Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy

Czabotar, P.E.; Lessène, Guillaume; Strasser, Andreas; Adams, Jerry M.

doi:10.1038/nrm3722

Cited by 2,640 publications

(2,417 citation statements)

References 215 publications

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“…Because of this pivotal role in dictating life and death, MOMP is highly regulated through interactions between Bcl-2 family members 16 . There are three subfamilies of Bcl-2 proteins: anti-apoptotic Bcl-2 proteins (such as BCL-2 or BCL-xL), pro-apoptotic BH3-only proteins (including PUMA, BID and BIM) and pro-apoptotic effector proteins (BAX, BAK and BOK).…”

Section: Apoptotic Signaling Pathwaysmentioning

confidence: 99%

“…There are three subfamilies of Bcl-2 proteins: anti-apoptotic Bcl-2 proteins (such as BCL-2 or BCL-xL), pro-apoptotic BH3-only proteins (including PUMA, BID and BIM) and pro-apoptotic effector proteins (BAX, BAK and BOK). BH3-only proteins relay diverse apoptotic signals to activate BAX and BAK at the mitochondrial outer membrane whereupon BAX and BAK trigger MOMP 16 .…”

Section: Apoptotic Signaling Pathwaysmentioning

confidence: 99%

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A fate worse than death: apoptosis as an oncogenic process

2016

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Section: Apoptotic Signaling Pathwaysmentioning

confidence: 99%

Section: Apoptotic Signaling Pathwaysmentioning

confidence: 99%

A fate worse than death: apoptosis as an oncogenic process

2016

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“…12 Initiation of the BCL-2-regulated apoptotic pathway is controlled, as the name implies, by interactions between members of the BCL-2 protein family. [14][15][16][17][18][19] This family consists of three groups of structurally related proteins: the pro-survival BCL-2-like proteins, the multi-BH domain pro-apoptotic BAX/BAK proteins, and the pro-apoptotic BH3-only proteins.…”

Section: The Bcl-2-regulated Apoptotic Pathwaymentioning

confidence: 99%

“…25 The pro-apoptotic BH3-only proteins (BIM, PUMA, BID, BAD, BIK, BMF, NOXA, HRK) share only the BH3 domain with each other and their more distant relatives. 19,26,27 These proteins are unstructured in isolation but assume an α-helical fold when bound to BCL-2 pro-survival family members. 28 The exception to this rule is BID, which is produced as an inactive globular protein that is converted into its active form, tBID (truncated BID), through caspase-8-mediated cleavage.…”

Section: The Bcl-2-regulated Apoptotic Pathwaymentioning

confidence: 99%

The BCL-2 protein family, BH3-mimetics and cancer therapy

2015

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Escape from apoptosis is a key attribute of tumour cells and facilitates chemo-resistance. The 'BCL-2-regulated' or 'intrinsic' apoptotic pathway integrates stress and survival signalling to govern whether a cancer cell will live or die. Indeed, many pro-apoptotic members of the BCL-2 family have demonstrated tumour-suppression activity in mouse models of cancer and are lost or repressed in certain human cancers. Conversely, overexpression of pro-survival BCL-2 family members promotes tumorigenesis in humans and in mouse models. Many of the drugs currently used in the clinic mediate their therapeutic effects (at least in part) through the activation of the BCL-2-regulated apoptotic pathway. However, initiators of this apoptotic pathway, such as p53, are mutated, lost or silenced in many human cancers rendering them refractory to treatment. To counter such resistance mechanisms, a novel class of therapeutics, 'BH3-mimetics', has been developed. These drugs directly activate apoptosis by binding and inhibiting select antiapoptotic BCL-2 family members and thereby bypass the requirement for upstream initiators, such as p53. In this review, we discuss the role of the BCL-2 protein family in the development and treatment of cancer, with an emphasis on mechanistic studies using well-established mouse models of cancer, before describing the development and already recognised potential of the BH3-mimetic compounds.

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“…These Bcl‐2 proteins function to prevent apoptosis through safeguarding mitochondrial outer membrane integrity by binding to Bax/Bak and disrupting interactions among Bcl‐2 family proteins upstream of the executioner caspases (see Fig. 1 (Kang & Reynolds, 2009; Vogler et al ., 2009; Strasser et al ., 2011; Czabotar et al ., 2014; Correia et al ., 2015)).…”

Section: Introductionmentioning

confidence: 99%

Identification of a novel senolytic agent, navitoclax, targeting the Bcl‐2 family of anti‐apoptotic factors

et al. 2016

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SummaryClearing senescent cells extends healthspan in mice. Using a hypothesis‐driven bioinformatics‐based approach, we recently identified pro‐survival pathways in human senescent cells that contribute to their resistance to apoptosis. This led to identification of dasatinib (D) and quercetin (Q) as senolytics, agents that target some of these pathways and induce apoptosis preferentially in senescent cells. Among other pro‐survival regulators identified was Bcl‐xl. Here, we tested whether the Bcl‐2 family inhibitors, navitoclax (N) and TW‐37 (T), are senolytic. Like D and Q, N is senolytic in some, but not all types of senescent cells: N reduced viability of senescent human umbilical vein epithelial cells (HUVECs), IMR90 human lung fibroblasts, and murine embryonic fibroblasts (MEFs), but not human primary preadipocytes, consistent with our previous finding that Bcl‐xl siRNA is senolytic in HUVECs, but not preadipocytes. In contrast, T had little senolytic activity. N targets Bcl‐2, Bcl‐xl, and Bcl‐w, while T targets Bcl‐2, Bcl‐xl, and Mcl‐1. The combination of Bcl‐2, Bcl‐xl, and Bcl‐w siRNAs was senolytic in HUVECs and IMR90 cells, while combination of Bcl‐2, Bcl‐xl, and Mcl‐1 siRNAs was not. Susceptibility to N correlated with patterns of Bcl‐2 family member proteins in different types of human senescent cells, as has been found in predicting response of cancers to N. Thus, N is senolytic and acts in a potentially predictable cell type‐restricted manner. The hypothesis‐driven, bioinformatics‐based approach we used to discover that dasatinib (D) and quercetin (Q) are senolytic can be extended to increase the repertoire of senolytic drugs, including additional cell type‐specific senolytic agents.

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Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy

Cited by 2,640 publications

References 215 publications

A fate worse than death: apoptosis as an oncogenic process

A fate worse than death: apoptosis as an oncogenic process

The BCL-2 protein family, BH3-mimetics and cancer therapy

Identification of a novel senolytic agent, navitoclax, targeting the Bcl‐2 family of anti‐apoptotic factors

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