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RNA-seq of mouse colon to investigate how suppression of HSF1 activity by wildtype p53 creates a driving force for p53 loss-of-heterozygosity

ABSTRACT: RNA-seq of mouse colon to investigate how suppression of HSF1 activity by wildtype p53 creates a driving force for p53 loss-of-heterozygosity

PROVIDER: PRJEB42819 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	ERR5216740_1.fastq.gz	Fastqsanger.gz
	ERR5216740_2.fastq.gz	Fastqsanger.gz
	ERR5216731_1.fastq.gz	Fastqsanger.gz
	ERR5216731_2.fastq.gz	Fastqsanger.gz
	ERR5216741_1.fastq.gz	Fastqsanger.gz

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Suppression of HSF1 activity by wildtype p53 creates a driving force for p53 loss-of-heterozygosity

Project description:Suppression of HSF1 activity by wildtype p53 creates a driving force for p53 loss-of-heterozygosity

| PRJEB44756 | ENA

Suppression of HSF1 activity by wildtype p53 creates a driving force for p53 loss-of-heterozygosity

Project description:p53LOH in murine CRC organoids de-represses HSF1 activity and triggers mutp53-driven invasion.

2021-05-17 | E-MTAB-10416 | biostudies-arrayexpress

Suppression of HSF1 activity by wildtype p53 creates a driving force for p53 loss-of-heterozygosity.

Project description:The vast majority of human tumors with p53 mutations undergo loss of the remaining wildtype p53 allele (loss-of-heterozygosity, p53LOH). p53LOH has watershed significance in promoting tumor progression. However, driving forces for p53LOH are poorly understood. Here we identify the repressive WTp53-HSF1 axis as one driver of p53LOH. We find that the WTp53 allele in AOM/DSS chemically-induced colorectal tumors (CRC) of p53R248Q/+ mice retains partial activity and represses heat-shock factor 1 (HSF1), the master regulator of the proteotoxic stress response (HSR) that is ubiquitously activated in cancer. HSR is critical for stabilizing oncogenic proteins including mutp53. WTp53-retaining CRC tumors, tumor-derived organoids and human CRC cells all suppress the tumor-promoting HSF1 program. Mechanistically, retained WTp53 activates CDKN1A/p21, causing cell cycle inhibition and suppression of E2F target MLK3. MLK3 links cell cycle with the MAPK stress pathway to activate the HSR response. In p53R248Q/+ tumors WTp53 activation by constitutive stress represses MLK3, thereby weakening the MAPK-HSF1 response necessary for tumor survival. This creates selection pressure for p53LOH which eliminates the repressive WTp53-MAPK-HSF1 axis and unleashes tumor-promoting HSF1 functions, inducing mutp53 stabilization enabling invasion.

| S-EPMC8242083 | biostudies-literature

RNA-seq of mouse colon to investigate how suppression of HSF1 activity by wildtype p53 creates a driving force for p53 loss-of-heterozygosity

Project description:Mice with colonic tumors (chemically induced by AOM/DSS) were treated with Nutlin or control vehicle solution to analyze p53 target gene expression in vivo.

2021-04-20 | E-MTAB-10041 | biostudies-arrayexpress

E-MTAB-10416

Project description:Suppression of HSF1 activity by wildtype p53 creates a driving force for p53 loss-of-heterozygosity

2025-07-07 | E-MTAB-10416 | ExpressionAtlas

Enhancement of colorectal cancer therapy through interruption of the HSF1-HSP90 axis by p53 activation or cell cycle inhibition

Project description:The heat-shock protein 90 (HSP90) is a promising target in cancer therapy, but its inhibitors' clinical trial failures are partly due to a compensatory heat-shock response (HSR) mediated by heat-shock factor 1 (HSF1). We previously showed that wildtype p53 reduces HSR by repressing HSF1 via a p21-CDK4/6-MAPK-HSF1 axis. Here, we explore if simultaneous p53 activation or cell cycle inhibition can disrupt the HSF1-HSR axis and enhance HSP90 inhibitors' efficiency. mRNA sequencing was performed on HCT116 cells treated for 24 hours with DMSO, 50 nM Ganetespib, 1 µM RG-7388, or their combination. We found that the p53 activator Idasanutlin suppresses HSF1-HSR activity in HSP90 inhibitor-based therapies, synergistically reducing cell viability and accelerating cell death in p53-proficient colorectal cancer (CRC) cells and organoids. Combination therapy upregulates p53 pathways, apoptosis, and inflammation. In a CRC mouse model, dual HSF1-HSP90 inhibition represses tumor growth and alters immune cell composition. CDK4/6 inhibition under HSP90 inhibition mimics HSR repression in p53-proficient CRC cells. In p53-deficient CRC cells and p53-mutated organoids, combined HSP90 and CDK4/6 inhibition suppresses HSF1-HSR and reduces cancer growth, offering a p53-independent strategy for CRC treatment. In conclusion, we present new options to improve HSP90-based therapies for enhanced CRC treatment.

2025-03-28 | E-MTAB-14877 | biostudies-arrayexpress

E-MTAB-10041

Project description:RNA-seq of mouse colon to investigate how suppression of HSF1 activity by wildtype p53 creates a driving force for p53 loss-of-heterozygosity

2024-11-14 | E-MTAB-10041 | ExpressionAtlas

Acute HSF1 depletion induces cellular senescence through activation of the MDM2-p53-p21 pathway in human diploid fibroblasts

Project description:Heat shock transcription factor 1 (HSF1) regulates the expression of a wide array of genes, controlling expression of heat shock proteins (HSPs) and cell growth. Although acute depletion of HSF1 induces cellular senescence, the underlying mechanisms are poorly understood. Here, we report that HSF1 depletion-induced senescence (HDIS) of human diploid fibroblasts (HDFs) was independent of HSP-mediated proteostasis, but dependent on activation of the p53-p21 pathway, partly because of increased expression of dehydrogenase/reductase 2 (DHRS2), a putative MDM2 inhibitor. We observed that HDIS occurred without decreased levels of major HSPs or increased proteotoxic stress in HDFs. Additionally, an inhibitor of HSP70 family proteins increased proteotoxicity and suppressed cell growth, but failed to induce senescence. Importantly, we found that activation of the p53-p21 pathway due to reduced MDM2-dependent p53 degradation was required for HDIS. Furthermore, we provide evidence that increased DHRS2 expression contribute to p53 stabilization and HDIS. Collectively, our observations uncovered a molecular pathway in which HSF1 depletion-induced DHRS2 expression leads to activation of the MDM2-p53-p21 pathway required for HDIS.

2018-05-01 | GSE111355 | GEO

DDX41 heterozygosity impairs hematopoietic progenitor cell fitness and cooperates with p53 mutation to drive malignancy [MOLM13]

Project description:Germline heterozygous mutations in DDX41 predispose individuals to hematologic malignancies in adulthood. Most of these DDX41 mutations result in a truncated protein, leading to loss of protein function. To investigate the impact of these mutations on hematopoiesis, we generated mice with hematopoietic-specific knockout of one Ddx41 allele. Under normal steady-state conditions, there was minimal effect on lifelong hematopoiesis, resulting in a mild yet persistent reduction in red blood cell counts. However, stress induced by transplantation of the Ddx41+/- BM resulted in hematopoietic stem/progenitor cell (HSPC) defects and onset of hematopoietic failure upon aging. Transcriptomic analysis of HSPC subsets from the transplanted BM revealed activation of cellular stress responses, including upregulation of p53 target genes in erythroid progenitors. To understand how the loss of p53 affects the phenotype of Ddx41+/- HSPCs, we generated mice with combined Ddx41 and Trp53 heterozygous deletions. The reduction in p53 expression rescued the fitness defects in HSPC caused by Ddx41 heterozygosity. However, the combined Ddx41 and Trp53 mutant mice were prone to developing hematologic malignancies that resemble human myelodysplastic syndrome and acute myeloid leukemia. In conclusion, DDX41 heterozygosity causes dysregulation of the response to hematopoietic stress, which increases the risk of transformation with a p53 mutation.

2024-06-13 | GSE247408 | GEO

DDX41 heterozygosity impairs hematopoietic progenitor cell fitness and cooperates with p53 mutation to drive malignancy [LSK]

2024-06-13 | GSE247404 | GEO