Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics

Letaï, Anthony; Bassik, Michael C.; Walensky, Loren D.; Sorcinelli, Mia D.; Weiler, Solly; Korsmeyer, Stanley J.

doi:10.1016/s1535-6108(02)00127-7

Cited by 1,468 publications

(1,523 citation statements)

References 36 publications

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“…Using a large array of synthetic BH3 peptides, two groups later showed that some of these peptides (Bid, Bim and Puma) could directly induce oligomerization of Bax and Bak to release cytochrome c, whereas the others could not (Letai et al, 2002;Kuwana et al, 2005;Kim et al, 2006b). The term 'activator' was chosen to describe this particular ability.…”

Section: Direct Activation Modelmentioning

confidence: 99%

“…When an apoptotic stimulus is received, the 'sensitizer' BH3-only proteins are activated, which bind to the pro-survival proteins to liberate the 'activator' BH3-only proteins that are now able to interact with Bax/Bak to induce apoptosis (Letai et al, 2002). Various groups have reported evidence to support the existence of the two proposed classes of BH3-only proteins.…”

Section: S130mentioning

confidence: 99%

“…The direct activation model defines Bim and Bid as the sole BH3-only direct activators of Bax and Bak (Letai et al, 2002;Kuwana et al, 2005). However, Willis et al showed that Bax and Bak can mediate apoptosis without discernable association with the putative BH3-only activators, even in cells with no Bim or Bid (Willis et al, 2007).…”

Section: S131mentioning

confidence: 99%

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BH3-only proteins and their roles in programmed cell death

2008

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Section: Direct Activation Modelmentioning

confidence: 99%

Section: S130mentioning

confidence: 99%

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BH3-only proteins and their roles in programmed cell death

2008

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“…Activators (initially this group was limited to Bid and Bim but was later extended to include Puma) are suggested directly to bind Bax and cause its activation. Sensitizers, on the other hand, lack this capacity, and their function is limited to binding to prosurvival Bcl-2 proteins, thereby liberating activators and contributing to apoptosis (Kuwana et al, 2002(Kuwana et al, , 2005Letai et al, 2002;Kim et al, 2006). However, a central prediction of this model is that the combined loss of activators blocks all Bax/Bak-dependent apoptosis, but this is not the case (Kim et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Frequent loss of expression of the pro-apoptotic protein Bim in renal cell carcinoma: evidence for contribution to apoptosis resistance

Zantl

Weirich²,

Zall³

et al. 2007

Oncogene

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Renal cell carcinoma (RCC) is resistant to chemotherapy, and this resistance is mirrored by a high apoptosis resistance of many RCC lines in vitro. Here, we report the loss of the pro-apoptotic BH3-only protein Bim in a large part of clinical RCC cases and provide evidence for a functional relevance of this loss. Immunohistochemistry of clear cell renal cell carcinoma cases and corresponding normal kidney showed strong Bim reactivity in renal tubules of all cases but loss of Bim in 35 of 45 RCC samples. Out of nine RCC cell lines investigated, six showed strongly diminished or undetectable levels of Bim protein by western blotting. Four RCC lines of varying apoptosis sensitivity were analysed further. Bcl-2, Bcl-x L , Mcl-1, Bax and Bak expression did not correlate with apoptosis sensitivity. All cell lines underwent apoptosis upon forced expression of Bax and Bim, suggesting an upstream difference. In all four lines, adriamycin induced p53 but not its targets Puma or Noxa. However, apoptosis sensitivity correlated with levels of Bim protein. Bim siRNA reduced apoptosis sensitivity in a susceptible cell line. Furthermore, inhibition of histone deacetylation restored Bim expression in cell lines. These data suggest that Bim has a function as a tumor suppressor in RCC.

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“…4,5 They are activated by BH3-only proteins binding to the α2-α5 surface groove, [6][7][8][9][10][11][12] or for Bax, to the α1/α6 'rear pocket'. 13 Binding triggers dissociation of the latch domain (α6-α8) from the core domain (α2-α5), together with exposure of N-terminal epitopes and the BH3 domain.…”

mentioning

confidence: 99%

Bak apoptotic pores involve a flexible C-terminal region and juxtaposition of the C-terminal transmembrane domains

et al. 2015

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Bak and Bax mediate apoptotic cell death by oligomerizing and forming a pore in the mitochondrial outer membrane. Both proteins anchor to the outer membrane via a C-terminal transmembrane domain, although its topology within the apoptotic pore is not known. Cysteine-scanning mutagenesis and hydrophilic labeling confirmed that in healthy mitochondria the Bak α9 segment traverses the outer membrane, with 11 central residues shielded from labeling. After pore formation those residues remained shielded, indicating that α9 does not line a pore. Bak (and Bax) activation allowed linkage of α9 to neighboring α9 segments, identifying an α9:α9 interface in Bak (and Bax) oligomers. Although the linkage pattern along α9 indicated a preferred packing surface, there was no evidence of a dimerization motif. Rather, the interface was invoked in part by Bak conformation change and in part by BH3:groove dimerization. The α9:α9 interaction may constitute a secondary interface in Bak oligomers, as it could link BH3:groove dimers to high-order oligomers. Moreover, as high-order oligomers were generated when α9:α9 linkage in the membrane was combined with α6:α6 linkage on the membrane surface, the α6-α9 region in oligomerized Bak is flexible. These findings provide the first view of Bak carboxy terminus (C terminus) membrane topology within the apoptotic pore. Mitochondrial permeabilization during apoptosis is regulated by the Bcl-2 family of proteins. 1-3 Although the Bcl-2 homology 3 (BH3)-only members such as Bid and Bim trigger apoptosis by binding to other family members, the prosurvival members block apoptosis by sequestering their pro-apoptotic relatives. Two remaining members, Bak and Bax, form the apoptotic pore within the mitochondrial outer membrane (MOM).Bak and Bax are globular proteins comprising nine α-helices. 4,5 They are activated by BH3-only proteins binding to the α2-α5 surface groove, 6-12 or for Bax, to the α1/α6 'rear pocket'. 13 Binding triggers dissociation of the latch domain (α6-α8) from the core domain (α2-α5), together with exposure of N-terminal epitopes and the BH3 domain. 6,7,14-16 The exposed BH3 domain then binds to the hydrophobic groove in another Bak or Bax molecule to generate symmetric homodimers. 6,7,14,17,18 In addition to dimerizing, parts of activated Bak and Bax associate with the lipid bilayer. 19 In Bax, the α5 and α6 helices may insert into the MOM, 20 although recent studies indicate that they lie in-plane on the membrane surface, with the hydrophobic α5 sandwiched between the membrane and a BH3:groove dimer interface. 7,[21][22][23] The dimers can be linked via cysteine residues placed in α6, 18,24,25 and more recently via cysteine residues in either α3 or α5, 6,21 allowing detection of the higherorder oligomers associated with pore formation. 26,27 However, whether these interactions are required for high-order oligomers and pore formation remains unclear.Like most Bcl-2 members, Bak and Bax are targeted to the MOM via a hydrophobic C-terminal region. The C terminus targets Bak to the...

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Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics

Cited by 1,468 publications

References 36 publications

BH3-only proteins and their roles in programmed cell death

BH3-only proteins and their roles in programmed cell death

Frequent loss of expression of the pro-apoptotic protein Bim in renal cell carcinoma: evidence for contribution to apoptosis resistance

Bak apoptotic pores involve a flexible C-terminal region and juxtaposition of the C-terminal transmembrane domains

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