Multiple Functions of BCL-2 Family Proteins
TL;DR: Before apoptosis is induced, BCL-2 proteins have critical roles in normal cell physiology related to neuronal activity, autophagy, calcium handling, mitochondrial dynamics and energetics, and other processes of normal healthy cells.
Abstract: BCL-2 family proteins are the regulators of apoptosis, but also have other functions. This family of interacting partners includes inhibitors and inducers of cell death. Together they regulate and mediate the process by which mitochondria contribute to cell death known as the intrinsic apoptosis pathway. This pathway is required for normal embryonic development and for preventing cancer. However, before apoptosis is induced, BCL-2 proteins have critical roles in normal cell physiology related to neuronal activity, autophagy, calcium handling, mitochondrial dynamics and energetics, and other processes of normal healthy cells. The relative importance of these physiological functions compared to their apoptosis functions in overall organismal physiology is difficult to decipher. Apoptotic and noncanonical functions of these proteins may be intertwined to link cell growth to cell death. Disentanglement of these functions may require delineation of biochemical activities inherent to the characteristic three-dimensional shape shared by distantly related viral and cellular BCL-2 family members.
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Lorenzo Galluzzi1, Lorenzo Galluzzi2, Ilio Vitale3, Stuart A. Aaronson4 +183 more•Institutions (111)
TL;DR: The Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives.
Abstract: Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.
3,301 citations
TL;DR: These dynamic interactions cause conformational changes in the Bcl-2 proteins that modulate their apoptotic function, providing additional potential modes of regulation.
Abstract: The Bcl-2 family of proteins controls a critical step in commitment to apoptosis by regulating permeabilization of the mitochondrial outer membrane (MOM). The family is divided into three classes: multiregion proapoptotic proteins that directly permeabilize the MOM; BH3 proteins that directly or indirectly activate the pore-forming class members; and the antiapoptotic proteins that inhibit this process at several steps. Different experimental approaches have led to several models, each proposed to explain the interactions between Bcl-2 family proteins. The discovery that many of these interactions occur at or in membranes as well as in the cytoplasm, and are governed by the concentrations and relative binding affinities of the proteins, provides a new basis for rationalizing these models. Furthermore, these dynamic interactions cause conformational changes in the Bcl-2 proteins that modulate their apoptotic function, providing additional potential modes of regulation.
559 citations
Cites background from "Multiple Functions of BCL-2 Family ..."
...…profile of expression of the proteins in different cell types and organs in whole animals, with the result that each protein has different physiological roles that are apparent in the phenotypes of the knockout mice with different antiapoptotic members (for review, see Hardwick and Soane 2013)....
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TL;DR: It is argued that fully understanding this dark side will be required to optimally engage apoptosis, thereby maximizing tumour cell kill while minimizing unwanted pro-tumorigenic effects.
Abstract: Apoptotic cell death is widely considered a positive process that both prevents and treats cancer. Although undoubtedly having a beneficial role, paradoxically, apoptosis can also cause unwanted effects that may even promote cancer. In this Opinion article we highlight some of the ways by which apoptosis can exert oncogenic functions. We argue that fully understanding this dark side will be required to optimally engage apoptosis, thereby maximizing tumour cell kill while minimizing unwanted pro-tumorigenic effects.
333 citations
TL;DR: Various mechanisms of Akt dysregulation in cancers are discussed, including epigenetic modifications like methylation, post-transcriptional non-coding RNAs-mediated regulation, and the overexpression and mutation.
307 citations
TL;DR: The mitochondria-mediated apoptosis pathway is discussed and its physiological roles and therapeutic implications are discussed, showing that cytochrome c release from mitochondria does not always lead to irreversible cell death, and that caspase activation can also have non-death functions.
Abstract: The mitochondria-mediated caspase activation pathway is a major apoptotic pathway characterized by mitochondrial outer membrane permeabilization (MOMP) and subsequent release of cytochrome c into the cytoplasm to activate caspases. MOMP is regulated by the Bcl-2 family of proteins. This pathway plays important roles not only in normal development, maintenance of tissue homeostasis and the regulation of immune system, but also in human diseases such as immune disorders, neurodegeneration and cancer. In the past decades the molecular basis of this pathway and the regulatory mechanism have been comprehensively studied, yet a great deal of new evidence indicates that cytochrome c release from mitochondria does not always lead to irreversible cell death, and that caspase activation can also have non-death functions. Thus, many unsolved questions and new challenges are still remaining. Furthermore, the dysfunction of this pathway involved in cancer development is obvious, and targeting the pathway as a therapeutic strategy has been extensively explored, but the efficacy of the targeted therapies is still under development. In this review we will discuss the mitochondria-mediated apoptosis pathway and its physiological roles and therapeutic implications.
299 citations
Cites background from "Multiple Functions of BCL-2 Family ..."
...The released cytochrome c activates the caspase cascade to induce apoptosis (Hardwick and Soane, 2013) (Fig....
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TL;DR: Apoptosis seems to be involved in cell turnover in many healthy adult tissues and is responsible for focal elimination of cells during normal embryonic development, and participates in at least some types of therapeutically induced tumour regression.
Abstract: The term apoptosis is proposed for a hitherto little recognized mechanism of controlled cell deletion, which appears to play a complementary but opposite role to mitosis in the regulation of animal cell populations. Its morphological features suggest that it is an active, inherently programmed phenomenon, and it has been shown that it can be initiated or inhibited by a variety of environmental stimuli, both physiological and pathological.The structural changes take place in two discrete stages. The first comprises nuclear and cytoplasmic condensation and breaking up of the cell into a number of membrane-bound, ultrastructurally well-preserved fragments. In the second stage these apoptotic bodies are shed from epithelial-lined surfaces or are taken up by other cells, where they undergo a series of changes resembling in vitro autolysis within phagosomes, and are rapidly degraded by lysosomal enzymes derived from the ingesting cells.Apoptosis seems to be involved in cell turnover in many healthy adult tissues and is responsible for focal elimination of cells during normal embryonic development. It occurs spontaneously in untreated malignant neoplasms, and participates in at least some types of therapeutically induced tumour regression. It is implicated in both physiological involution and atrophy of various tissues and organs. It can also be triggered by noxious agents, both in the embryo and adult animal.
15,416 citations
"Multiple Functions of BCL-2 Family ..." refers background in this paper
...The term apoptosis (Gk: falling off, like a tree leaf ) had been coined some years earlier to refer to deliberate cell death, and thus was applied to the type of cell death blocked by BCL-2 (Kerr et al. 1972; Hockenbery et al. 1991)....
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TL;DR: Overexpressed Bax accelerates apoptotic death induced by cytokine deprivation in an IL-3-dependent cell line and counters the death repressor activity of B cl-2, suggesting a model in which the ratio of Bcl-2 to Bax determines survival or death following an apoptotic stimulus.
6,193 citations
"Multiple Functions of BCL-2 Family ..." refers background in this paper
...Proapoptotic BAX was first identified as an inhibitory binding partner of BCL-2 (Oltvai et al. 1993)....
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TL;DR: It is shown that growth factor activation of the PI3'K/Akt signaling pathway culminates in the phosphorylation of the BCL-2 family member BAD, thereby suppressing apoptosis and promoting cell survival.
5,831 citations
"Multiple Functions of BCL-2 Family ..." refers background in this paper
...This is consistent with the evidence that dephosphorylated BAD binds and inactivates antiapoptotic BCL-2 family proteins (Datta et al. 1997)....
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...However, this classical explanation of sequestering away proapoptotic BAD when phosphorylated is rather unsatisfying when attempting to explain how overexpression of phosphomimetic mutants of BAD show a gain of anti-death activity (Datta et al. 1997; Seo et al. 2004)....
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TL;DR: The results indicate that BID is a mediator of mitochondrial damage induced by Casp8, and coexpression of BclxL inhibits all the apoptotic changes induced by tBID.
4,556 citations
"Multiple Functions of BCL-2 Family ..." refers background in this paper
...Cleavage of BID by caspase-8 in the extrinsic pathway generates amino-terminally deleted BID known as truncated BID (tBID) (Li et al. 1998; Luo et al. 1998; Gross et al. 1999). tBID then activates the intrinsic pathway by well-studied mechanisms in which tBID transiently binds and induces BAX…...
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...Cleavage of BID by caspase-8 in the extrinsic pathway generates amino-terminally deleted BID known as truncated BID (tBID) (Li et al. 1998; Luo et al. 1998; Gross et al. 1999)....
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TL;DR: The purification of a cytosolic protein that induces cytochrome c release from mitochondria in response to caspase-8, the apical caspases activated by cell surface death receptors such as Fas and TNF is reported.
3,711 citations
"Multiple Functions of BCL-2 Family ..." refers background in this paper
...Cleavage of BID by caspase-8 in the extrinsic pathway generates amino-terminally deleted BID known as truncated BID (tBID) (Li et al. 1998; Luo et al. 1998; Gross et al. 1999). tBID then activates the intrinsic pathway by well-studied mechanisms in which tBID transiently binds and induces BAX…...
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...Cleavage of BID by caspase-8 in the extrinsic pathway generates amino-terminally deleted BID known as truncated BID (tBID) (Li et al. 1998; Luo et al. 1998; Gross et al. 1999)....
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