P53-independent partial restoration of the p53 pathway in tumors with mutated p53 through ATF4 transcriptional modulation by ERK1/2 and CDK9
| Autor: | David T. Dicker, Avital Lev, Amriti R. Lulla, Nagib Ahsan, Xiaobing Tian, Philip Abbosh, Shengliang Zhang, Wafik S. El-Deiry |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Cancer Research Cancer therapy Genes myc Apoptosis MYC DMSO dimethyl sulfoxide Transcriptome GRO global run-on 0302 clinical medicine PG3-Oc Puma ATF4 Original Research Gene Editing ERK1/2 biology Effector Endoplasmic Reticulum Stress lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Cell biology Gene Expression Regulation Neoplastic Mutant p53 030220 oncology & carcinogenesis Reprogramming Signal Transduction Programmed cell death Cell Survival MAP Kinase Signaling System CDK9 Models Biological lcsh:RC254-282 ER endoplasmic reticulum Inhibitory Concentration 50 03 medical and health sciences Downregulation and upregulation Cell Line Tumor PUMA Humans DR5 p53 pathway restoration Autophagy IPA ingenuity pathway analysis biology.organism_classification Activating Transcription Factor 4 Cyclin-Dependent Kinase 9 030104 developmental biology Mutation CRISPR-Cas Systems Tumor Suppressor Protein p53 |
| Zdroj: | Neoplasia: An International Journal for Oncology Research, Vol 23, Iss 3, Pp 304-325 (2021) Neoplasia (New York, N.Y.) |
| ISSN: | 1476-5586 |
| DOI: | 10.1016/j.neo.2021.01.004 |
| Popis: | A long-term goal in the cancer-field has been to develop strategies for treating p53-mutated tumors. A novel small-molecule, PG3-Oc, restores p53 pathway-signaling in tumor cells with mutant-p53, independently of p53/p73. PG3-Oc partially upregulates the p53-transcriptome (13.7% of public p53 target-gene dataset; 15.2% of in-house dataset) and p53-proteome (18%, HT29; 16%, HCT116-p53−/−). Bioinformatic analysis indicates critical p53-effectors of growth-arrest (p21), apoptosis (PUMA, DR5, Noxa), autophagy (DRAM1), and metastasis-suppression (NDRG1) are induced by PG3-Oc. ERK1/2- and CDK9-kinases are required to upregulate ATF4 by PG3-Oc which restores p53 transcriptomic-targets in cells without functional-p53. PG3-Oc represses MYC (ATF4-independent), and upregulates PUMA (ATF4-dependent) in mediating cell death. With largely nonoverlapping transcriptomes, induced-ATF4 restores p53 transcriptomic targets in drug-treated cells including functionally important mediators such as PUMA and DR5. Our results demonstrate novel p53-independent drug-induced molecular reprogramming involving ERK1/2, CDK9, and ATF4 to restore upregulation of p53 effector genes required for cell death and tumor suppression. |
| Databáze: | OpenAIRE |
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