BH3-only proteins and their roles in programmed cell death

Giam, Maybelline; Huang, David C.S.; Bouillet, Philippe

doi:10.1038/onc.2009.50

Cited by 196 publications

(180 citation statements)

References 58 publications

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Section: Discussionmentioning

confidence: 99%

“…The BH3-only proteins are the major sentinels for cellular stress, and diverse signaling pathways converge on these proteins (Giam et al, 2008). BIK operates with other BH3-only proteins to cause rapid activation of caspases (Giam et al, 2008). The expression of BIK is induced by diverse treatments including doxorubicin, g-irradiation or overexpression of p53 (Hur et al, 2004;Mathai et al, 2005;Chinnadurai et al, 2008) and is sufficient to induce apoptosis in cancer cells (Zou et al, 2002;Naumann et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

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MT1-MMP protects breast carcinoma cells against type I collagen-induced apoptosis

et al. 2011

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As invading breast carcinoma cells breach their underlying basement membrane, they become confronted with a dense three-dimensional reactive stroma dominated by type I collagen. To develop metastatic capabilities, invading tumor cells must acquire the capacity to negotiate this novel microenvironment. Collagen influences the fate of epithelial cells by inducing apoptosis. However, the mechanisms used by invading tumor cells to evade collagen-induced apoptosis remain to be defined. We demonstrate that membrane type-1 matrix metalloproteinase (MT1-MMP/MMP-14) confers breast cancer cells with the ability to escape apoptosis when embedded in a collagen gel and after orthotopic implantation in vivo. In the absence of MMP-14-dependent proteolysis, type I collagen triggers apoptosis by inducing the expression of the pro-apoptotic Bcl-2-interacting killer in luminallike breast cancer cells. These findings reveal a new mechanism whereby MMP-14 activity promotes tumor progression by circumventing apoptosis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

MT1-MMP protects breast carcinoma cells against type I collagen-induced apoptosis

et al. 2011

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“…Members possessing 3 domains (BH1 to 3) such as Bax and Bak exert a pro-apoptotic function, whereas those expressing 4 domains (BH1 to 4), such as Bcl-2, Bcl-Xl are anti-apoptotic (another anti-apoptotic member, Mcl-1 has a different anti-apoptotic domain (Day et al, 2005)). The BH3-only group consists of proteins possessing only one (BH3) of the BH domains (Giam et al, 2008), and exerting regulatory roles.…”

Section: Bcl-2 Familymentioning

confidence: 99%

Multistep and multitask Bax activation

Ghibelli

Diederich

2010

Mitochondrion

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Bax is a pro-apoptotic protein allowing apoptosis to occur through the intrinsic, damage-induced pathway, and amplifying that one occurring via the extrinsic, receptor mediated pathway. Bax is present in viable cells and activated by pro-apoptotic stimuli. Activation implies structural changes, consisting of exposure of the N terminus and hydrophobic domains; changes in localization, consisting in migration from cytosol to mitochondria and endoplasmic reticulum membranes; changes in the aggregation status, from monomer to dimer and multimer. Bax has multiple critical domains, namely the N terminus exposed after activation; two hydrophobic stretches exposed for membrane anchorage; two reactive cysteines allowing multimerization; the BH3 domain for interactions with the Bcl-2 family members; alpha helix 1 for t-Bid interaction. Bax has also multiple functions: it releases different mitochondrial factors such as cytochrome c, SMAC/diablo; it regulates mitochondrial fission, the mitochondrial permeability transition pore; it promotes Ca 2+ leakage through ER membrane. Altogether, Bax activation is a complex multi-step phenomenon. Here, we analyze these events as logically separable or alternative steps, attempting to assess their role, timing and reciprocal relation.

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“…3 The latter contain only a BH3 domain, which is essential for apoptosis initiation upon activation in response to apoptotic stimuli. 4 By a series of complex and still controversially discussed protein-protein interactions, activated BH3-only proteins transmit the apoptotic signal to BAX and BAK, which are essential for mitochondrial outer membrane permeabilization (MOMP). 5,6 MOMP is commonly seen as the point-of-no-return in the intrinsic apoptotic pathway; it unleashes the activation of apoptotic caspases that are responsible for the demolition of many vital cellular substrates and consequently the morphological changes observed during apoptosis.…”

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confidence: 99%

Intracellular localization of the BCL-2 family member BOK and functional implications

et al. 2013

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The pro-apoptotic BCL-2 family member BOK is widely expressed and resembles the multi-BH domain proteins BAX and BAK based on its amino acid sequence. The genomic region encoding BOK was reported to be frequently deleted in human cancer and it has therefore been hypothesized that BOK functions as a tumor suppressor. However, little is known about the molecular functions of BOK. We show that enforced expression of BOK activates the intrinsic (mitochondrial) apoptotic pathway in BAX/ BAK-proficient cells but fails to kill cells lacking both BAX and BAK or sensitize them to cytotoxic insults. Interestingly, major portions of endogenous BOK are localized to and partially inserted into the membranes of the Golgi apparatus as well as the endoplasmic reticulum (ER) and associated membranes. The C-terminal transmembrane domain of BOK thereby constitutes a 'tail-anchor' specific for targeting to the Golgi and ER. Overexpression of full-length BOK causes early fragmentation of ER and Golgi compartments. A role for BOK on the Golgi apparatus and the ER is supported by an abnormal response of Bok-deficient cells to the Golgi/ER stressor brefeldin A. Based on these results, we propose that major functions of BOK are exerted at the Golgi and ER membranes and that BOK induces apoptosis in a manner dependent on BAX and BAK.

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BH3-only proteins and their roles in programmed cell death

Cited by 196 publications

References 58 publications

MT1-MMP protects breast carcinoma cells against type I collagen-induced apoptosis

MT1-MMP protects breast carcinoma cells against type I collagen-induced apoptosis

Multistep and multitask Bax activation

Intracellular localization of the BCL-2 family member BOK and functional implications

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