Posttranslational N-Myristoylation of BID as a Molecular Switch for Targeting Mitochondria and Apoptosis

Zha, Jiping; Weiler, Solly; Oh, Kyoung Joon; Wei, Michael C.; Korsmeyer, Stanley J.

doi:10.1126/science.290.5497.1761

Cited by 510 publications

(417 citation statements)

References 24 publications

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“…Alternatively, it has been described that myristoylation of tBid is required for its translocation to mitochondria. 39 However, it is unlikely that an alteration of this post-translational modification by PKC/MAPK could be responsible for the inhibition of the mitochondrial localization of truncated Bid as the GFP-ttBid construct lacks the specific myristoylation sequence (also GFP-tBid can not be myristoylated since the GFP blocks the glycine target site).…”

Section: Discussionmentioning

confidence: 99%

The mitogen-activated protein kinase pathway can inhibit TRAIL-induced apoptosis by prohibiting association of truncated Bid with mitochondria

et al. 2006

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Breast cancer cells often show increased activity of the mitogen-activated protein kinase (MAPK) pathway. We report here that this pathway reduces their sensitivity to death ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and present the underlying mechanism. Activation of protein kinase C (PKC) inhibited TRAIL-induced apoptosis in a protein synthesis-independent manner. Deliberate activation of MAPK was also inhibitory. In digitonin-permeabilized cells, PKC activation interfered with the capacity of recombinant truncated (t)Bid to release cytochrome c from mitochondria. MAPK activation did not affect TRAIL or tumor necrosis factor (TNF)a-induced Bid cleavage. However, it did inhibit translocation of (t)Bid to mitochondria as determined both by subcellular fractionation analysis and confocal microscopy. Steady state tBid mitochondrial localization was prohibited by activation of the MAPK pathway, also when the Bcl-2 homology domain 3 (BH3) domain of tBid was disrupted. We conclude that the MAPK pathway inhibits TRAIL-induced apoptosis in MCF-7 cells by prohibiting anchoring of tBid to the mitochondrial membrane. This anchoring is independent of its interaction with resident Bcl-2 family members.

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Section: Discussionmentioning

confidence: 99%

The mitogen-activated protein kinase pathway can inhibit TRAIL-induced apoptosis by prohibiting association of truncated Bid with mitochondria

et al. 2006

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“…The model of CL as a mitochondrial "docking" site for tBid is supported by several studies. For example, in vitro assays using artificial membranes or isolated mitochondria showed that recombinant tBid can bind CL and MLCL [78][79][80][81][82][83]. Adding tBid to isolated mitochondria immediately inhibits ADP-stimulated respiration and oxidative phosphorylation, as a result of ANT inactivation [84,85].…”

Section: Cardiolipin: Docking Site For Tbidmentioning

confidence: 99%

Cardiolipin: Setting the beat of apoptosis

2007

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Cardiolipin (CL) is a mitochondria-specific phospholipid which is known to be intimately linked with the mitochondrial bioenergetic machinery. Accumulating evidence now suggests that this unique lipid also has active roles in several of the mitochondria-dependant steps of apoptosis. CL is closely associated with cytochrome c at the outer leaflet of the mitochondrial inner membrane. This interaction makes the process of cytochrome c release from mitochondria more complex than previously assumed, requiring more than pore formation in the mitochondrial outer membrane. While CL peroxidation could be crucial for enabling cytochrome c dissociation from the mitochondrial inner membrane, cytochrome c itself catalyzes CL peroxidation. Moreover, peroxy-CL directly activates the release of cytochrome c and other apoptogenic factors from the mitochondria. CL is also directly involved in mitochondrial outer membrane permeabilization by enabling docking and activation of proapoptotic Bcl-2 proteins. It appears therefore that CL has multiple roles in apoptosis and that CL metabolism contributes to the complexity of the apoptotic process.

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“…Bcl-2 locates to mitochondrial, endoplasmic reticulum membranes and nuclear envelope, and Bcl-XL to the mitochondrial membranes via their transmembrane (TM) domain (Krajewski et al, 1993;Kaufmann et al, 2003). Bid does not possess one TM domain but can be translocated to the membranes and interact with Bcl-2 or Bax (Zha et al, 2000). Here, we used a Bax version lacking the a-helix 9.…”

Section: Inhibition Of Homologous Recombination By Bax or Bidmentioning

confidence: 99%

Bax and Bid, two proapoptotic Bcl-2 family members, inhibit homologous recombination, independently of apoptosis regulation

et al. 2006

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In order to analyse the relationships between regulation of apoptosis and homologous recombination (HR), we overexpressed proapoptotic Bax or only-BH3 Bid proteins or antiapoptotic Bcl-2 or Bcl-XL, in hamster CHO cells or in SV40-transformed human fibroblasts. We measured HR induced by c-rays, UVC or a specific double-strand cleavage targeted in the recombination substrate by the meganuclease I-SceI. We show here that the induction of both recombinant cells and recombinant colonies was impaired when expressing Bcl-2 family members, in hamster as well as in human cells. Moreover, the pro-as well as antiapoptotic Bcl-2 family members inhibited HR, independently of degradation of the RAD51 recombination protein and of their impact on apoptosis. These data reveal a mechanism of HR downregulation by potentially proapoptotic proteins, distinct from and parallel to degradation of recombination proteins, a situation that should also optimize the efficiency of programmed cell death.

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Posttranslational N-Myristoylation of BID as a Molecular Switch for Targeting Mitochondria and Apoptosis

Cited by 510 publications

References 24 publications

The mitogen-activated protein kinase pathway can inhibit TRAIL-induced apoptosis by prohibiting association of truncated Bid with mitochondria

The mitogen-activated protein kinase pathway can inhibit TRAIL-induced apoptosis by prohibiting association of truncated Bid with mitochondria

Cardiolipin: Setting the beat of apoptosis

Bax and Bid, two proapoptotic Bcl-2 family members, inhibit homologous recombination, independently of apoptosis regulation

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