Bcl-2 Protein Family Members: Versatile Regulators of Calcium Signaling in Cell Survival and Apoptosis

Department of Medicine and Pharmacology, Comprehensive Cancer Center and University Hospitals of Cleveland, Case Western Reserve University, Cleveland, OH 44106, USA.
Annual Review of Physiology (Impact Factor: 18.51). 02/2008; 70(1):73-91. DOI: 10.1146/annurev.physiol.70.021507.105852
Source: PubMed


Bcl-2 family members are important regulators of cell survival and cell death. Researchers have focused mainly on mitochondria, where both proapoptotic and antiapoptotic family members function to regulate the release of cytochrome c and other mediators of apoptosis. However, as reviewed here, Bcl-2 family members also operate on another front, the endoplasmic reticulum (ER), to both positively and negatively regulate the release of Ca2+. There is abundant evidence that Ca2+ signals trigger apoptosis in response to a wide variety of agents and conditions. Conversely, Ca2+ signals can also mediate cell survival. Recent findings indicate that Bcl-2 interacts with inositol 1,4,5-trisphosphate (IP3) receptor Ca2+ channels on the ER, regulating their opening in response to IP3- and thus inhibiting IP3-mediated Ca2+ signals that induce apoptosis while enhancing Ca2+ signals that support cell survival.

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    • "First, the metabolic rewiring of neoplastic cells should not be considered as a self-standing hallmark of malignancy, but rather as a phenomenon that intimately accompanies, allows for and cannot be mechanistically separated from many, if not all, aspects of oncogenesis (Galluzzi et al., 2013; Locasale & Cantley, 2011; Wellen & Thompson, 2012). Accumulating evidence indicates indeed that (1) several metabolic intermediates such as ATP, acetyl-CoA, a-ketoglutarate, and reactive oxygen species play a major role in cell-intrinsic as well as cell-extrinsic signaling pathways (Galluzzi, Kepp, & Kroemer, 2012; Locasale & Cantley, 2011; Wellen & Thompson, 2012); (2) multiple proteins with prominent metabolic functions such as cytochrome c (which operates as an electron shuttle in the mitochondrial respiratory chain) and the M2 isoform of pyruvate kinase (PKM2, which catalyzes the last step glycolysis) participate in signal transduction (Galluzzi, Kepp, & Kroemer, 2012; Galluzzi, Kepp, Trojel-Hansen, & Kroemer, 2012; Gao, Wang, Yang, Liu, & Liu, 2012; Luo et al., 2011; Yang et al., 2011); and (3) several proteins initially viewed as " pure " signal transducers including (but not limited to) the antiapoptotic Bcl-2 family members BCL-X L and MCL1 also impact on metabolic functions such as the handling of Ca 2+ ions at the endoplasmic reticulum and the enzymatic activity of the F 1 F 0 ATP synthase (Alavian et al., 2011; Perciavalle et al., 2012; Rong & Distelhorst, 2008). "

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    • "Bcl-2 is originally found in a translocation chromosomal fragment in B-cell lymphoma and is proved as a protooncogene [12]. The members of Bcl-2 family all contain a BH (Bcl-2 homology) domain structure and are divided into two major groups: one composed of antiapoptotic molecules, including Bcl-2, Bcl-xL, Bcl-w, Mcl-1, Boo/Diva, and A1/Bfl- 1 [13] and the other comprises proapoptotic molecules, such as Bax, Bak, Bad, Bim, Bik, PUMA, and NOXA [14]. Under normal conditions, the Bcl-2 or Bcl-xL complexes with Bax or Bak to form homo-or hetero dimer, and such interaction will neutralize proapoptotic molecules to prevent cell death. "
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