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Regulation of Immunological Tolerance by the p53-Inhibitor iASPP [mNET-Seq]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE202444 | GEO | 2023/02/02

REPOSITORIES: GEO

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Regulation of Immunological Tolerance by the p53-Inhibitor iASPP

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

Regulation of Immunological Tolerance by the p53-Inhibitor iASPP

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

Regulation of Immunological Tolerance by the p53-Inhibitor iASPP [ChIP-seq]

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 | GSE202443 | GEO

Selective and direct p53 inhibition by iASPP

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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Transcriptional impact of iASPP knockout in mouse keratinocytes

Project description:iASPP (PPP1R13L) is an evolutionarily conserved regulator of p53 family members. In mice, iASPP deletion in keratin 14-expressing keratinocytes is sufficient to cause detrimental phenotypes with squamous epithelium abnormalities. In human skin, wild-type nuclear iASPP colocalizes with the key squamous differentiation regulatory factor, TP63, and iASPP mutations also show abnormalities in skin development. To clarify how iASPP influences the keratinocyte transcriptome, iASPP WT and iASPP KO primary mouse keratinocytes (MKC) were compared.

2022-10-25 | GSE188371 | GEO

Impact of iASPP knockout on p63 genome occupancy in mouse keratinocytes

Project description:iASPP (PPP1R13L) is an evolutionarily conserved regulator of p53 family members. In mice, iASPP deletion in keratin 14-expressing keratinocytes is sufficient to cause detrimental phenotypes with squamous epithelium abnormalities. In human skin, wild-type nuclear iASPP colocalizes with the key squamous differentiation regulatory factor, TP63, and iASPP mutations are associated with abnormalities in skin development. To clarify how iASPP modulates p63 genome occupancy, p63 ChIP-seq data from iASPP WT and iASPP KO primary mouse keratinocytes (MKC) were compared.

2022-10-25 | GSE188447 | GEO

RNAseq analysis for transcriptomes of colon cancer cell line HCT116 upon p53 and/or iASPP knockdown with or without nutlin treatment

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.

2022-10-29 | GSE139546 | GEO

Selective and direct p53 inhibition by iASPP

Project description:Selective and direct p53 inhibition by iASPP

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Epigenetic regulation of iASPP-p63 feedback loop in cutaneous squamous cell carcinoma

Project description:Keratinocyte skin cancer, comprising cutaneous squamous (cSCC) and basal cell carcinoma, is the most common malignancy in the UK. P53 is frequently mutated in cSCC. iASPP is a key inhibitor of p53 and NF-kB signalling pathways and has been documented as highly expressed in several types of human cancer. We have previously identified an autoregulatory feedback loop between iASPP and p63, which is critical in epidermal homeostasis. We hypothesised a potential role for dysregulation of this axis in the pathogenesis of keratinocyte malignancies. Immunostaining of 116 cSCC clinical samples revealed increased iASPP and ΔNp63 expression but also highlighted a significant alteration of iASPP cellular localisation, with consequent deregulation of its function. Expression patterns, functionality, gene and microRNA expression analysis were further investigated in 10 cSCC cell lines. Our data suggest that whilst direct effects of iASPP and p63 upon each other’s expression are maintained in cSCC, epigenetic dysregulation of the feedback loop occurs at the microRNA level by a novel mechanism controlling p63 expression. We demonstrate that this autoregulatory feedback loop controls cell migration in cSCC by blocking EMT and promoting proliferation, and provides future directions for clinical biomarker and therapeutic target discovery in cutaneous SCC.

2019-11-20 | GSE123189 | GEO

p53 inhibitor iASPP is an unexpected suppressor of KRAS and inflammation driven pancreatic cancer

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.

2023-07-06 | GSE226595 | GEO

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