Disease relevance of AIFM1

• Activation-induced cell death of human melanoma specific cytotoxic T lymphocytes is mediated by apoptosis-inducing factor [1].
• Apoptosis-inducing factor determines the chemoresistance of non-small-cell lung carcinomas [2].
• CD44 ligation induces caspase-independent cell death via a novel calpain/AIF pathway in human erythroleukemia cells [3].
• Novel inosine monophosphate dehydrogenase inhibitor VX-944 induces apoptosis in multiple myeloma cells primarily via caspase-independent AIF/Endo G pathway [4].
• Our data demonstrate that OSU-03012 promotes glioma cell killing that is dependent on endoplasmic reticulum stress, lysosomal dysfunction, and BID-dependent release of AIF from mitochondria, and whose lethality is enhanced by irradiation or by inhibition of protective signaling pathways [5].

Psychiatry related information on AIFM1

• In these cells, we examined mitochondrial apoptosis-inducing factor (AIF) and cytochrome c (cyt c) release to the cytosol in PG time-response studies [6].
• In this study, we investigated AIF protein expression levels in frontal and temporal cortices of normal subjects of various ages, as well as in subjects with Alzheimer's disease (AD) [7].

High impact information on AIFM1

• The nuclear localization of AIF can be inhibited by blocking upstream signals of apoptosis [8].
• The contribution of AIF to cell death depends on the cell type and apoptotic insult and is only seen when caspases are inhibited or not activated [8].
• Apoptosis-inducing factor (AIF) is a NADH oxidase with a local redox function that is essential for optimal oxidative phosphorylation and for an efficient anti-oxidant defense [8].
• The absence of AIF can cause neurodegeneration, skeleton muscle atrophy and dilated cardiomyopathy [8].
• When added to intact cells or purified mitochondria, micromolar and submicromolar doses of synthetic Vpr cause a rapid dissipation of the mitochondrial transmembrane potential (DeltaPsi(m)), as well as the mitochondrial release of apoptogenic proteins such as cytochrome c or apoptosis inducing factor [9].

Chemical compound and disease context of AIFM1

• Human colon cancer cells differ in their sensitivity to curcumin-induced apoptosis and heat shock protects them by inhibiting the release of apoptosis-inducing factor and caspases [10].
• Effect of 3-aminobenzamide on Bcl-2, Bax and AIF localization in hippocampal neurons altered by ischemia-reperfusion injury. the immunocytochemical study [11].
• Two bacterial toxins, pneumolysin and, to a lesser extent, H(2)O(2), induce apoptosis by translocation of AIF, suggesting new neuroprotective strategies for pneumococcal meningitis [12].
• Role of caspases and apoptosis-inducing factor (AIF) in cladribine-induced apoptosis of B cell chronic lymphocytic leukemia [13].
• We have investigated the expression of AIF-1 in the rat C6 glioblastoma and 9L gliosarcoma tumor models and additionally assessed AIF- expression in a diverse range of human astrocytomas by immunohistochemistry [14].

Biological context of AIFM1

• During the initial, caspase-independent stage of chromatin condensation that accompanies apoptosis, AIF and CypA were found to coimmunolocalize in the nucleus [15].
• The AIF-dependent large-scale DNA fragmentation was less pronounced in CypA knockout cells as compared to controls [15].
• Recombinant AIF and CypA proteins synergized in vitro in the degradation of plasmid DNA, as well as in the capacity to induce DNA loss in purified nuclei [15].
• The contribution of apoptosis-inducing factor, caspase-activated DNase, and inhibitor of caspase-activated DNase to the nuclear phenotype and DNA degradation during apoptosis [16].
• Moreover, we show that calpain protease was activated before the appearance of apoptosis, and that calpain inhibitors or transfection of calpain-siRNA decrease A3D8-induced cell death, and block AIF release [3].

Anatomical context of AIFM1

• Cerebral endothelial cell apoptosis after ischemia-reperfusion: role of PARP activation and AIF translocation [17].
• While RNA interference-mediated knockdown of AIF protected melanocytes against apoptosis induced by serum withdrawal, apoptotic responses to UVB, cisplatin, and 4-TBP were not compromised by AIF knockdown, even in the presence of zVAD-fmk [18].
• High extracellular KCl also attenuated translocation of apoptosis-inducing factor (AIF) and endonuclease G (EndoG) from mitochondria to nuclei [19].
• Inhibition of K(+) efflux prevents mitochondrial dysfunction, and suppresses caspase-3-, apoptosis-inducing factor-, and endonuclease G-mediated constitutive apoptosis in human neutrophils [19].
• By contrast, Endo G resides in the mitochondrial intermembrane space in normal cells, and is released into the nucleus upon apoptotic disruption of mitochondrial membrane permeability in association with co-activators such as apoptosis-inducing factor (AIF) [20].

Associations of AIFM1 with chemical compounds

• Together, these data suggest that the oxidoreductase function of AIF is required for the maintenance of glutathione levels in stress conditions and that glutathione is a major regulator of SG [21].
• All these effects including cell death, loss of mitochondrial DeltaPsim and AIF release were blocked by pretreatment with the poly (ADP-ribose) polymerase inhibitor isoquinoline [3].
• Further studies in ARPE-19 cells undergoing menadione-induced cell death demonstrated mitochondrial membrane depolarization, release of cytochrome c, nuclear translocation of apoptosis-inducing factor and subsequent 50 kilo-base pair laddering, and nuclear shrinkage [22].
• In the present study, we show that, on cadmium exposure, the human hepatocarcinoma Hep3B cells undergo caspase-independent apoptosis associated with nuclear translocation of endonuclease G and apoptosis-inducing factor, two mitochondrial apoptogenic proteins [23].
• N-acetyl L-cysteine significantly inhibited the translocation of AIF induced by UVB [24].

Physical interactions of AIFM1

• In this work, we determined by deletional mutagenesis that a domain of AIF comprised between amino acids 150 and 228 is engaged in a molecular interaction with the substrate-binding domain of HSP70 [25].

Regulatory relationships of AIFM1

• PARP1-dependent radiosensitization was suppressed by a pan-caspase inhibitor and by knockdown of apoptosis-inducing factor expression [26].
• We have assessed the contribution of apoptosis-inducing factor (AIF) and inhibitor of caspase-activated DNase (ICAD) to the nuclear morphology and DNA degradation pattern in staurosporine-induced apoptosis [16].
• Loss of BH3-interacting domain (BID) function, overexpression of BCL(XL), and inhibition of cathepsin B function suppressed cell killing and apoptosis-inducing factor (AIF) release from mitochondria [5].
• HSP72 inhibits apoptosis-inducing factor release in ATP-depleted renal epithelial cells [27].

Other interactions of AIFM1

• AIF mutants lacking the CypA-binding domain were inefficient apoptosis sensitizers in transfection experiments [15].
• We show here that AICD in human melanoma epitope-specific primary CTL involves selective mitochondrio-nuclear translocation of the apoptosis inducing factor (AIF) without cytochrome c release, caspase-3 and caspase-8 activation, and results from large-scale DNA fragmentation [1].
• While mitochondrial levels of AIF and endonuclease G were higher in TLE samples than controls, nuclear localization of AIF was limited and restricted to cells that were negative for cleaved caspase-3 [28].
• The c-jun-N terminal kinase (JNK) inhibitor, SP600125, blocks the mitochondrio-nuclear translocation of AIF and prevents AICD in these CTL [1].
• We conclude that DeltaPsi(m) loss and ROS production are an early step in CD47-dependent killing and neither cytochrome c, nor AIF are implicated in this new cell death pathway [29].

Analytical, diagnostic and therapeutic context of AIFM1

• Confocal and electron microscopy reveal that, in normal cells, AIF is strictly confined to mitochondria and thus colocalizes with heat shock protein 60 (hsp60) [30].
• These data suggest that CD44 ligation triggers a novel caspase-independent cell death pathway via calpain-dependent AIF release in erythroleukemic HEL cells.Oncogene (2006) 25, 5741-5751. doi:10.1038/sj.onc.1209581; published online 24 April 2006 [3].
• In addition, microinjection of an anti-AIF antibody prevented AIF from translocating to the nuclei of STS-treated U1810 cells and reduced STS-induced cell death [2].
• The mitochondrio-nuclear translocation of apoptosis-inducing factor (AIF) was evaluated by confocal laser microscopy [24].
• Further, upon treatment of cells with ox-LDL AIF translocated from mitochondria to the nucleus, as determined by immunocytochemistry [31].

References