Adenine nucleotide translocase 3 (ANT3) overexpression induces apoptosis in cultured cells

Zamora, Mónica; Granell, Meritxell; Mampel, Teresa; Viñas, Octavi

doi:10.1016/s0014-5793(04)00293-5

Cited by 94 publications

(71 citation statements)

References 27 publications

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“…However, mouse knockout studies led to the conclusion that ANT would not (always) be required for apoptotic MOMP (Kokoszka et al, 2004). Recent evidence suggests that some ANT isoforms (ANT1, ANT3) are apoptogenic while others are not (ANT2) (Schubert and Grimm, 2004;Zamora et al, 2004). In 2005, a fourth ANT isoform (ANT4) has been identified in man (Dolce et al, 2005) and mouse (Rodic et al, 2005) by means of two independent experimental approaches.…”

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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Section: Mitochondrial Membrane Permeabilization: the Central Event Omentioning

confidence: 99%

Mitochondria as therapeutic targets for cancer chemotherapy

et al. 2006

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“…40 Despite their close homology, distinct ANT isoforms may have opposed (and perhaps context dependent) roles in cell death. Thus, the overexpression of human ANT1 (which is mainly expressed in the heart and skeletal muscles) and ANT3, but not of ANT2 (which is ubiquitous), can induce apoptosis, 41,42 and the siRNA-mediated knockdown of ANT2 reportedly sensitizes cancer cells to MMPinducing agents, 43 suggesting that ANT1 and ANT3 are pro-apoptotic proteins whereas ANT2 exerts pro-survival functions. In line with these notions, an interactor of ANT2 (i.e.…”

Section: Ant and Its Homologs In Mammalian Cell Deathmentioning

confidence: 99%

Adenine nucleotide translocase: a component of the phylogenetically conserved cell death machinery

2009

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Lethal mitochondrial membrane permeabilization has been depicted as the result of two fundamentally distinct processes, namely primary mitochondrial outer membrane permeabilization (MOMP) versus permeability transition (PT) ignited at the level of the mitochondrial inner membrane. MOMP and PT have been connected to apoptosis and necrosis, respectively. Moreover, it has been thought that MOMP was mediated by pro-apoptotic multidomain proteins of the Bcl-2 family (Bax and Bak), which would operate near-to-independently from the permeability transition pore complex (PTPC) composed by voltage-dependent anion channel (VDAC), adenine nucleotide translocase (ANT) and cyclophilin D. A recent paper in Molecular and Cellular Biology now reveals the obligate contribution of one particular ANT isoform to the execution of developmental and homeostatic cell death in Caenorhabditis elegans. The physical and functional interaction between CED-9, the sole multidomain Bcl-2 protein of C. elegans, and ANT emphasizes the existence of an intricate, phylogenetically conserved crosstalk between Bcl-2 family proteins and constituents of the PTPC. In this issue of Cell Death and Differentiation, Malorni et al. further corroborate this notion by showing that type 2 transglutaminase (TG2) is essential for the correct assembly/function of ANT1, and that, at least in some experimental settings, TG2 might be required to enable and/or stabilize the pro-apoptotic association of Bax with ANT1. The 'core' machinery of apoptosis was discovered by screening Caenorhabditis elegans mutations that suppressed developmental cell death, yielding a number of genes whose mammalian equivalents also have an important function in physiological and disease-associated apoptosis. Once it has been transcriptionally upregulated, EGL-1 (the only BH3-only protein encoded by C. elegans) disrupts a molecular complex composed by CED-9 (a Bcl-2 ortholog localized in mitochondrial membranes) and CED-4 (the nematode counterpart of Apaf-1, which is also normally present at mitochondria). As a consequence, CED-4 becomes free to translocate to the nuclear envelope and to activate CED-3 (the worm caspase), thereby inducing apoptosis. 1,2 Now, a new protein, WAN-1, the nematode ortholog of mammalian adenine nucleotide translocase (ANT) has been added to the 'core' machinery. 3 The 'Core' Machinery for Cell Death ExecutionThe scenario of a conserved cell death 'core' machinery composed by EGL-1, CED-9, CED-4 and CED-3 has been dominating the field of cell death research up to the point that some investigators suggested the existence of a ternary molecular complex made by Apaf-1, caspase-9 and the Bcl-2 homolog Bcl-X L also in mammalian cells, 4,5 which turned out to be a bold artifact. [6][7][8] Similarly, the idea that EGL-1, CED-9, CED-4 and CED-3 might have other functions than mediating cell death (EGL-1 as an inducer of autophagy, 9 CED-4 as part of the intra-S-phase DNA damage checkpoint, 2 CED-3 in the innate immune system 10 ) met incredulity and resistance. Prominent ...

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“…The presence of numerous SP1-binding sites could favor apoptosis in a positive manner , because SP1 induces inhibition of cell cycle progression that precedes apoptosis and a transcriptional response targeting genes containing Sp1-binding sites in its promoter region, suggesting Sp1-driven gene transcription . Regarding the role of ANT3 in apoptosis, Zamora et al (2004a, b) showed that ANT3 exerts a similar effects to ANT1 upon overexpression in HeLa cells, in contrast with the lack of apoptotic activity of ANT2 (Bauer et al, 1999;Zamora et al, 2004a). Both studies claimed that the effects of ANT1 and ANT3 result from proteinprotein interaction within the PTPC complex because the cytotoxic effects of ANT3 can be prevented by the inhibitors of PTPC (CsA) and ANT (BA), respectively.…”

Section: Ant1 Isoform Is Pro-apoptotic and Its Expression Is Frequentmentioning

confidence: 99%

“…More recently, a third major breakthrough has been made in terms of role of ANT in apoptosis. Thus, ANT is expressed as four tissue-specific isoforms, ANT1 to ANT4, and we and others postulated that each ANT isoform might have a specific role in influencing cell fate, notably in cancer cells (Bauer et al, 1999;Zamora et al, 2004a;Le Bras et al, 2006;Gallerne et al, 2010). In this review, we recapitulate our knowledge of the role that the various isoforms of ANT play in apoptosis, examine the expression and the function of the four ANT isoforms in cancer cells and discuss recent evidence to propose a novel classification of ANT isoforms and their function in cancer cell death.…”

Section: Introductionmentioning

confidence: 99%