Suppression of hypoxic cell death by APIP-induced sustained activation of AKT and ERK1/2

Dh, Cho; Hj, Lee; Kim, Hyung Jun; Hong, Shaodong; Jo, Pyo; C, Cho; Jung, Yong‐Keun

doi:10.1038/sj.onc.1210080

Cited by 35 publications

(30 citation statements)

References 13 publications

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“…3D). The data confirmed previous reports (31,36) of APIP inhibiting apoptosis and revealed a role in inhibition of pyroptosis.…”

Section: Resultssupporting

confidence: 91%

“…Others have reported that MTA can both inhibit and increase apoptosis depending on the cell type (50,51). Published studies showing APIP inhibition through binding to APAF-1 (31) and regulation of protein phosphorylation (36) provide alternative mechanisms where APIP could regulate apoptosis independent of its role in methionine salvage. For the regulation of apoptosis by APIP, multiple mechanisms are likely involved with their relative importance determined by cell type, metabolic state, and specific stimuli.…”

Section: Resultsmentioning

confidence: 99%

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Functional genetic screen of human diversity reveals that a methionine salvage enzyme regulates inflammatory cell death

Ko¹,

Gamazon

Shukla³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Genome-wide association studies can identify common differences that contribute to human phenotypic diversity and disease. When genome-wide association studies are combined with approaches that test how variants alter physiology, biological insights can emerge. Here, we used such an approach to reveal regulation of cell death by the methionine salvage pathway. A common SNP associated with reduced expression of a putative methionine salvage pathway dehydratase, apoptotic protease activating factor 1 (APAF1)-interacting protein (APIP), was associated with increased caspase-1-mediated cell death in response to Salmonella. The role of APIP in methionine salvage was confirmed by growth assays with methionine-deficient media and quantitation of the methionine salvage substrate, 5′-methylthioadenosine. Reducing expression of APIP or exogenous addition of 5′-methylthioadenosine increased Salmonellae-induced cell death. Consistent with APIP originally being identified as an inhibitor of caspase-9-dependent apoptosis, the same allele was also associated with increased sensitivity to the chemotherapeutic agent carboplatin. Our results show that common human variation affecting expression of a single gene can alter susceptibility to two distinct cell death programs. Furthermore, the same allele that promotes cell death is associated with improved survival of individuals with systemic inflammatory response syndrome, suggesting a possible evolutionary pressure that may explain the geographic pattern observed for the frequency of this SNP. Our study shows that in vitro association screens of disease-related traits can not only reveal human genetic differences that contribute to disease but also provide unexpected insights into cell biology.HapMap | lymphoblastoid | pyroptosis | quantitative trait | polygenic adaptation

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“…3D). The data confirmed previous reports (31,36) of APIP inhibiting apoptosis and revealed a role in inhibition of pyroptosis.…”

Section: Resultssupporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Functional genetic screen of human diversity reveals that a methionine salvage enzyme regulates inflammatory cell death

Ko¹,

Gamazon

Shukla³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Contrary to the weak up-regulation of APIP and UACA mRNA expression, the expression of serpinB9 mRNA was strongly induced in several ADC-treated NSCLC cell lines (Rousalova et al, unpublished data). It has been reported that ischemia/hypoxia up-regulates the expression of APIP in some tissues and tumour cells (25)(26)(27). Although there is evidence that the microenvironment of NSCLC tumours contains many ischemic regions characterized by hypoxia and acidosis (43), we frequently observed decreased expression of APIP mRNA and protein in NSCLC tumours.…”

Section: Discussioncontrasting

confidence: 50%

“…APIP, which is a cytosolic protein, binds to the CARD domain of Apaf-1 and prevents PC-9 recruitment to the apoptosome (25,26). Moreover, during hypoxic conditions, APIP induces sustained activation of AKT and ERK1/2 kinases, which directly phosphorylate PC-9 to inhibit its activation in the apoptosome (27). UACA/nucling, showing both cytoplasmic and perinuclear/nuclear localization (28)(29)(30), interacts with Apaf-1 and induces its translocation into the nucleus upon proapoptotic stress (31).…”

Section: Introductionmentioning

confidence: 99%

Down-regulated expression of apoptosis-associated genes APIP and UACA in non-small cell lung carcinoma

et al. 2012

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Abstract. The Apaf-1 interacting protein (APIP) and the uveal autoantigen with coiled coil domains and ankyrin repeats (UACA) belong to endogenous regulators of the apoptosome apparatus, but their role in tumourigenesis and progression of non-small cell lung carcinoma (NSCLC) is not known. Previous studies demonstrated that APIP inhibits the apoptosome-mediated procaspase-9 activation while UACA induces translocation of Apaf-1 from the cytoplasm into the nucleus. Here, we report for the first time that the expression of APIP and UACA genes is down-regulated on the level of both mRNA and protein in NSCLC cells and tumours. In particular, the expression of APIP protein was strikingly decreased and the expression of UACA mRNA and protein was frequently down-regulated in NSCLC tumours of different histopathological types. Moreover, stage IA NSCLC tumours showed significantly lower expression of UACA mRNA compared to higher stage tumours. The weak increase of both APIP and UACA mRNA levels in the 5-aza-2'-deoxycytidine-treated NSCLC cells indicates that mechanisms other than DNA methylation are involved in the regulation of APIP and UACA gene expression in these cancer cells. Taken together, the down-regulation of APIP and UACA expression suggests that the threshold to activate the apoptosome apparatus may be decreased in NSCLC cells due to the lack of APIP-mediated suppression and UACA-assisted Apaf-1 nuclear entry. Moreover, the loss of UACA-assisted Apaf-1 nuclear translocation may underlie the failure of DNA damage checkpoint activation in NSCLC cells leading to their genomic instability. IntroductionThe apoptosome apparatus is a stress-induced cell death signalling platform that is assembled in the cytosol via the cytochrome-c (cyt-c)-and (d)ATP-mediated formation of an Apaf-1 heptameric complex, which recruits and activates the apoptosis initiator procaspase-9 (PC-9) (1-3). Both epigenetic and transcriptional factor-mediated regulation of Apaf-1 and PC-9 expression levels plays an important role in predisposition of cells to activate the apoptosome apparatus (4-8). However, the processes of apoptosome assembly and functioning in cancer cells are under a variety of negative and positive modes of post-translational regulation (9,10). There is evidence that the hypersensitivity of certain malignant neoplasms such as brain tumours and breast carcinomas, as opposed to their normal tissue counterparts, to the cyt-c-induced apoptosis is due to up-regulation of Apaf-1 and its regulator PHAPI, respectively, in cancer cells (11,12). On the other hand, deficient signalling in the apoptosome pathway, due to the lack of apoptosome core component expression or apoptosome dysfunction, contributes to tumourigenesis and progression of malignant neoplasms as well as to their chemo-and radioresistance (8,(13)(14)(15)(16)(17)(18)(19)(20).The activation of apoptosome apparatus is often impaired in non-small cell lung carcinoma (NSCLC) cells and tissues (21,22). The molecular basis of apoptosome apparatus suppression in NSCLC is sti...

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“…Hypoxia was achieved by culturing the cells in MEM (Invitrogen) in an air-tight Plexiglass chamber with GasPak Plus (BD Biosciences) (38) or cells were exposed to hypoxia (0.1% O2) by incubating cells at 37°C in 5% CO 2/10% H2/85% N2 anaerobic incubator (Forma Scientific). Cells were then placed under normoxic conditions.…”

mentioning

confidence: 99%

Intracellular cleavage of osteopontin by caspase-8 modulates hypoxia/reoxygenation cell death through p53

Kim

Lee

Jun

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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O steopontin (OPN) is a secreted glycosylated phosphoprotein that is involved in a number of physiological events including bone formation and remodeling (1), immune responses (2, 3), and tumor progression, such as cell proliferation, angiogenesis, metastasis, and anti-apoptosis (4). Especially, OPN is highly up-regulated in cancer patients' plasma, thus it is considered a candidate as a prognostic marker for human cancer diagnosis (4). Multiple cancer-related functions of OPN are mediated by its interaction with integrins or CD44 variants as a cytokine. Generally, secreted OPN acts as an intact protein or fragments cleaved by thrombin; Arg-Gly-Asp (RGD) motif in OPN interacts with integrins (␣ v ␤ 3 , ␣ v ␤ 5 ) and C-terminal region of OPN binds to CD44 variants, which subsequently activates a PI3K-AKT, NIK, or MEKK1 kinase cascade (4, 5). In addition, alternative isoform of OPN is found in cytosol (6) and OPN is detected as a CD44-ERM complex in the cytosolic side of CD44 (7). Further, OPN also associates with polo-like kinase-1 in the nucleus during cell cycle (8). These observations show diverse roles and subcellular localizations of OPN.OPN is also highly induced during hypoxia/reoxygenation (Hyp/ RO), which is closely related to pathological conditions including myocardial ischemia/reperfusion injury, stroke, inflammation, and solid tumors (9, 10). During Hyp/RO, cell death generally occurs after massive generation of reactive oxygen species (ROS) and caspases activation. Several caspases including caspases-8, -9, and -3 were reported to be activated during reoxygenation, which is required for Hyp/RO-induced cell death (11,12). Among these caspases, caspase-8 is a well known receptor-proximal caspase. However, accumulating evidence suggests atypical roles of caspase-8 in nonreceptor-mediated cell deaths (13, 14) and . In addition, caspase-8 deficiency is also detected in human cancers (16,17) and facilitates cellular transfomation (18), showing critical functions of caspase-8 in tumorigenesis and cell death. In the group of hundreds' cellular substrates of various caspases, only a few proteins, such as Bid, p28 Bap31, RIP-1, and plectin, are reported as caspase-8 substrates (19)(20)(21)(22).In this study, we performed genome-wide screening and isolated OPN as a caspase-8 substrate. OPN expression is rapidly increased during Hyp/RO and subsequently cleaved by caspase-8, leading to both inactivation of AKT survival signal and activation of cell death signal via its caspase cleavage fragment in tumor cells. Results OPN Is Cleaved by Caspase-8 in Vitro and in Apoptotic Cells DuringHyp/RO. To unearth caspase substrates, we undertook caspase substrate screening using human cDNA library. Small cDNA pools were transcribed and translated in vitro in the presence of [35 S]methionine and then incubated with recombinant caspases (23). From this analysis, we isolated OPN as a putative substrate of caspase-8. To characterize the cleavage, in vitro translated OPN was incubated with various recombinant active caspases (ca...

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Suppression of hypoxic cell death by APIP-induced sustained activation of AKT and ERK1/2

Cited by 35 publications

References 13 publications

Functional genetic screen of human diversity reveals that a methionine salvage enzyme regulates inflammatory cell death

Functional genetic screen of human diversity reveals that a methionine salvage enzyme regulates inflammatory cell death

Down-regulated expression of apoptosis-associated genes APIP and UACA in non-small cell lung carcinoma

Intracellular cleavage of osteopontin by caspase-8 modulates hypoxia/reoxygenation cell death through p53

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