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Pyrimidine Triones as Potential Activators of p53 Mutants

ABSTRACT: Pyrimidine Triones as Potential Activators of p53 Mutants

PROVIDER: PRJNA1140516 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR30003363_1.fastq.gz	Fastqsanger.gz
	SRR30003363_2.fastq.gz	Fastqsanger.gz
	SRR30003364_1.fastq.gz	Fastqsanger.gz
	SRR30003364_2.fastq.gz	Fastqsanger.gz
	SRR30003365_1.fastq.gz	Fastqsanger.gz

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Pyrimidine Triones as Potential Activators of p53 Mutants

Project description:p53 is a crucial tumor suppressor in vertebrates that is frequently mutated in human cancers. Most mutations are missense mutations that render p53 inactive in suppressing tumor initiation and progression. Developing small molecule drugs to convert mutant p53 into an active, wild-type-like conformation is a significant focus for personalized cancer therapy. Prior research indicates that reactivating p53 suppresses cancer cell proliferation and tumor growth in animal models. Early clinical evidence with a compound selectively targeting p53 mutants with substitutions of tyrosine 220 suggests potential therapeutic benefits of reactivating p53 in patients. This study identifies and examines the UCI-1001 compound series as a potential corrector for several p53 mutations. The findings indicate that UCI-1001 treatment in p53 mutant cancer cell lines inhibits growth and reinstates wild-type p53 activities, including DNA binding, target gene activation, and induction of cell death. Cellular thermal shift assays, conformation-specific immunofluorescence staining, and differential scanning fluorometry suggest that UCI-1001 interacts with and alters the conformation of mutant p53 in cancer cells. These initial results identify pyrimidine trione derivatives of the UCI-1001 series as candidates for p53 corrector drug development.

2024-08-05 | GSE273169 | GEO

Pyrimidine Triones as Potential Activators of p53 Mutants.

Project description:p53 is a crucial tumor suppressor in vertebrates that is frequently mutated in human cancers. Most mutations are missense mutations that render p53 inactive in suppressing tumor initiation and progression. Developing small-molecule drugs to convert mutant p53 into an active, wild-type-like conformation is a significant focus for personalized cancer therapy. Prior research indicates that reactivating p53 suppresses cancer cell proliferation and tumor growth in animal models. Early clinical evidence with a compound selectively targeting p53 mutants with substitutions of tyrosine 220 suggests potential therapeutic benefits of reactivating p53 in patients. This study identifies and examines the UCI-1001 compound series as a potential corrector for several p53 mutations. The findings indicate that UCI-1001 treatment in p53 mutant cancer cell lines inhibits growth and reinstates wild-type p53 activities, including DNA binding, target gene activation, and induction of cell death. Cellular thermal shift assays, conformation-specific immunofluorescence staining, and differential scanning fluorometry suggest that UCI-1001 interacts with and alters the conformation of mutant p53 in cancer cells. These initial results identify pyrimidine trione derivatives of the UCI-1001 series as candidates for p53 corrector drug development.

| S-EPMC11352488 | biostudies-literature

TMPRSS2-ERG and gain-of-function p53 mutants co-dictate pyrimidine synthesis and prostate cancer fitness [ERG and p53 ChIP-seq]

Project description:TMPRSS2-ERG fusion is the most common genetic alteration in prostate cancer (PCa) and TP53 is the most frequently mutated gene in human cancers. However, their precise roles in PCa pathogenesis remain elusive. Here we showed that TMPRSS2-ERG fusion co-occurred with TP53 deletion/mutation in PCa patient specimens. ERG overexpression and Trp53 knockout/R172H mutant knockin induced pyrimidine synthesis gene (PSG) expression and prostate tumorigenesis in mice. Gain-of-function p53 mutants bound to the CTNNB1 promoter and upregulated β-Catenin. Overexpressed ERG and β-Catenin co-occupied PSG loci and mediated PSG expression, and high PSG expression associated with increased β-Catenin level and poor overall survival of PCa patients. β-Catenin inhibition by proteolysis-targeting chimeras (PROTACs) of its co-activator CBP and partner proteins LEF1/TCFs blocked ERG/p53-mutant PCa growth. Our study identifies CTNNB1 as a transcriptional target of p53 GOF-mutants, and reveals a druggable dependency on β-Catenin and pyrimidine synthesis in p53-mutated cancers with or without TMPRSS2-ERG fusion.

2023-06-27 | GSE184623 | GEO

TMPRSS2-ERG and gain-of-function p53 mutants co-dictate pyrimidine synthesis and prostate cancer fitness [RNA-seq-2021 ERG-p53 project]

2023-06-27 | GSE184625 | GEO

TMPRSS2-ERG and gain-of-function p53 mutants co-dictate pyrimidine synthesis and prostate cancer fitness [RNA-seq-2018 ERG-p53 project]

2023-06-27 | GSE184624 | GEO

Pyrimidine synthase CAD deamidates and inactivates p53

Project description:Pyrimidine synthase CAD deamidates and inactivates p53

| PRJNA1209001 | ENA

Pyrimidine synthase CAD deamidates and inactivates p53

Project description:p53, a critical tumor suppressor, regulates the cell cycle in response to DNA damage and metabolic changes. While p53 stability and activity are predominantly governed by post-translational modifications, the role of deamidation in modulating p53 function remains unclear. This study demonstrates that 6-diazo-5-oxo-L-norleucine (DON) inhibits CAD, a glutamine amidotransferase, to block p53 deamidation, thereby activating the p53 signaling pathway and suppressing tumor cell proliferation. Metabolomic analyses confirmed that DON inhibits CAD-mediated pyrimidine biosynthesis, but this metabolic disruption is not the primary driver of p53 activation. CAD deamidates p53 at N235 and N239, impairing its transcriptional activity and promoting tumor growth. DON restores p53 function by inhibiting CAD’s deamidase activity. Clinical data revealed elevated CAD expression in tumors with wild-type TP53, correlating with poor patient survival. Our findings uncover a novel mechanism by which CAD suppresses p53 activity via deamidation and propose that DON treatment may benefit cancer patients with wild-type TP53 and high CAD expression.

2025-01-12 | GSE286372 | GEO

TMPRSS2-ERG and gain-of-function p53 mutants co-dictate pyrimidine synthesis and prostate cancer fitness

Project description:TMPRSS2-ERG and gain-of-function p53 mutants co-dictate pyrimidine synthesis and prostate cancer fitness

| PRJNA765377 | ENA

TMPRSS2-ERG and gain-of-function p53 mutants co-dictate pyrimidine synthesis and prostate cancer fitness [ERG and p53 ChIP-seq]

Project description:TMPRSS2-ERG and gain-of-function p53 mutants co-dictate pyrimidine synthesis and prostate cancer fitness [ERG and p53 ChIP-seq]

| PRJNA765379 | ENA

TMPRSS2-ERG and gain-of-function p53 mutants co-dictate pyrimidine synthesis and prostate cancer fitness [RNA-seq-2018 ERG-p53 project]

Project description:TMPRSS2-ERG and gain-of-function p53 mutants co-dictate pyrimidine synthesis and prostate cancer fitness [RNA-seq-2018 ERG-p53 project]

| PRJNA765380 | ENA

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