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P53 restoration in small cell lung cancer identifies a latent cyclophilin-dependent necrosis mechanism (ChIP-Seq)

ABSTRACT: p53 restoration in small cell lung cancer identifies a latent cyclophilin-dependent necrosis mechanism (ChIP-Seq)

PROVIDER: PRJNA967322 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24442456.fastq.gz	Fastqsanger.gz
	SRR24442457.fastq.gz	Fastqsanger.gz
	SRR24442458.fastq.gz	Fastqsanger.gz
	SRR24442459.fastq.gz	Fastqsanger.gz
	SRR24442460.fastq.gz	Fastqsanger.gz

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Similar Datasets

p53 restoration in small cell lung cancer identifies a latent cyclophilin-dependent necrosis mechanism (ChIP-Seq)

Project description:The p53 tumor suppressor regulates multiple context-dependent tumor suppressive programs. Although p53 is mutated in ~90% of small cell lung cancer (SCLC) tumors, how p53 mediates tumor suppression in this context is unknown. Here, using a mouse model of SCLC in which endogenous p53 expression can be conditionally and temporally regulated, we show that SCLC tumors maintain a requirement for p53 inactivation. However, we identified tumor subtype heterogeneity between SCLC tumors such that p53 reactivation induces a canonical senescence response in a subset of tumors, while, in others, p53 induces a non-apoptotic form of cell death that culminates in necrosis. We pinpointed the cyclophilin family of peptidyl prolyl cis-trans isomerases as critical determinants of a p53-induced transcriptional program that is specific to SCLC tumors and cell lines that are poised to undergo p53- mediated necrosis. Importantly, inhibition of cyclophilin isomerase activity, or genetic ablation of specific cyclophilin genes, suppresses p53-mediated necrosis by limiting p53 transcriptional output without impacting p53 chromatin binding. Our study demonstrates that a previously unappreciated intertumoral heterogeneity in SCLC can influence the biological response to p53 restoration, describes a novel mechanism of p53-regulated cell death, and uncovers putative mechanisms for the treatment of this most-recalcitrant tumor type.

2023-06-05 | GSE231701 | GEO

p53 restoration in small cell lung cancer identifies a latent cyclophilin-dependent necrosis mechanism (RNA-Seq II)

2023-06-05 | GSE231704 | GEO

p53 restoration in small cell lung cancer identifies a latent cyclophilin-dependent necrosis mechanism (RNA-Seq I)

2023-06-05 | GSE231703 | GEO

p53 restoration in small cell lung cancer identifies a latent cyclophilin-dependent necrosis mechanism

Project description:p53 restoration in small cell lung cancer identifies a latent cyclophilin-dependent necrosis mechanism

| PRJNA967320 | ENA

p53 restoration in small cell lung cancer identifies a latent cyclophilin-dependent necrosis mechanism (RNA-Seq I)

Project description:p53 restoration in small cell lung cancer identifies a latent cyclophilin-dependent necrosis mechanism (RNA-Seq I)

| PRJNA967323 | ENA

p53 restoration in small cell lung cancer identifies a latent cyclophilin-dependent necrosis mechanism (RNA-Seq II)

Project description:p53 restoration in small cell lung cancer identifies a latent cyclophilin-dependent necrosis mechanism (RNA-Seq II)

| PRJNA967324 | ENA

p53 restoration in small cell lung cancer identifies a latent cyclophilin-dependent necrosis mechanism.

Project description:The p53 tumor suppressor regulates multiple context-dependent tumor suppressive programs. Although p53 is mutated in ~90% of small cell lung cancer (SCLC) tumors, how p53 mediates tumor suppression in this context is unknown. Here, using a mouse model of SCLC in which endogenous p53 expression can be conditionally and temporally regulated, we show that SCLC tumors maintain a requirement for p53 inactivation. However, we identify tumor subtype heterogeneity between SCLC tumors such that p53 reactivation induces senescence in a subset of tumors, while in others, p53 induces necrosis. We pinpoint cyclophilins as critical determinants of a p53-induced transcriptional program that is specific to SCLC tumors and cell lines poised to undergo p53-mediated necrosis. Importantly, inhibition of cyclophilin isomerase activity, or genetic ablation of specific cyclophilin genes, suppresses p53-mediated necrosis by limiting p53 transcriptional output without impacting p53 chromatin binding. Our study demonstrates that intertumoral heterogeneity in SCLC influences the biological response to p53 restoration, describes a cyclophilin-dependent mechanism of p53-regulated cell death, and uncovers putative mechanisms for the treatment of this most-recalcitrant tumor type.

| S-EPMC10362054 | biostudies-literature

p53 restoration in small cell lung cancer identifies a latent cyclophilin-dependent necrosis mechanism

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

2023-06-05 | GSE231705 | GEO

Stage-specific sensitivity to p53 restoration in lung cancer

Project description:This SuperSeries is composed of the following subset Series: GSE23873: Stage-specific sensitivity to p53 restoration in lung cancer: cell line data GSE23874: Stage-specific sensitivity to p53 restoration in lung cancer: tumor data Refer to individual Series

2010-11-24 | E-GEOD-23875 | biostudies-arrayexpress

Stage-specific sensitivity to p53 restoration in lung cancer: tumor data

Project description:Tumorigenesis is a multistep process that results from the sequential accumulation of mutations in key oncogene and tumor-suppressor pathways. The quest to personalize cancer medicine based on targeting these underlying genetic abnormalities presupposes that sustained inactivation of tumor suppressors and activation of oncogenes are required for tumor maintenance. Mutations in the p53 tumor-suppressor pathway are a hallmark of cancer and significant efforts toward pharmaceutical reactivation of mutant p53 pathways are underway1-3. Here we show that restoration of p53 in established murine lung tumors leads to significant but incomplete tumor cell loss specifically in malignant adenocarcinomas but not in adenomas. Also, we define amplification of MAPK signaling as a critical determinant of malignant progression. The differential response to p53 restoration depends on activation of the Arf tumor suppressor downstream of hyperactive MAPK signaling. We propose that p53 naturally limits malignant progression by responding to increased oncogenic signaling, but is unresponsive to low levels of oncogene activity that are sufficient for early stages of lung tumor development. These data suggest that restoration of pathways important in tumor progression, as opposed to initiation, may lead to incomplete tumor regression due to the stage-heterogeneity of tumor cell populations. 18 tumors of different grade and treatment status. 6 treated grade 3, 4 treated grade2, 4 untreated grade3, 4 untreated grade2

2010-11-24 | E-GEOD-23874 | biostudies-arrayexpress

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