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

Article · Literature Review · February 2008with31 Reads
DOI: 10.1146/annurev.physiol.70.021507.105852 · Source: PubMed
Abstract
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.
  • ...Proteins in the Bcl-2 family play a vital role in controlling intracellular Ca 2+ signals because of their ability to affect—either directly or indirectly—Ca 2+ storage in the endoplasmic reticulum by interacting with the inositol 1,4,5-trisphosphate receptor[32,34]. AsBcl-2, Bcl-xL, Bax, Bad, CyclinD1, p53, Caspase3an anti-apoptotic gene, Bcl-2 inhibits calcium release from the endoplasmic reticulum and mitochondrial calcium uptake, whereas Bax—a member of the proapoptotic Bcl-2 family—induces calcium release from the endoplasmic reticulum as well as mitochondrial Ca 2+ uptake[31,32,35]. In our present study, GosB increased the expression of Bcl-2, inhibited cytosolic and mitochondrial calcium accumulation, and protected C2C12 cells from apoptosis induced by acute increases in intracellular Ca 2+ concentrations. ...
  • ...Bcl-2 also emerged as a crucial regulator of Ca 2+-mediated cell death in mammals, where it was implicated in the suppression of pro-apoptotic Ca 2+ release events originating from the endoplasmic reticulum (ER), the main intracellular Ca 2+ store [13,14]. Different mechanisms were described [15], including direct targeting of the main intracellular Ca 2+ release channel, the inositol 1,4,5-trisphosphate receptor (IP 3 R), which results in inhibition of the channel activity [14,[16][17][18]. It was demonstrated that the interaction between Bcl-2 and IP 3 R was mediated through the BH4 domain of Bcl-2 (BH4-Bcl-2) [19]. ...
  • ...Mitochondria play a key regulatory role in this setting as they integrate anti-and pro-apoptotic signals to seal the cellular fate ( Tait and Green, 2010;Taylor et al., 2008;Kroemer et al., 2007;Galluzzi et al., 2012a). Thus, while in the course of adaptive responses to stress mitochondrial integrity is actively preserved via multiple mechanisms ( Gomes et al., 2011;Rong and Distelhorst, 2008;Rambold et al., 2011), when pro-apoptotic signals predominate over their antiapoptotic counterparts most mitochondria lose their structural (and hence functional) integrity via either of two intimately intertwined mechanisms, MOMP and MPT (see below) ( Brenner and Moulin, 2012;Brenner and Grimm, 2006;Tait and Green, 2010;Kroemer et al., 2007). This is catastrophic for at least two reasons. ...
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