Activation of mitochondrial voltage-dependent anion channel by apro-apoptotic BH3-only protein Bim

Sugiyama, Tomoyasu; Shimizu, Shigeomi; Matsuoka, Yosuke; Yoneda, Yoshihiro; Tsujimoto, Yoshihide

doi:10.1038/sj.onc.1205621

Cited by 113 publications

(76 citation statements)

References 44 publications

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“…VDAC participates in apoptosis by releasing apoptogenic factors such as cytochrome c (10,47) from the mitochondria to the cytosol to activate the apoptotic cascade, although the detailed molecular mechanisms of how VDAC forms a protein-conducting channel for the passage of cytochrome c are still controversial (34,39). 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.…”

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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“…This group is proposed to either bind directly to the anti-apoptotic members preventing their function or through competition for a common binding site (Tsujimoto, 1998;Shimizu et al, 2000;Sugiyama et al, 2002).…”

Section: Bcl-2 Protein Familymentioning

confidence: 99%

Synthetic retinoids as inducers of apoptosis in ovarian carcinoma cell lines

Holmes¹,

Soprano²,

Soprano³

2004

Journal Cellular Physiology

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Apoptosis is also known as programmed cell death. Apoptosis plays an essential role in maintaining normal tissue and cell physiology in multicellular organisms. Clearance of aberrant or pre-cancerous cells occurs through the induction of apoptosis. It has been reported that many tumors and tumor cell lines have dysfunctional apoptosis signaling, causing these tumors to escape immune monitoring and internal cellular control mechanisms. One potential cause of this dysfunctional apoptosis is the tumor suppressor p53, an important regulator of growth arrest and apoptosis that is mutated in over 50% of all cancers. Retinoids have great potential in the areas of cancer therapy and chemoprevention. While some tumor cells are sensitive to the growth inhibitory effects of natural retinoids such as all-trans-retinoic acid (ATRA), many ovarian tumor cells are not. 6-[3-(1-Admantyl)]-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) and fenretinide N-[4-hydroxyphenyl] retinamide (4-HPR) are conformationally restricted synthetic retinoids that induce growth arrest and apoptosis in both ATRA-sensitive and ATRA-resistant ovarian tumor cell lines. Recently, we have identified the molecular pathways of apoptosis induced by treatment of ovarian carcinoma cells with mutated p53 by CD437 and 4-HPR.

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“…Bim protein has previously been shown to disrupt mitochondrial membrane potential and promote the release of mitochondrial cytochrome c, both early and critical events in many apoptotic processes (40). It was of interest, therefore, to determine whether TGF␤ stimulation alters mitochondrial membrane potential in S3D cells.…”

Section: Tgf␤ Promotes Mitochondrial Bim Accumulation Bim Heterodimementioning

confidence: 99%

Smad3 Potentiates Transforming Growth Factor β (TGFβ)-induced Apoptosis and Expression of the BH3-only Protein Bim in WEHI 231 B Lymphocytes

Wildey

Patil

Howe

2003

Journal of Biological Chemistry

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Activation of mitochondrial voltage-dependent anion channel by apro-apoptotic BH3-only protein Bim

Cited by 113 publications

References 44 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

Synthetic retinoids as inducers of apoptosis in ovarian carcinoma cell lines

Smad3 Potentiates Transforming Growth Factor β (TGFβ)-induced Apoptosis and Expression of the BH3-only Protein Bim in WEHI 231 B Lymphocytes

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