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Identification of a molecular network of DNA damage-induced neural cell death

ABSTRACT: DNA damage plays a major role in neural cell death by necrosis and/or apoptosis. However, our understanding of the molecular mechanisms of neural cell death remains still incomplete. To acquire a global understanding of the various mediators related to DNA damage-induced neural cell death pathways, we performed a whole genomic wide screen in neural stem cells by using a siRNA library. We identified 80 genes required for DNA damage-induced cell death. 14 genes (17.5%) are directly related to cell death and/or apoptosis. 66 genes have not been previously directly linked to DNA damage-induced cell death. Using an integrated approach with functional and bioinformatics analysis, we have uncovered a molecular network containing several partially overlapping and interconnected pathways and/or protein complexes that are required for DNA damage-induced neural cell death. The identification of the network of neural cell death mediators will greatly enhance our understanding of the molecular mechanisms of neural cell death and provide therapeutic targets for nervous system disorders.

ORGANISM(S): Mus musculus

PROVIDER: GSE31666 | GEO | 2018/05/29

REPOSITORIES: GEO

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Project description:Certain anticancer drugs, particularly cyclophosphamide (CTX), were shown to enhance the antitumor efficacy of immunotherapy through different immunomodulatory mechanisms. A better understanding of the cellular and molecular basis of CTX-mediated immunomodulation is needed to improve the efficacy of chemoimmunotherapy. Transcript profiling and flow cytometry were used to explore CTX immune-enhancing activity in patients with hematologic malignancies. A single high-dose treatment quickly (1-2 days) induced an extensive transcriptional modulation in peripheral blood mononuclear cells, leading to the reduction of cell cycle and biosynthetic/metabolic processes and to the augmentation of transcripts related to DNA damage and cell death (p53 signaling pathway, CDKN1A, CCND3, BAX, BBC3, BID, DDB2, SESN2), of scavenger receptors involved in the recognition of death (MARCO, CD68, CD163L1, SCARB2), of antigen processing/presentation mediators (CIITA, CTSC, CTSL1, CTSZ, GLA, GAA, TPP1, NEU1, SLC11A1, LAMP-2), of T cell activation markers (CD69, OX40) and, noticeably, of a type I interferon (IFN-I) signature (OAS1, CXCL10, BAFF, IFITM2, IFI6, IRF5, IRF7, STAT2, UBE2L6, UNC93B1, ISG20L1, TYK2). Moreover, the plasma levels of IFN-I-induced proinflammatory mediators (CXCL10, CCL2, IL-8, BAFF) were increased by treatment. Accordingly, CTX preconditioning induced both monocyte and lymphocyte activation, leading to the expansion of CD14+CD16+ monocytes, of HLA-DR+, IL8RA+, MARCO+ monocytes/dendritic cells and of CD69+, OX40+, IL8RA+ lymphocytes. Altogether, these data define for the first time the immunomodulatory factors induced by CTX in humans and indicate that preconditioning chemotherapy may stimulate immunity as a consequence of danger perception associated to its cytotoxic action on blood cells, through p53 and IFN-I-related mechanisms. Four-condition experiment, Untreated (10 Biological replicates) - Cyclophosphamide-treated 1 day (10 Biological replicates) - Cyclophosphamide-treated 2 days (8 Biological replicates) - Cyclophosphamide-treated 5 days (5 Biological replicates). Each sample labeled with Cy5 and co-hybridized with Cy3-labeled M-bM-^@M-^\referenceM-bM-^@M-^] aRNA. One replicate per array.

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Identification of a molecular network of DNA damage-induced neural cell death

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