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P53 restoration in small cell lung cancer identifies a latent cyclophilin-dependent necrosis mechanism

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

PROVIDER: PRJNA967320 | ENA |

REPOSITORIES: ENA

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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 (ChIP-Seq)

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

| PRJNA967322 | 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

Cyclophilin B supports the survuval of glioblastoma multiforme cells

Project description:We have found that cyclophilin B (CypB) expression is important for malignant glioblastoma multiforme (GBM) cell proliferation. To identify molecular mechanisms that could explain CypB-dependent survival in human GBM cells, a microarray analysis was performed using RNA prepared from U251MG GBM cells transduced with lentiviral CypB shRNA. These data revealed that about 130 genes were more than 2-fold affected by CypB depletion. Significant alterations in the expression of genes related to cell death, cell proliferation and cell migration were found in the shCypB cells. U251 glioblastoma cells transduced with lentivirus expressing non-target control shRNA (shCON) were compared to cells transduced with lentivirus expressing shRNA sequence against cyclophilin B (shCypB). Cells transduced with the lentiviral shRNA (shCON VS shCypB) for 5 days before total RNA extraction. Three biological replicates of cells treated with each shRNA (shCON or shCypB) were profiled.

2013-09-12 | E-GEOD-50756 | biostudies-arrayexpress

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