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PKCl/i inhibition activates an ULK2-mediated interferon response to repress tumorigenesis [ATAC-Seq]

ABSTRACT: PKCl/i inhibition activates an ULK2-mediated interferon response to repress tumorigenesis [ATAC-Seq]

PROVIDER: PRJNA747048 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15168756_1.fastq.gz	Fastqsanger.gz
	SRR15168756_2.fastq.gz	Fastqsanger.gz
	SRR15168757_1.fastq.gz	Fastqsanger.gz
	SRR15168757_2.fastq.gz	Fastqsanger.gz
	SRR15168758_1.fastq.gz	Fastqsanger.gz

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PKCl/i inhibition activates an ULK2-mediated interferon response to repress tumorigenesis

Project description:PKCl/i inhibition activates an ULK2-mediated interferon response to repress tumorigenesis

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PKCl/i inhibition activates an ULK2-mediated interferon response to repress tumorigenesis [RNA-Seq]

Project description:PKCl/i inhibition activates an ULK2-mediated interferon response to repress tumorigenesis [RNA-Seq]

| PRJNA747047 | ENA

PKCl/i inhibition activates an ULK2-mediated interferon response to repress tumorigenesis [ATAC-Seq]

Project description:The interferon (IFN) pathway is critical for cytotoxic T cell activation, which is central to tumor immunosurveillance and successful immunotherapy. We demonstrate here that PKCl/i inactivation results in the hyper-stimulation of the IFN cascade and the enhanced recruitment of CD8+ T cells that impaired the growth of intestinal tumors. PKCl/i directly phosphorylates and represses the activity of ULK2, promoting its degradation through an endosomal microautophagy-driven ubiquitin-dependent mechanism. Loss of PKCl/i results in increased levels of enzymatically active ULK2 that by direct phosphorylation activates TBK1 to foster the activation of the STING-mediated IFN response. PKCl/i inactivation also triggers autophagy that prevents STING degradation by chaperone-mediated autophagy. Thus, PKCl/i is a hub regulating the IFN pathway and three autophagic mechanisms that serve to maintain its homeostatic control. Importantly, single cell multiplex imaging and bioinformatics analysis demonstrated that low PKCl/i levels correlate with enhanced IFN signaling and good prognosis in colorectal cancer patients.

2021-09-23 | GSE180223 | GEO

PKCl/i inhibition activates an ULK2-mediated interferon response to repress tumorigenesis [RNA-Seq]

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PKCl/i inhibition activates an ULK2-mediated interferon response to repress tumorigenesis

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-09-23 | GSE180224 | GEO

PKCλ/ι inhibition activates an ULK2-mediated interferon response to repress tumorigenesis.

Project description:The interferon (IFN) pathway is critical for cytotoxic T cell activation, which is central to tumor immunosurveillance and successful immunotherapy. We demonstrate here that PKCλ/ι inactivation results in the hyper-stimulation of the IFN cascade and the enhanced recruitment of CD8+ T cells that impaired the growth of intestinal tumors. PKCλ/ι directly phosphorylates and represses the activity of ULK2, promoting its degradation through an endosomal microautophagy-driven ubiquitin-dependent mechanism. Loss of PKCλ/ι results in increased levels of enzymatically active ULK2, which, by direct phosphorylation, activates TBK1 to foster the activation of the STING-mediated IFN response. PKCλ/ι inactivation also triggers autophagy, which prevents STING degradation by chaperone-mediated autophagy. Thus, PKCλ/ι is a hub regulating the IFN pathway and three autophagic mechanisms that serve to maintain its homeostatic control. Importantly, single-cell multiplex imaging and bioinformatics analysis demonstrated that low PKCλ/ι levels correlate with enhanced IFN signaling and good prognosis in colorectal cancer patients.

| S-EPMC8571054 | biostudies-literature

Trisomy 21 consistently activates the interferon response

Project description:Trisomy 21 consistently activates the interferon response

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FANCD2 Activates Transcription of TAp63 and Suppresses Tumorigenesis

Project description:Fanconi Anemia (FA) is a rare genetic disorder characterized by an increased susceptibility to squamous cell cancers. Fifteen FA genes are known, and the encoded proteins cooperate in a common DNA repair pathway. A critical step is the monoubiquitination of the FANCD2 protein, and cells from most FA patients are deficient in this step. How monoubiquitinated FANCD2 suppresses squamous cell cancers is unknown. Here we show that Fancd2-deficient mice are prone to Ras oncogene-driven skin carcinogenesis, while Usp1-deficient mice, expressing elevated cellular levels of Fancd2-Ub, are resistant to skin tumors. Moreover, Fancd2-Ub activates the transcription of the tumor suppressor TAp63, thereby promoting cellular senescence and blocking skin tumorigenesis. For FA patients, the reduction of FANCD2-Ub and TAp63 protein levels may account for their susceptibility to squamous cell neoplasia. Taken together, Usp1 inhibition may be a useful strategy for upregulating TAp63 and preventing or treating squamous cell cancers in the general non-FA population. Examination of FANCD2 binding after UV treatment in 293T cells

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Impaired immunosurveillance by the simultaneous loss of both atypical PKCs drives serrated intestinal cancer

Project description:The serrated adenocarcinoma subtype accounts for 15-30% of all colorectal cancers (CRCs) and is aggressive and treatment-resistant. it is an alternative mechanism for CRC development characterized by dysregulation of the MAPK pathway. We show that human serrated tumors display reduced expression of PKCz and PKCl/i, and that the simultaneous inactivation of these genes in the mouse intestinal epithelium resulted in spontaneous tumorigenesis through the serrated pathway that progressed to advanced cancer. Whereas epithelial PKCl/i deficiency led to immunogenic cell death that repressed tumor initiation, interferon and CD8+ T cell responses were impaired concomitant with stromal activation and immunosuppression driven by PKCz loss. Thus, PKCz and PKCl/i cooperatively suppress serrated tumorigenesis. Targeting this stromal activation and immunosuppression showed synergistic curative activity.

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Impaired immunosurveillance by the simultaneous loss of both atypical PKCs drives intestinal cancer through the serrated pathway [IECs DKO aPKC]

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