Identification of the protein–protein contact site and interaction mode of human VDAC1 with Bcl-2 family proteins

Shi, Yong; Chen, Jianjun; Weng, Changjiang; Chen, Rui; Zheng, Yanhua; Chen, Quan; Tang, Hong

doi:10.1016/s0006-291x(03)00871-4

Cited by 136 publications

(111 citation statements)

References 53 publications

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“…Several pro-or antiapoptotic proteins, including Bcl-2 family proteins and kinases, have been reported to interact physically with VDAC to modulate its function (2,24,33), suggesting that VDAC might also play a distinct role independent of channel formation. However, it is not clear at present whether HGTD-P participates directly in channel formation in association with VDAC or modulates its channel-forming activity.…”

Section: Discussionmentioning

confidence: 99%

Identification of the Hypoxia-Inducible Factor 1α-Responsive HGTD-P Gene as a Mediator in the Mitochondrial Apoptotic Pathway

Lee

Kim

Suk

et al. 2004

Molecular and Cellular Biology

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Hypoxia-inducible factor 1␣ (HIF-1␣) controls the cellular responses to hypoxia, activating transcription of a range of genes involved in adaptive processes such as increasing glycolysis and promoting angiogenesis. However, paradoxically, HIF-1␣ also participates in hypoxic cell death. Several gene products, such as BNip3, RTP801, and Noxa, were identified as HIF-1␣-responsive proapoptotic proteins, but the complicated hypoxic cell death pathways could not be completely explained by the few known genes. Moreover, molecules linking the proapoptotic signals of HIF-1␣ directly to mitochondrial permeability transition are missing. In this work, we report the identification of an HIF-1␣-responsive proapoptotic molecule, HGTD-P. Its expression was directly regulated by HIF-1␣ through a hypoxia-responsive element on the HGTD-P promoter region. When overexpressed, HGTD-P was localized to mitochondria and facilitated apoptotic cell death via typical mitochondrial apoptotic cascades, including permeability transition, cytochrome c release, and caspase 9 activation. In the process of permeability transition induction, the death-inducing domain of HGTD-P physically interacted with the voltage-dependent anion channel. In addition, suppression of HGTD-P expression by small interfering RNA or antisense oligonucleotides protected against hypoxic cell death. Taken together, our data indicate that HGTD-P is a new HIF-1␣-responsive proapoptotic molecule that activates mitochondrial apoptotic cascades.Hypoxia is the most common cellular stress, with important pathological implications in many disease processes, including cerebral ischemia and myocardial infarction (15). Cells in hypoxia express a variety of adaptive or death gene products to satisfy altered metabolic demands or to remove irreversibly damaged cells (4). Adaptive genes allow increased O 2 delivery to the peripheral tissues through vasodilation and angiogenesis, facilitate ATP synthesis through the glycolytic pathway, or reduce proliferative rates (12,29,30). In addition, antiapoptotic Bcl-2 family proteins prevent hypoxic cell death by stabilization of mitochondria or inhibition of caspase activation (28). However, in the case of severe hypoxic damage beyond the cell's adaptive capability, death-promoting genes are expressed, resulting in necrosis or apoptosis (4).Hypoxia-inducible factor 1␣ (HIF-1␣) is known to be a master transactivator in hypoxia, which is induced, stabilized, and translocated to the nucleus to regulate the transcription of a variety of genes involved in adaptive responses such as increased O 2 delivery and angiogenesis (5, 31). While HIF-1␣ participates largely in adaptive responses to hypoxia, paradoxically it also mediates hypoxic cell death via the interaction with p53 or modulation of its effector expression (3, 14, 17). Although several proapoptotic genes induced by HIF-1␣ have been reported (3, 17, 37), the hypoxic cell death pathway might be too complicated to be explained by the few known genes.To better understand the molecular mechanism...

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Section: Discussionmentioning

confidence: 99%

Identification of the Hypoxia-Inducible Factor 1α-Responsive HGTD-P Gene as a Mediator in the Mitochondrial Apoptotic Pathway

Lee

Kim

Suk

et al. 2004

Molecular and Cellular Biology

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“…One theory promotes the assumption that VDAC serves as the entity that permeabilizes the OMM during apoptosis and therefore is the route through which Cyt c and other IMS proteins exit the mitochondria [16]. This theory is based on the observation that several BCL-2 family members interact with VDAC [19][20][21][22]. It was reported, using proteoliposomes and electrophysiological measurements, that BCL-X L promotes the closure of VDAC whereas BAX together with VDAC form a mega channel large enough for the passage of Cyt c [21].…”

Section: The Involvement Of Vdac In Apoptosismentioning

confidence: 99%

Mitochondrial carriers and pores: Key regulators of the mitochondrial apoptotic program?

2007

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Mitochondria play a pivotal role in the process of apoptosis. Alterations in mitochondrial structure and function during apoptosis are regulated by proteins of the BCL-2 family, however their exact mechanism of action is largely unknown. Mitochondrial carriers and pores play an essential role in maintaining the normal function of mitochondria, and BCL-2 family members were shown to interact with several mitochondrial carriers/pores and to affect their function. This review focuses on the involvement of several of these mitochondrial carriers/pores in the regulation of the mitochondrial death pathway.

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“…Bax has been reported to interact with the adenine nucleotide translocator (23)(24)(25)(26), with VDAC (27)(28)(29), and with the complexes they form (22,30) (Bcl-x L also interacts with VDAC (28,31)). These interactions reportedly result in the appearance of channels different from those formed by the individually isolated and reconstituted proteins.…”

mentioning

confidence: 99%

Bax Does Not Directly Participate in the Ca2+-induced Permeability Transition of Isolated Mitochondria

Marchi¹,

Campello²,

Szabó

et al. 2004

Journal of Biological Chemistry

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The mitochondrial permeability transition pore and Bax have both been proposed to be involved in the release of pro-apoptotic factors from mitochondria in the "intrinsic" pathway of apoptosis. The permeability transition pore is widely thought to be a supramolecular complex including or interacting with Bax. Given the relevance of the permeability transition in vivo, we have verified whether Bax influences the formation and/or the properties of the Ca 2؉ /P i -induced permeability transition by using mitochondria isolated from isogenic human colon cancer bax ؉/؊ and bax ؊/؊ HCT116 cell lines. We used mitochondria isolated from both types of cells and from Bax ؉ cells exposed to apoptotic stimuli, as well as Bax-less mitochondria into which exogenous Bax had been incorporated. All exhibited the same behavior and pharmacological profile in swelling and Ca 2؉ -retention experiments. Mitochondria from a bax ؊ /bak ؊ cell line also underwent an analogous Ca 2؉ /P i -inducible swelling. This similarity indicates that Bax has no major role in regulating the Ca 2؉ -induced mitochondrial permeability transition.

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Identification of the protein–protein contact site and interaction mode of human VDAC1 with Bcl-2 family proteins

Cited by 136 publications

References 53 publications

Identification of the Hypoxia-Inducible Factor 1α-Responsive HGTD-P Gene as a Mediator in the Mitochondrial Apoptotic Pathway

Identification of the Hypoxia-Inducible Factor 1α-Responsive HGTD-P Gene as a Mediator in the Mitochondrial Apoptotic Pathway

Mitochondrial carriers and pores: Key regulators of the mitochondrial apoptotic program?

Bax Does Not Directly Participate in the Ca2+-induced Permeability Transition of Isolated Mitochondria

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