The p53-inducible apoptotic protein AMID is not required for normal development and tumor suppression

Mei, Jie; Webb, Saiphone; Zhang, B; Hb, Shu

doi:10.1038/sj.onc.1209121

Cited by 29 publications

(24 citation statements)

References 29 publications

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“…These results show in detail the actual process of nuclear translocation of endoG and AIF and they question the proposed role of AMID in apoptosis [8,31,32]. They are also supported by a recent study demonstrating that knockout mice lacking AMID are viable and apparently normal and do not display any differences in development from wild-type mice [58]. Moreover, the authors also found no differences in the frequencies of natural tumor occurrence or 3-methylcholanthrene-induced sarcoma in these mice compared to wild type.…”

Section: Translocation Of Endog Aif and Amid To Nucleussupporting

confidence: 43%

Bioinformatic and image analyses of the cellular localization of the apoptotic proteins endonuclease G, AIF, and AMID during apoptosis in human cells

et al. 2007

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We studied the cellular localization of the apoptotic proteins endonuclease G, AIF, and AMID in silico using three prediction tools and in living cells using both single-cell colocalization image analysis and nuclear translocation analysis. We confirmed the mitochondrial localization of endonuclease G and AIF by prediction analysis and by single-cell colocalization image analysis. We found the AMID protein to be cytoplasmic, most probably incorporated into the cytoplasmic side of the membranes of various organelles. The highest concentration of AMID was observed associated with the Golgi. Colocalization of AMID with lysosomes was also indirectly confirmed by analysis of AMID-rich vesicle velocity using manual tracking analysis. Bioinformatic analysis also detected nuclear localization signals in endonuclease G and AIF, but not in AMID. A novel analysis of time-lapse fluorescence image data during staurosporine-induced apoptosis revealed nuclear translocation only for endonuclease G and AIF.

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Section: Translocation Of Endog Aif and Amid To Nucleussupporting

confidence: 43%

Bioinformatic and image analyses of the cellular localization of the apoptotic proteins endonuclease G, AIF, and AMID during apoptosis in human cells

et al. 2007

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“…This is consistent with the apparent lack of an extended N-terminal mitochondrial targeting sequence analogous to that found in AIF (18,21). AIF-M2 is transcriptionally up-regulated by p53 and by genotoxic chemicals, suggesting that it might contribute to the arrest of cell growth on exposure to such agents (23). AIF-M2 is a DNA-binding protein with nicotinamide coenzyme-dependent oxidoreductase activity, and it is usual for the purified protein to contain 6-hydroxy-FAD (19).…”

supporting

confidence: 61%

“…Such a model would require that AIF-M2 has a physiological role in preventing apoptosis. As with AIF, knock out of AIF-M2 protein expression has no effect on both normal and tumor cell viability (23), thus pointing to other sources of ROS to maintain ROS production for survival signaling (17). With AIF knock-outs there is increased sensitivity to peroxide-induced apoptosis, but comparable studies with AIF-M2 knockouts have not been reported.…”

Section: Discussionmentioning

confidence: 78%

DNA Binding Suppresses Human AIF-M2 Activity and Provides a Connection between Redox Chemistry, Reactive Oxygen Species, and Apoptosis

Gong

Hay

Marshall

et al. 2007

Journal of Biological Chemistry

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Human AIF-M2 is an unusual flavoprotein oxidoreductase that binds DNA, nicotinamide coenzyme, and the modified flavin 6-hydroxy-FAD. Using multiple solution methods to investigate the redox chemistry and binding interactions of AIF-M2, we demonstrate that binding of DNA and coenzyme to AIF-M2 is mutually exclusive. We also show that DNA binding does not perturb the redox chemistry of AIF-M2, but it has significant effects on the reduction kinetics of the 6-hydroxy-FAD cofactor by NAD(P)H. Based on quantitative analysis of ligand binding and redox chemistry, we propose a model for the function of AIF-M2. In this model, DNA binding suppresses the redox activity of AIF-M2 by preventing the binding of the reducing coenzyme NAD(P)H. This DNA-mediated suppression of AIF-M2 activity is expected to lower cellular levels of superoxide and peroxide, thereby lessening survival signaling by Ras, NF-B, or AP-1, as suggested from knock-out studies of the related AIF in human colon cancer cell lines. We show marked differences between AIF-M2 and AIF. DNA and coenzyme binding activity is retained in the C-terminal deletion mutant AIF-M2-(⌬319 -613), whereas DNA binds to the C-terminal D3 domain of AIF. Our work provides the first analysis of AIF-M2 ligand interactions and redox chemistry and identifies an important mechanistic connection between coenzyme and DNA binding, redox activity, and the apoptotic function of AIF-M2. Through its DNA binding activity, we suggest that AIF-M2 lessens survival cell signaling in the presence of foreign (e.g. bacterial and (retro)viral) cytosolic DNA, thus contributing to the onset of apoptosis.Apoptosis (programmed cell death), a cellular process in higher organisms by which cells die (1, 2), can be induced by toxic insult (e.g. chemical damage) or physical disruption of cells. It is critical in the development of multicellular organisms, including the development of the embryo and vital organs, and in cellular homeostasis (3). Up to 70 billion human adult cells undergo apoptosis each day (4). Lesions in the apoptotic process or its regulation result in developmental defects, immortalized cells, and cancers (3). The mitochondrion is a key apoptosis regulator, and pro-apoptotic and cell damage-controlled pathways feed back to the mitochondrion and induce permeabilization of mitochondrial membranes (5). In part, this is under the control of the Bcl-2 protein family, which contains members with either pro-(e.g. Bax) or anti-apoptotic (e.g. Bcl-2) functions (6). Cytotoxic molecules in the mitochondrial intermembrane space are released on membrane permeabilization and act as cell death effectors, some depending on activation by caspase proteases (7). Release of cytochrome c triggers activation of the initiator caspase-9. Downstream activation of other caspases leads to proteolytic cleavage of key target molecules (e.g. laminins) leading to cell morphology changes such as plasma membrane perturbations, condensation and fragmentation of nuclear chromatin, and compaction of cytoplasmic organelles and...

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“…(36) Although expression of AMID is upregulated by p53 and genotoxins, and downregulated in many tumors, analysis of AMID À/À mice indicates that AMID is not essential for normal development and provides no evidence for any role in p53-dependent tumor suppression. (38,39) These studies imply that AMID is unlikely to be part of an AIF-dependent pathway, and its cellular localization makes it improbable that it compensates for loss of AIF in neurons. Although ROS were not directly measured, indirect evidence implied that AIF-deficient ES or HeLa cells exhibited similar or marginally lower levels of ROS to AIF-expressing cells in unstressed conditions.…”

mentioning

confidence: 96%

Does apoptosis‐inducing factor (AIF) have both life and death functions in cells?

Porter

Urbano

2006

BioEssays

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Apoptosis-inducing factor (AIF) is expelled from mitochondria after some apoptotic stimuli and translocates to the nucleus, which may contribute to DNA and nuclear fragmentation in some non-physiological mammalian cell deaths. Conversely, the requirement for mitochondrial AIF in oxidative phosphorylation and energy generation provides a plausible explanation for the embryonic lethality or neurodegeneration that has been found in different AIF-deficient mouse models. These findings may help illuminate the ability of mitochondrial AIF to suppress cytoplasmic stress granule formation and to promote the tumorigenic growth of cancer cells. AIF is ideally located in the mitochondrion to perform a vital normal function in energy production. Once it translocates to the nucleus, however, the cell might die either of energy failure or nuclear fragmentation (or both). We propose that the main function of AIF is to support energy production in both normal and transformed cell physiology, whereas nuclear-translocated AIF might contribute to stress-induced or pathological cell death in certain scenarios.

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The p53-inducible apoptotic protein AMID is not required for normal development and tumor suppression

Cited by 29 publications

References 29 publications

Bioinformatic and image analyses of the cellular localization of the apoptotic proteins endonuclease G, AIF, and AMID during apoptosis in human cells

Bioinformatic and image analyses of the cellular localization of the apoptotic proteins endonuclease G, AIF, and AMID during apoptosis in human cells

DNA Binding Suppresses Human AIF-M2 Activity and Provides a Connection between Redox Chemistry, Reactive Oxygen Species, and Apoptosis

Does apoptosis‐inducing factor (AIF) have both life and death functions in cells?

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