MAP-1 is a mitochondrial effector of Bax

Tan, Kuan Onn; Fu, Nai Yang; Sukumaran, Sunil K.; Chan, Shing Leng; Kang, Jiunn Hian; Poon, Kar Lai; Chen, Bin Shun; Yu, Victor C.

doi:10.1073/pnas.0503524102

Cited by 109 publications

(127 citation statements)

References 47 publications

(77 reference statements)

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“…29 It has been recently reported that an outer membrane mitochondrial protein, the modulator of apoptosis-1 (MAP-1), is a critical effector of Bax function. 30 Indeed, we show in this work that the association of Bax with mitochondria requires TOM22, a mitochondrial outer membrane protein. However, as stated by Newmeyer and Ferguson-Miller, 31 the latter observations are Figure 2 Bax interacts with TOM22.…”

Section: Discussionmentioning

confidence: 59%

TOM22, a core component of the mitochondria outer membrane protein translocation pore, is a mitochondrial receptor for the proapoptotic protein Bax

et al. 2006

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The association of Bax with mitochondria is an essential step in the implementation of apoptosis. By using a bacterial two-hybrid assay and crosslinking strategies, we have identified TOM22, a component of the translocase of the outer mitochondrial membrane (TOM), as a mitochondrial receptor of Bax. Peptide mapping showed that the interaction of Bax with TOM22 involved the first alpha helix of Bax and possibly two central alpha helices, which are homologous to the pore forming domains of some toxins. Antibodies directed against TOM22 or an antisense knockdown of the expression of TOM22 specifically inhibited the association of Bax with mitochondria and prevented Bax-dependent apoptosis. In yeast, a haploid strain for TOM22 exhibited a decreased expression of TOM22 and mitochondrial association of ectopically expressed human Bax. Our data provide a new perspective on the mechanism of association of Bax with mitochondria as it involves a classical import pathway. Apoptosis is a cell death program, which is central in many aspects to metazoan cell physiology and pathology. 1 Proteins of the Bcl-2 family are key players in the execution phase of apoptosis and their main functions is to control the release of apoptogenic proteins, such as cytochrome c (cyt c) and apoptosis inducing factor (AIF) from the mitochondria. 2 The Bcl-2 family is composed of antiapoptotic members such as Bcl-2 and proapoptotic proteins such as Bax or Bak, which share several domains of homology called BH. 1 In addition to these proteins, a third Bcl-2-related family of proteins have been identified as major amplifiers and/inducers of apoptosis. 2 The latter family has a homology to Bcl-2 limited to the BH3 domain and thus is called the BH3 only proteins. 2 The double knockout of Bax and Bak renders cells completely resistant to cell death 2 highlighting the essential role of these proteins during apoptosis.The determination of the solution structure of Bax showed its organization around nine a-helices (Ha1 to Ha9) 3 of which Ha2 contained most of the BH3 domain and Ha5 and Ha6, a putative pore forming domain that has been shown to be involved in the integration of Bax into the membrane. 4,5 Bax resides in an inactive state in the cytosol in many resting cells and is translocated to the mitochondria at the onset of apoptosis. 6 This translocation is associated with major conformational changes in Bax as both the amino-terminal end (N-T) and carboxy terminal end (C-T) become exposed facilitating its mitochondrial addressing and membrane insertion. 5,7 Bax mitochondrial membrane insertion and oligomerization is closely associated with the release into the cytosol of several intermembrane space proteins such as cyt c, second mitochondrial apoptotic factor (Smac) and AIF. 2 The nature of the different stimuli involved in the activation or in the inhibition of Bax is still largely unknown although this step remains one of the most critical points of control of the apoptotic program during which therapeutic interventions can be envisaged. 2 The mit...

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Section: Discussionmentioning

confidence: 59%

TOM22, a core component of the mitochondria outer membrane protein translocation pore, is a mitochondrial receptor for the proapoptotic protein Bax

et al. 2006

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“…This suggests a functional interaction between Bax and the CsAsensitive permeability transition pore complex (PTPC) (Marzo et al, 1998b;Belzacq et al, 2003). Another protein outside of the PTPC that may be required for Bax-mediated MOMP is the so-called modulator of apoptosis 1 (MAP-1) (Baksh et al, 2005;Tan et al, 2005).…”

Section: Mitochondrial Membrane Permeabilization: the Central Event Omentioning

confidence: 99%

Mitochondria as therapeutic targets for cancer chemotherapy

et al. 2006

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Mitochondria are vital for cellular bioenergetics and play a central role in determining the point-of-no-return of the apoptotic process. As a consequence, mitochondria exert a dual function in carcinogenesis. Cancer-associated changes in cellular metabolism (the Warburg effect) influence mitochondrial function, and the invalidation of apoptosis is linked to an inhibition of mitochondrial outer membrane permeabilization (MOMP). On theoretical grounds, it is tempting to develop specific therapeutic interventions that target the mitochondrial Achilles' heel, rendering cancer cells metabolically unviable or subverting endogenous MOMP inhibitors. A variety of experimental therapeutic agents can directly target mitochondria, causing apoptosis induction. This applies to a heterogeneous collection of chemically unrelated compounds including positively charged a-helical peptides, agents designed to mimic the Bcl-2 homology domain 3 of Bcl-2-like proteins, ampholytic cations, metals and steroid-like compounds. Such MOMP inducers or facilitators can induce apoptosis by themselves (monotherapy) or facilitate apoptosis induction in combination therapies, bypassing chemoresistance against DNA-damaging agents. In addition, it is possible to design molecules that neutralize inhibitor of apoptosis proteins (IAPs) or heat shock protein 70 (HSP70). Such IAP or HSP70 inhibitors can mimic the action of mitochondrion-derived mediators (Smac/DIABLO, that is, second mitochondria-derived activator of caspases/direct inhibitor of apoptosis-binding protein with a low isoelectric point, in the case of IAPs; AIF, that is apoptosis-inducing factor, in the case of HSP70) and exert potent chemosensitizing effects.

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confidence: 99%

“…MOAP-1 contains a BH3-like motif and is capable of triggering apoptosis in mammalian cells when overexpressed (10,11). Knocking down MOAP-1 by RNAi confers inhibition of apoptotic signaling triggered by multiple apoptotic stimuli and promotes anchorage-independent growth of tumor cells (11). Remarkably, isolated mitochondria from MOAP-1 knockdown cells were highly resistant to the cytochrome c (Cyto c)-releasing effect of recombinant Bax, suggesting that MOAP-1 may act as an effector for facilitating Bax function in mitochondria (11).…”

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confidence: 99%

“…Knocking down MOAP-1 by RNAi confers inhibition of apoptotic signaling triggered by multiple apoptotic stimuli and promotes anchorage-independent growth of tumor cells (11). Remarkably, isolated mitochondria from MOAP-1 knockdown cells were highly resistant to the cytochrome c (Cyto c)-releasing effect of recombinant Bax, suggesting that MOAP-1 may act as an effector for facilitating Bax function in mitochondria (11). Interestingly, it has recently been demonstrated that the tumor suppressor RASSF1A specifically links cell death receptor-(12) and activated ⌲-Rasmediated (13) apoptotic signaling to Bax activation through binding to MOAP-1.…”

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confidence: 99%

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Inhibition of ubiquitin-mediated degradation of MOAP-1 by apoptotic stimuli promotes Bax function in mitochondria

Sukumaran

2007

Proc. Natl. Acad. Sci. U.S.A.

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The multidomain proapoptotic protein Bax of the Bcl-2 family is a central regulator for controlling the release of apoptogenic factors from mitochondria. Recent evidence suggests that the Baxassociating protein MOAP-1 may act as an effector for promoting Bax function in mitochondria. Here, we report that MOAP-1 protein is rapidly up-regulated by multiple apoptotic stimuli in mammalian cells. MOAP-1 is a short-lived protein (t1 ͞2 Ϸ 25 min) that is constitutively degraded by the ubiquitin-proteasome system. Induction of MOAP-1 by apoptotic stimuli ensues through inhibition of its polyubiquitination process. Elevation of MOAP-1 levels sensitizes cells to apoptotic stimuli and promotes recombinant Bax-mediated cytochrome c release from isolated mitochondria. Mitochondria depleted of short-lived proteins by cycloheximide (CHX) become resistant to Bax-mediated cytochrome c release. Remarkably, incubation of these mitochondria with in vitrotranslated MOAP-1 effectively restores the cytochrome c releasing effect of recombinant Bax. We propose that apoptotic stimuli can facilitate the proapoptotic function of Bax in mitochondria through stabilization of MOAP-1.apoptosis ͉ Bcl-2 family ͉ proteasome ͉ DNA damage

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MAP-1 is a mitochondrial effector of Bax

Abstract: apoptosis ͉ mitochondria ͉ Bcl-2 family ͉ tumor suppressor

Cited by 109 publications

References 47 publications

TOM22, a core component of the mitochondria outer membrane protein translocation pore, is a mitochondrial receptor for the proapoptotic protein Bax

TOM22, a core component of the mitochondria outer membrane protein translocation pore, is a mitochondrial receptor for the proapoptotic protein Bax

Mitochondria as therapeutic targets for cancer chemotherapy

Inhibition of ubiquitin-mediated degradation of MOAP-1 by apoptotic stimuli promotes Bax function in mitochondria

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