Activation of ASC induces apoptosis or necrosis, depending on the cell type, and causes tumor eradication

Motani, Kou; Kawase, Kouji; Imamura, Ryu; Kinoshita, Takeshi; Kushiyama, Hiroko; Suda, Takafumi

doi:10.1111/j.1349-7006.2010.01610.x

Cited by 26 publications

(34 citation statements)

References 25 publications

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“…54 PYCARD (also known as ASC and TMS1) codes for a pro-apoptotic protein and is aberrantly methylated in about a third of gastric cancers, in association with worse prognosis. 55,56 Chromosomal instability tumors generally had variable levels of methylation and gene expression, and poor methylation/expression correlation, as might be expected if genomic structural abnormalities associated with the chromosomal instability type, rather than epigenetics, were causing expression changes. In addition, gene copy-number changes in the assayed CpG regions may bias quantitative methylation measurements.…”

Section: Discussionmentioning

confidence: 99%

High-definition CpG methylation of novel genes in gastric carcinogenesis identified by next-generation sequencing

et al. 2016

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Gastric cancers are the most frequent gastric malignancy and usually arise in the sequence of Helicobacter pylori-associated chronic gastritis. CpG methylation is a central mechanism of epigenetic gene regulation affecting cancer-related genes, and occurs early in gastric carcinogenesis. DNA samples from non-metaplastic gastric mucosa with variable levels of gastritis (non-metaplastic mucosa), intestinal metaplasia, or gastric cancer were screened with methylation arrays for CpG methylation of cancer-related genes and 30 gene targets were further characterized by high-definition bisulfite next-generation sequencing. In addition, data from The Cancer Genome Atlas were analyzed for correlation of methylation with gene expression. Overall, 13 genes had significantly increased CpG methylation in gastric cancer vs non-metaplastic mucosa (BRINP1, CDH11, CHFR, EPHA5, EPHA7, FGF2, FLI1, GALR1, HS3ST2, PDGFRA, SEZ6L, SGCE, and SNRPN). Further, most of these genes had corresponding reduced expression levels in gastric cancer compared with intestinal metaplasia, including novel hypermethylated genes in gastric cancer (FLI1, GALR1, SGCE, and SNRPN), suggesting that they may regulate neoplastic transformation from non-malignant intestinal metaplasia to cancer. Our data suggest a tumor-suppressor role for FLI1 in gastric cancer, consistent with recently reported data in breast cancer. For the genes with strongest methylation/expression correlation, namely FLI1, the expression was lowest in microsatellite-unstable tumors compared with other gastric cancer molecular subtypes. Importantly, reduced expression of hypermethylated BRINP1 and SGCE was significantly associated with favorable survival in gastric cancer. In summary, we report novel methylation gene targets that may have functional roles in discrete stages of gastric carcinogenesis and may serve as biomarkers for diagnosis and prognosis of gastric cancer.

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Section: Discussionmentioning

confidence: 99%

High-definition CpG methylation of novel genes in gastric carcinogenesis identified by next-generation sequencing

et al. 2016

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“…This discrepancy may stem from inflammasomeindependent functions for the upstream molecule NLRP3 and ASC. Activation of ASC, also known as TMS1, has been implicated in the induction of cell death (72). The loss of ASC could dysregulate apoptosis in response to infection and lead to an increase in viral load.…”

Section: Discussionmentioning

confidence: 99%

Murine Gammaherpesvirus 68 Pathogenesis Is Independent of Caspase-1 and Caspase-11 in Mice and Impairs Interleukin-1β Production upon Extrinsic Stimulation in Culture

Cieniewicz

Dong

et al. 2015

J Virol

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Gammaherpesviruses establish lifelong infections that are associated with the development of cancer. These viruses subvert many aspects of the innate and adaptive immune response of the host. The inflammasome, a macromolecular protein complex that controls inflammatory responses to intracellular danger signals generated by pathogens, is both activated and subverted during human gammaherpesvirus infection in culture. The impact of the inflammasome response on gammaherpesvirus replication and latency in vivo is not known. Caspase-1 is the inflammasome effector protease that cleaves the proinflammatory cytokines interleukin-1␤ (IL-1␤) and IL-18. We infected caspase-1-deficient mice with murine gammaherpesvirus 68 (MHV68) and observed no impact on acute replication in the lung or latency and reactivation from latency in the spleen. This led us to examine the effect of viral infection on inflammasome responses in bone marrow-derived macrophages. We determined that infection of macrophages with MHV68 led to a robust interferon response but failed to activate caspase-1 or induce the secretion of IL-1␤. In addition, MHV68 infection led to a reduction in IL-1␤ production after extrinsic lipopolysaccharide stimulation or upon coinfection with Salmonella enterica serovar Typhimurium. Interestingly, this impairment occurred at the proIL-1␤ transcript level and was independent of the RTA, the viral lytic replication and transcription activator. Taken together, MHV68 impairs the inflammasome response by inhibiting IL-1␤ production during the initial stages of infection. IMPORTANCEGammaherpesviruses persist for the lifetime of the host. To accomplish this, they must evade recognition and clearance by the immune system. The inflammasome consists of proteins that detect foreign molecules in the cell and respond by secreting proinflammatory signaling proteins that recruit immune cells to clear the infection. Unexpectedly, we found that murine gammaherpesvirus pathogenesis was not enhanced in mice lacking caspase-1, a critical inflammasome component. This led us to investigate whether the virus actively impairs the inflammasome response. We found that the inflammasome was not activated upon macrophage cell infection with murine gammaherpesvirus 68. Infection also prevented the host cell inflammasome response to other pathogen-associated molecular patterns, indicated by reduced production of the proinflammatory cytokine IL-1␤ upon bacterial coinfection. Taken together, murine gammaherpesvirus impairment of the inflammatory cytokine IL-1␤ in macrophages identifies one mechanism by which the virus may inhibit caspase-1-dependent immune responses in the infected animal. G ammaherpesviruses establish lifelong latent infections that are associated with significant morbidity and the development of malignancies (1-3). Gammaherpesviruses initially infect the mucosal tissues of naive hosts and undergo productive replication prior to colonization of latency reservoirs, including B lymphocytes and macrophages (4-6). Murine gammaherpes...

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“…Thus, ASC-mediated apoptosis seems to be important for tumor suppression and for cancer cell chemosensitivity. Furthermore, we recently demonstrated that transplanted human tumors in nude mice were completely eradicated by ASC activation in the tumor cells (18). Thus, ASC is a promising molecular target for cancer therapy.…”

Section: Ascmentioning

confidence: 99%

Caspase-1 Protein Induces Apoptosis-associated Speck-like Protein Containing a Caspase Recruitment Domain (ASC)-mediated Necrosis Independently of Its Catalytic Activity

Motani

Kushiyama

Imamura

et al. 2011

Journal of Biological Chemistry

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Background: ASC mediates apoptosis and necrosis of tumor cells and necrosis of microbe-infected macrophages. Results: ASC mediates necrosis only when cells express caspase-1; however, inhibition of caspase-1 proteolytic activity did not suppress the necrosis. Conclusion: Caspase-1 but not its proteolytic activity is essential for ASC-mediated necrosis. Significance: This study explains why ASC induces apoptosis or necrosis depending on the cell type.

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Activation of ASC induces apoptosis or necrosis, depending on the cell type, and causes tumor eradication

Cited by 26 publications

References 25 publications

High-definition CpG methylation of novel genes in gastric carcinogenesis identified by next-generation sequencing

High-definition CpG methylation of novel genes in gastric carcinogenesis identified by next-generation sequencing

Murine Gammaherpesvirus 68 Pathogenesis Is Independent of Caspase-1 and Caspase-11 in Mice and Impairs Interleukin-1β Production upon Extrinsic Stimulation in Culture

Caspase-1 Protein Induces Apoptosis-associated Speck-like Protein Containing a Caspase Recruitment Domain (ASC)-mediated Necrosis Independently of Its Catalytic Activity

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