Comparison of genotoxic versus nongenotoxic stabilization of p53 provides insight into parallel stress-responsive transcriptional networks
| Autor: | Charly R. Good, Morgan A. Sammons, Allison N. Catizone, Katherine A. Alexander, Shelley L. Berger |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
p53
Transcriptional Activation 0301 basic medicine DNA damage Gene regulatory network Apoptosis Biology Piperazines Cell Line 03 medical and health sciences 0302 clinical medicine Nitriles Gene expression Humans Gene Regulatory Networks Sulfones Molecular Biology Gene Etoposide Protein Stability Imidazoles NF-kappa B Proto-Oncogene Proteins c-mdm2 Cell Biology Fibroblasts Gene signature Chromatin Assembly and Disassembly Chromatin Cell biology ChIP-seq 030104 developmental biology Gene Expression Regulation 030220 oncology & carcinogenesis biology.protein Mdm2 Tumor Suppressor Protein p53 Transcription Research Paper DNA Damage Protein Binding Developmental Biology P53 binding |
| Zdroj: | Cell Cycle |
| ISSN: | 1551-4005 1538-4101 |
| Popis: | The tumor suppressor protein p53 is activated in response to diverse intrinsic and extrinsic cellular stresses and controls a broad cell-protective gene network. Whether p53:DNA binding and subsequent transcriptional activation differs downstream of these diverse intrinsic and extrinsic activators is controversial. Using primary human fibroblasts, we assessed the genome-wide profile of p53 binding, chromatin structure, and transcriptional dynamics after either genotoxic or nongenotoxic activation of p53. Activation of p53 by treatment with either etoposide or the small-molecule MDM2 inhibitor nutlin 3A yields strikingly similar genome-wide binding of p53 and concomitant changes to local chromatin modifications and structure. DNA damage, but not p53 activation per se, leads to increased expression of genes in an inflammatory cytokine pathway. The NF-κB pathway inhibitor Bay 11-7082 abrogates etoposide-mediated activation of the inflammation gene signature but does not affect expression of canonical p53 target genes. Our data demonstrate that differential activation of p53 within the same cell type leads to highly similar genome-wide binding, chromatin dynamics, and gene expression dynamics and that DNA damage-mediated signaling through NF-κB likely controls the observed pro-inflammatory cytokine gene expression pattern. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|