Modulation of endoplasmic reticulum calcium pump by Bcl-2

Abstract

Members of the bcl-2 gene family encode proteins that function either to promote or to inhibit apoptosis. Despite numerous eorts, the mechanism of action of Bcl-2, an anti-apoptotic protein, is still not clear. In particular, the relation between Bcl-2 and the endoplasmic reticulum (ER) calcium store is not well-understood. In the present work, we examined the eect of Bcl-2 on the ER store. We demonstrate that overexpression of Bcl-2 in breast epithelial cells modulates ER store by upregulating calcium pump (SERCA) expression without aecting the release channel (IP 3 R). The steady state levels of SERCA2 mRNA and protein were both increased in Bcl-2 expression clones. The increase in SERCA2 protein leads to accelerated calcium uptake and enhanced Ca 2+ loading. In addition, we also show the detection of intracellular interaction between Bcl-2 and SERCA molecules by co-immunoprecipitation. Since high lumenal Ca 2+ concentration of ER is essential for normal cell functions, the results suggest that Bcl-2 preserves the ER Ca 2+ store by upregulating SERCA gene expression as well as by a possible interaction with the pump.

Apoptotic crosstalk between the endoplasmic reticulum and mitochondria controlled by Bcl-2

“…Third, Bcl-2 may modulate ER membrane permeability by either forming an ion channel or regulating ERbased channels or pumps such as the IP 3 -receptor calcium channel or the Ca 2+ ATPase pump (SERCA) (Berridge et al, 1998). Bcl-2 can interact with SERCA and either maintain calcium uptake into the ER or reduce calcium e ux of the ER in cells treated with the SERCA inhibitor thapsigargin (Kuo et al, 1998;He et al, 1997). Finally, we propose that Bcl-2 may act on any intracellular membrane to sequester yet unknown cytoplasmic activators of cytochrome c release.…”

“…Consistent with this idea, both CHOP/Gadd153 (Brenner et al, 1997;Zinszner et al, 1998) and NFkB (Baichwal and Baeuerle, 1997) have been implicated in apoptosis regulation. Moreover, several ER membrane proteins have been reported which interact with Bcl-2 family members such as Bax inhibitor I (Xu and Reed, 1998), Bap31 (Ng et al, 1997), calnexin (Torgler et al, 1997) and the calcium pump SERCA (Kuo et al, 1998) although the purpose of these interactions is yet unknown.…”

Proapoptotic multidomain Bcl-2/Bax-family proteins: mechanisms, physiological roles, and therapeutic opportunities

“…Indeed, evidence has been obtained to suggest an effect of Bcl-2 and/or Bcl-X L on Inositol Triphosphate (IP 3 )-gated Ca 2 þ channels (IP 3 Rs) or on the Ca 2 þ -ATPase of the ER, but many details are lacking that would unify all the available data into a coherent model. 60,[62][63][64][65][66][67][68] Mechanisms of MDP Activation Figure 1 Hierarchy of functional interactions among Bcl-2-family proteins differs at mitochondria versus endoplasmic reticulum. The apparent hierarchies of functional interactions among Bcl-2-family proteins are contrasted for mitochondria (top) and ER (bottom).…”

Bcl-2 and Ca2+ homeostasis in the endoplasmic reticulum

“…The authors suggest that the increase in the amount of Ca 2 þ released in Bcl-2-overexpressing cells is the consequence of the up regulation of SERCA gene expression and a direct activation possibly due to protein-protein interaction of Bcl-2 with SERCA. 59 Finding a reason for these discrepancies is not easy. One could argue that most of these studies monitor [Ca 2 þ ] er indirectly (i.e.…”