{"doi":"10.1101/2020.10.20.347401","title":"P53-independent restoration of p53 pathway in tumors with mutated p53 through ATF4 transcriptional modulation by ERK1/2 and CDK9","abstract":"Abstract 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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":124129,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9565,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":568422,"name":"Nagib Ahsan","orcid":"0000-0002-6813-7527","position":1,"is_corresponding":false},{"id":568423,"name":"Amriti R. Lulla","orcid":"0000-0002-7085-5755","position":2,"is_corresponding":false},{"id":495332,"name":"Avital Lev","orcid":"0000-0002-2127-7338","position":3,"is_corresponding":false},{"id":568424,"name":"Philip H. Abbosh","orcid":"0000-0003-3611-9532","position":4,"is_corresponding":false},{"id":495334,"name":"David T. Dicker","orcid":"0000-0002-0610-8317","position":5,"is_corresponding":false},{"id":556099,"name":"Shengliang Zhang","orcid":"0000-0001-6368-1147","position":6,"is_corresponding":false},{"id":94964,"name":"Wafik S. El‐Deiry","orcid":"0000-0002-9577-8266","position":7,"is_corresponding":false},{"id":569288,"name":"Xiaobing Tian","orcid":null,"position":0,"is_corresponding":true}],"reference_count":52,"raw_metadata":null,"created_at":"2026-07-18T23:15:07.789881Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}