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Unique Transcriptional Profiles Underlie Osteosarcomagenesis Driven by Different p53 Mutants

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE231852 | GEO | 2023/05/12

REPOSITORIES: GEO

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Unique Transcriptional Profiles Underlie Osteosarcomagenesis Driven by Different p53 Mutants.

Project description:Missense mutations in the DNA binding domain of p53 are characterized as structural or contact mutations based on their effect on the conformation of the protein. These mutations show gain-of-function (GOF) activities, such as promoting increased metastatic incidence compared with p53 loss, often mediated by the interaction of mutant p53 with a set of transcription factors. These interactions are largely context specific. To understand the mechanisms by which p53 DNA binding domain mutations drive osteosarcoma progression, we created mouse models, in which either the p53 structural mutant p53R172H or the contact mutant p53R245W are expressed specifically in osteoblasts, yielding osteosarcoma tumor development. Survival significantly decreased and metastatic incidence increased in mice expressing p53 mutants compared with p53-null mice, suggesting GOF. RNA sequencing of primary osteosarcomas revealed vastly different gene expression profiles between tumors expressing the missense mutants and p53-null tumors. Further, p53R172H and p53R245W each regulated unique transcriptomes and pathways through interactions with a distinct repertoire of transcription factors. Validation assays showed that p53R245W, but not p53R172H, interacts with KLF15 to drive migration and invasion in osteosarcoma cell lines and promotes metastasis in allogeneic transplantation models. In addition, analyses of p53R248W chromatin immunoprecipitation peaks showed enrichment of KLF15 motifs in human osteoblasts. Taken together, these data identify unique mechanisms of action of the structural and contact mutants of p53.SignificanceThe p53 DNA binding domain contact mutant p53R245W, but not the structural mutant p53R172H, interacts with KLF15 to drive metastasis in somatic osteosarcoma, providing a potential vulnerability in tumors expressing p53R245W mutation.

| S-EPMC10524763 | biostudies-literature

Unique Transcriptional Profiles Underlie Osteosarcomagenesis Driven by Different p53 Mutants (ATAC-Seq)

Project description:Open chromatin regions in the murine osteosarcoma cell lines expressing different mutants of p53 were identified using ATAC-seq

2023-05-12 | GSE231851 | GEO

Unique Transcriptional Profiles Underlie Osteosarcomagenesis Driven by Different p53 Mutants (ChIP-Seq)

Project description:To identify mutant p53 GOF and analyze mutant p53 ChIP peaks ChIP-seq was performed on hESC-derived human osteoblasts expressing homozygous WT p53 or heterozygous expression of p53R248W. Processing for ChIP was performed on day 24 after confirmation of osteoblast differentiation

2023-05-12 | GSE231850 | GEO

Unique Transcriptional Profiles Underlie Osteosarcomagenesis Driven by Different p53 Mutants (RNA-Seq)

Project description:To identify mutant p53 GOF, murine primary osteosarcomas expressing p53R172H or p53R245W over null and p53-null osteosarcomas were processed for bulk sequencing; DEGs were identified in p53R172H and p53R245W expressing tumors by comparing to p53-null tumors; DEGs were used to identify dysregulated pathways and mutant p53 GOF

2023-05-12 | GSE231849 | GEO

Unique Transcriptional Profiles Underlie Osteosarcomagenesis Driven by Different p53 Mutants

Project description:Unique Transcriptional Profiles Underlie Osteosarcomagenesis Driven by Different p53 Mutants

| PRJNA968023 | ENA

Unique Transcriptional Profiles Underlie Osteosarcomagenesis Driven by Different p53 Mutants (ChIP-Seq)

Project description:Unique Transcriptional Profiles Underlie Osteosarcomagenesis Driven by Different p53 Mutants (ChIP-Seq)

| PRJNA968024 | ENA

Unique Transcriptional Profiles Underlie Osteosarcomagenesis Driven by Different p53 Mutants (ATAC-Seq)

Project description:Unique Transcriptional Profiles Underlie Osteosarcomagenesis Driven by Different p53 Mutants (ATAC-Seq)

| PRJNA968026 | ENA

Unique Transcriptional Profiles Underlie Osteosarcomagenesis Driven by Different p53 Mutants (RNA-Seq)

Project description:Unique Transcriptional Profiles Underlie Osteosarcomagenesis Driven by Different p53 Mutants (RNA-Seq)

| PRJNA968025 | ENA

Unique miRNome and Transcriptome Profiles Underlie Microvascular Heterogeneity in Mouse Kidney

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

2023-06-30 | GSE220987 | GEO

Physical and functional CSL-p53 interactions underlie control of cancer stromal cell evolution

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2015-08-24 | E-GEOD-65474 | biostudies-arrayexpress

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