S30). The subfamily. They include MCL-1S (Bae et al., 2000; generation of a knockout mouse model that identified Bingle et al., 2000) and BCL-GS (Guo et al., 2001). In the function of BIM in mouse development and in cell C. elegans, a BH3-only member CED-13 (that shares a death induced by external stimuli (Bouillet et al., 1999) substantial homology with EGL-1 in the BH3 region) further substantiated the role of a BH3-only member in induced by the cep-1/p53 gene in response to genotoxic a vertebrate. The genetic studies in C. elegans and in stress has also been identified (Schumacher et al., 2005). mouse suggested that the BH3-only proteins function as Alternative splicing of the BH3-only members also apical sentinels of different cell death signals and initi- appear to contribute to the diversity of these proteins ators of the canonical apoptotic program in animals and regulate their functions. For example, multiple (reviewed in (Huang and Strasser, 2000; Bouillet and splice isoforms were described for BIM (O’Connor Strasser, 2002)). The generation of mouse models defi- et al., 1998; U et al., 2001; Marani et al., 2002), BID cient in several other BH3-only members, such as Noxa, (Renshaw et al., 2004), NOXA (Wang and Sun, 2008), Puma, Bnip3 and Bnip3L has established their role in BNIP1 (Zhang et al., 1999) and BMF (Morales et al., cell death in response to physiological and pathological 2004). Some of these splice isoforms (like in BIM) retain stimuli.
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