Bcl-2 proteins, cell migration and embryonic development: lessons from zebrafish.

Abstract

B-cell lymphoma-2 (Bcl-2) was cloned 30 years ago and associated with B-cell follicular lymphoma. A number of Bcl-2 homologs were identified later on. Importantly, the Bcl-2 family was found to control the mitochondrial outer membrane permeabilization: a key step of the mitochondrial pathway of apoptosis.1 Bcl-2 homologs are evolutionarily conserved throughout metazoans and considered as the hallmarks of multicellularity. Genetic manipulation in nematodes and mice demonstrated that the bcl-2 family has a pivotal role in tissue homeostasis by controlling cell death; however, an increased number of in vitro studies have identified additional non-apoptotic functions, suggesting that Bcl-2 proteins are in fact multitask factors (Figure 1a).2 Figure 1 Non-apoptotic functions of the Bcl-2 family of proteins. (a) Simplified representation of Bcl-2 proteins functions. Bcl-2 proteins are multitask factors and linked to non-apoptotic functions. The top panel represents the different Ca2+-independent ... Besides their mitochondrial localization, Bcl-2 proteins are also found in the endoplasmic reticulum (ER). In fact, a number of them contribute to apoptosis regulation though the control of Ca2+ exchanges at the level of the ER/mitochondria interface. Indeed physical proximity between these organelles creates intracellular microdomains, considered as Ca2+ hotspots.3 Mitochondria constantly uptake Ca2+ to ensure their physiological functions; they are also able to rapidly uptake Ca2+ when massively released from the ER, acting as a genuine Ca2+ buffer. This fast accumulation may lead to mitochondrial Ca2+ overload and, depending on Ca2+ levels, the cells will undergo apoptosis or necrosis.4 Bcl-2 proteins control Ca2+ exchanges through direct interactions with ER Ca2+ channels and pumps including the Inositol 1,4,5-Trisphosphate receptor (IP3R), the Ca2+-ATPase (SERCA) pump, the ryanodine receptor, the Bax inhibitor-1 channel, as well as, the voltage-dependent anion channel (VDAC) at the mitochondria (reviewed in Bonneau et al.2). It was reported that overexpression of Bcl-2 may lead to a decrease of the ER Ca2+ load,5 and the ability of Bcl-2 proteins to regulate intracellular Ca2+ homeostasis was linked to non-apoptotic functions (Figure 1a).