{"doi":"10.1016/j.jbc.2021.101365","title":"Tumor suppressor p53 promotes ferroptosis in oxidative stress conditions independent of modulation of ferroptosis by p21, CDKs, RB, and E2F","abstract":"p53 is a well-established critical cell cycle regulator. By inducing transcription of the gene encoding p21, p53 inhibits cyclin-dependent kinase (CDK)-mediated phosphorylation of cell cycle inhibitor retinoblastoma (RB) proteins. Phosphorylation of RB releases E2F transcription factor proteins that transactivate cell cycle–promoting genes. Here, we sought to uncover the contribution of p53, p21, CDK, RB, and E2F to the regulation of ferroptosis, an oxidative form of cell death. Our studies have uncovered unexpected complexity in this regulation. First, we showed that elevated levels of p53 enhance ferroptosis in multiple inducible and isogenic systems. On the other hand, we found that p21 suppresses ferroptosis. Elevation of CDK activity also suppressed ferroptosis under conditions where p21 suppressed ferroptosis, suggesting that the impact of p21 must extend beyond CDK inhibition. Furthermore, we showed that overexpression of E2F suppresses ferroptosis in part via a p21-dependent mechanism, consistent with reports that this transcription factor can induce transcription of p21. Finally, deletion of RB genes enhanced ferroptosis. Taken together, these results show that signals affecting ferroptotic sensitivity emanate from multiple points within the p53 tumor suppressor pathway. p53 is a well-established critical cell cycle regulator. By inducing transcription of the gene encoding p21, p53 inhibits cyclin-dependent kinase (CDK)-mediated phosphorylation of cell cycle inhibitor retinoblastoma (RB) proteins. Phosphorylation of RB releases E2F transcription factor proteins that transactivate cell cycle–promoting genes. Here, we sought to uncover the contribution of p53, p21, CDK, RB, and E2F to the regulation of ferroptosis, an oxidative form of cell death. Our studies have uncovered unexpected complexity in this regulation. First, we showed that elevated levels of p53 enhance ferroptosis in multiple inducible and isogenic systems. On the other hand, we found that p21 suppresses ferroptosis. Elevation of CDK activity also suppressed ferroptosis under conditions where p21 suppressed ferroptosis, suggesting that the impact of p21 must extend beyond CDK inhibition. Furthermore, we showed that overexpression of E2F suppresses ferroptosis in part via a p21-dependent mechanism, consistent with reports that this transcription factor can induce transcription of p21. Finally, deletion of RB genes enhanced ferroptosis. Taken together, these results show that signals affecting ferroptotic sensitivity emanate from multiple points within the p53 tumor suppressor pathway. Through an interconnected series of pathways, external growth factors, DNA damage, and other stresses regulate effector proteins that control progression through the cell cycle (1Friend S.H. Bernards R. Rogelj S. Weinberg R.A. Rapaport J.M. Albert D.M. Dryja T.P. A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma.Nature. 1986; 323: 643-646Crossref PubMed Scopus (2161) Google Scholar, 2Giacinti C. Giordano A. RB and cell cycle progression.Oncogene. 2006; 25: 5220-5227Crossref PubMed Scopus (756) Google Scholar). Mutations in the components of these pathways occur in cancer to drive uncontrolled proliferation (2Giacinti C. Giordano A. RB and cell cycle progression.Oncogene. 2006; 25: 5220-5227Crossref PubMed Scopus (756) Google Scholar). The p53 tumor suppressor controls a major pathway that coordinates the cellular response to DNA damage (3Agarwal M.L. Taylor W.R. Chernov M.V. Chernova O.B. Stark G.R. The p53 network.J. Biol. Chem. 1998; 273: 1-4Abstract Full Text Full Text PDF PubMed Scopus (644) Google Scholar). p53 induced in response to DNA damage upregulates the transcription of p21, an inhibitor of cyclin-dependent kinases (CDKs) (4el-Deiry W.S. Tokino T. Velculescu V.E. Levy D.B. Parsons R. Trent J.M. Lin D. Mercer W.E. Kinzler K.W. Vogelstein B. WAF1, a potential mediator of p53 tumor suppression.Cell. 1993; 75: 817-825A","journal":"Journal of Biological Chemistry","year":2021,"id":154140,"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":65,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9505,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":653431,"name":"Samkeliso Dlamini","orcid":"0000-0003-3732-7245","position":1,"is_corresponding":false},{"id":249419,"name":"L. M. Viranga Tillekeratne","orcid":"0000-0002-8326-564X","position":2,"is_corresponding":false},{"id":653432,"name":"William R. Taylor","orcid":"0000-0002-2798-9600","position":3,"is_corresponding":false},{"id":654379,"name":"Nishanth Kuganesan","orcid":null,"position":0,"is_corresponding":true}],"reference_count":62,"raw_metadata":null,"created_at":"2026-07-18T23:43:49.684414Z","pmid":"34728216","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":[]}