Regulation of Immunological Tolerance by the p53-Inhibitor iASPP
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ABSTRACT:
PROVIDER: PRJNA836123 | ENA |
REPOSITORIES: ENA
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Project description:Maintenance of immunological homeostasis between tolerance and autoimmunity is essential for the prevention of human diseases ranging from autoimmune disease to cancer. Accumulating evidence suggests that p53 can mitigate phagocytosis-induced adjuvanticity thereby promoting immunological tolerance following programmed cell death. Here we identify Inhibitor of Apoptosis Stimulating p53 Protein (iASPP), a negative regulator of p53 transcriptional activity, as a regulator of immunological tolerance. iASPP-deficiency promoted lung adenocarcinoma and pancreatic cancer tumorigenesis, while iASPP-deficient mice were less susceptible to autoimmune disease. Immune responses to iASPP-deficient tumors exhibited hallmarks of immunosuppression, including activated regulatory T cells and exhausted CD8+ T cells. Interestingly, iASPP-deficient tumor cells and tumor-infiltrating myeloid cells, CD4+, and gd T cells expressed elevated levels of PD-1H, a recently identified transcriptional target of p53 that promotes tolerogenic phagocytosis. Identification of an iASPP/p53 axis of immune homeostasis provides a therapeutic opportunity for both autoimmune disease and cancer.
2023-02-02 | GSE218389 | GEO
Project description:Maintenance of immunological homeostasis between tolerance and autoimmunity is essential for the prevention of human diseases ranging from autoimmune disease to cancer. Accumulating evidence suggests that p53 can mitigate phagocytosis-induced adjuvanticity thereby promoting immunological tolerance following programmed cell death. Here we identify Inhibitor of Apoptosis Stimulating p53 Protein (iASPP), a negative regulator of p53 transcriptional activity, as a regulator of immunological tolerance. iASPP-deficiency promoted lung adenocarcinoma and pancreatic cancer tumorigenesis, while iASPP-deficient mice were less susceptible to autoimmune disease. Immune responses to iASPP-deficient tumors exhibited hallmarks of immunosuppression, including activated regulatory T cells and exhausted CD8+ T cells. Interestingly, iASPP-deficient tumor cells and tumor-infiltrating myeloid cells, CD4+, and γδ T cells expressed elevated levels of PD-1H, a recently identified transcriptional target of p53 that promotes tolerogenic phagocytosis. Identification of an iASPP/p53 axis of immune homeostasis provides a therapeutic opportunity for both autoimmune disease and cancer.
2023-02-02 | GSE202445 | GEO
Project description:Maintenance of immunological homeostasis between tolerance and autoimmunity is essential for the prevention of human diseases ranging from autoimmune disease to cancer. Accumulating evidence suggests that p53 can mitigate phagocytosis-induced adjuvanticity thereby promoting immunological tolerance following programmed cell death. Here we identify Inhibitor of Apoptosis Stimulating p53 Protein (iASPP), a negative regulator of p53 transcriptional activity, as a regulator of immunological tolerance. iASPP-deficiency promoted lung adenocarcinoma and pancreatic cancer tumorigenesis, while iASPP-deficient mice were less susceptible to autoimmune disease. Immune responses to iASPP-deficient tumors exhibited hallmarks of immunosuppression, including activated regulatory T cells and exhausted CD8+ T cells. Interestingly, iASPP-deficient tumor cells and tumor-infiltrating myeloid cells, CD4+, and gamma-delta T cells expressed elevated levels of PD-1H, a recently identified transcriptional target of p53 that promotes tolerogenic phagocytosis. Identification of an iASPP/p53 axis of immune homeostasis provides a therapeutic opportunity for both autoimmune disease and cancer.
2023-02-02 | GSE202444 | GEO
Project description:Maintenance of immunological homeostasis between tolerance and autoimmunity is essential for the prevention of human diseases ranging from autoimmune disease to cancer. Accumulating evidence suggests that p53 can mitigate phagocytosis-induced adjuvanticity thereby promoting immunological tolerance following programmed cell death. Here we identify Inhibitor of Apoptosis Stimulating p53 Protein (iASPP), a negative regulator of p53 transcriptional activity, as a regulator of immunological tolerance. iASPP-deficiency promoted lung adenocarcinoma and pancreatic cancer tumorigenesis, while iASPP-deficient mice were less susceptible to autoimmune disease. Immune responses to iASPP-deficient tumors exhibited hallmarks of immunosuppression, including activated regulatory T cells and exhausted CD8+ T cells. Interestingly, iASPP-deficient tumor cells and tumor-infiltrating myeloid cells, CD4+, and gamma-delta T cells expressed elevated levels of PD-1H, a recently identified transcriptional target of p53 that promotes tolerogenic phagocytosis. Identification of an iASPP/p53 axis of immune homeostasis provides a therapeutic opportunity for both autoimmune disease and cancer.
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Project description:Regulation of Immunological Tolerance by the p53-Inhibitor iASPP
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Project description:Regulation of Immunological Tolerance by the p53-Inhibitor iASPP [mNET-Seq]
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Project description:Regulation of Immunological Tolerance by the p53-Inhibitor iASPP [ChIP-seq]
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Project description:We performed p53 ChIP-seq analysis of Nutlin-treated HCT116 cells to identify high-confident p53 regulated targets. And we performed ChIP-seq using an anti-p53 antibody in HCT116 cells treated with control or iASPP RNAi to identify iASPP regulated p53 targets.
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Project description:To investigate the transcriptomic effects of iASPP deletion or p53 mutation in the KRASG12D background Pdx1-Cre was used to delete iASPP in oncogenic KRASG12D expressing (KC) background to generate KC;iASPPΔ8/Δ8 mice. KC and KC;iASPPΔ8/Δ8 mice were then crossed with mice containing a p53R172H allele (equivalent to human p53 hotspot mutation R175H) to generate KPC and KPC;iASPPΔ8/Δ8 cohorts. Primary cell cultures were then derived from pancreatic ductal adenocarcinoma tissue for RNA-seq.
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Project description:The tumor suppressor p53 plays a critical role in the cellular response to various stresses, including DNA damage, hypoxia, nutrition starvation, and oncogene activation. However, wild-type p53 function was largely impaired in cancer cells, one of the reasons is the inhibition by p53 negative regulating proteins (iASPP, MDM2 etc.). To globally evaluate the transcriptome inhibited by iASPP and the potent synergy of co-inhibiting MDM2, we performed RNAseq analysis in colon cancer cell line HCT116 upon p53 or iASPP knockdown with or without Nutlin-3 treatment.
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