Proapoptotic Bak is sequestered by Mcl-1 and Bcl-x<sub>L</sub>, but not Bcl-2, until displaced by BH3-only proteins

Willis, Simon N.; Lin, Chen; Dewson, Grant; Wei, Andrew H.; Naik, Edwina; Fletcher, Jamie I.; Adams, Jerry M.; Huang, David C.S.

doi:10.1101/gad.1304105

Cited by 1,144 publications

(1,359 citation statements)

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“…Currently, it has been suggested that Bax translocation could be initiated by either BH3-only Bcl-2 family proteins or by the sequestration of anti-apoptotic proteins (Eskes et al, 2000;Kuwana et al, 2005;Willis et al, 2005). Pagliari et al (2005) have shown that heat treatment alone could lead to a direct activation of Bax.…”

Section: Discussionmentioning

confidence: 99%

Complete activation of Bax by a single site mutation

Zhou

Hou

et al. 2007

Oncogene

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Bax translocation from the cytosol to mitochondria culminates a key step by which this protein mediates cell death. Here, we identified two amino acids, L70 and D71, within the BH3 domain of Bax that play a critical role in regulating Bax's cytosolic vs mitochondrial distribution. Individual substitution of these amino acids with alanine resulted in Bax conformational change, oligomerization, localization to mitochondria and cell death. Further mutational analysis indicated that L70 interacts with T174, V177 and A178 of Bax's C-terminal hydrophobic segment, while the negative charge of D71 is required for maintaining Bax in its soluble monomeric state. In summary, we have identified a new regulatory site that controls Bax's subcellular distribution and activation.

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Section: Discussionmentioning

confidence: 99%

Complete activation of Bax by a single site mutation

Zhou

Hou

et al. 2007

Oncogene

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“…Intriguingly, recent data indicate that antiapoptotic Bcl-2 family members distinctly control the proapoptotic activity of Bax or Bak (Chen et al, 2005b;Gelinas and White, 2005). Proapoptotic Bak is controlled preferentially by Bcl-x L and Mcl-1 until released by proapoptotic signals, that is, by Noxa (Mcl-1) and Bad (Bcl-x L ) (Willis et al, 2005). These proteins appear to play selective roles, which may delineate a higher degree of specificity to the regulation of Bax and Bak in p14 ARF -induced cell death in analogy to other apoptosis-promoting stimuli (Theodorakis et al, 2002;Gillissen et al, 2003;Yu et al, 2003;von Haefen et al, 2004;Wendt et al, 2005), which clearly demands further investigation.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, the proapoptotic activity of Bax and Bak is hold in check by distinct antiapoptotic Bcl-2 family members. Finally, BH3-only proteins have recently been shown to preferentially activate either Bax-or Bak-dependent events in human cells Gillissen et al, 2003;Yu et al, 2003;Willis et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Bak functionally complements for loss of Bax during p14ARF-induced mitochondrial apoptosis in human cancer cells

et al. 2006

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In contrast to the initial notion that the biological activity of p14 ARF strictly depends on a functional mdm-2/p53 signaling axis, we recently demonstrated that p14 ARF mediates apoptosis in a p53/Bax-independent manner. Here, we show that p14 ARF induces breakdown of the mitochondrial membrane potential and cytochrome c release before triggering caspase-9-and caspase-3/7-like activities in p53/Bax-deficient DU145 prostate cancer cells expressing wild-type Bak. Re-expression of Bax in these cells failed to further enhance p14 ARF -induced apoptosis, suggesting that p14 ARF -induced apoptosis primarily depends on Bak but not Bax in these cells. To further define the role of Bak and Bax in p14 ARF -induced mitochondrial apoptosis, we employed short interference RNA for the knockdown of bak in isogeneic, p53 wildtype HCT116 colon cancer cells either proficient or deficient for Bax. There, combined loss of Bax and Bak attenuated p14 ARF -induced apoptosis whereas single loss of Bax or Bak was only marginally effective, as in the case of DU145. Notably, HCT116 cells deficient for Bax and Bak failed to release cytochrome c and showed attenuated activation of caspase-9 (LEHDase) and caspase-3/caspase-7 (DEVDase) upon p14 ARF expression. These data indicate that p14 ARF triggers apoptosis via a Bax/Bakdependent pathway in p53-proficient HCT116, whereas Bax is dispensable in p53-deficient DU145 cells. Nevertheless, a substantial proportion of p14 ARF -induced cell death proceeds in a Bax/Bak-independent manner. This is also the case for inhibition of clonogenic growth that occurs, at least in part, through an entirely Bax/Bakindependent mechanism.

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“…21 BAX and BAK bind to and are inhibited by different BCL-2-like pro-survival proteins to different extents. 22,23 BOK shares significant homology across all four BH domains to BAX and BAK; however, its role in apoptosis remains unclear, 24 although it may cooperate with BAX in the attrition of primordial follicle oocytes during ageing. 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.…”

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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Proapoptotic Bak is sequestered by Mcl-1 and Bcl-x_L, but not Bcl-2, until displaced by BH3-only proteins

Abstract: Commitment of cells to apoptosis is governed largely by the interaction between members of theSupplemental material is available at http://www.genesdev.org.

Cited by 1,144 publications

References 61 publications

Complete activation of Bax by a single site mutation

Complete activation of Bax by a single site mutation

Bak functionally complements for loss of Bax during p14ARF-induced mitochondrial apoptosis in human cancer cells

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

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Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins

Abstract: Commitment of cells to apoptosis is governed largely by the interaction between members of theSupplemental material is available at http://www.genesdev.org.

Cited by 1,144 publications

References 61 publications

Complete activation of Bax by a single site mutation

Complete activation of Bax by a single site mutation

Bak functionally complements for loss of Bax during p14ARF-induced mitochondrial apoptosis in human cancer cells

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

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Proapoptotic Bak is sequestered by Mcl-1 and Bcl-x_L, but not Bcl-2, until displaced by BH3-only proteins