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: 817-825Abstract Full Text PDF PubMed Scopus (7837) Google Scholar). Because CDKs phosphorylate retinoblastoma (RB) to modulate its activity, this p53/p21/CDK/RB pathway links DNA damage to cell cycle arrest by modulating RB phosphorylation. Phosphorylation of RB by CDKs reduces RB binding to E2F resulting in increased transcription of E2F targets encoding cell cycle proteins (2Giacinti C. Giordano A. RB and cell cycle progression.Oncogene. 2006; 25: 5220-5227Crossref PubMed Scopus (756) Google Scholar). Recent studies have added additional complexity to the understanding of phosphoregulation of RB. For example, CDK4/6 bound to D-cyclins phosphorylate RB at single sites to create a heterogeneous mixture of monophosphorylated RB during early G1. Monophosphorylated RB proteins still interact with a host of cellular proteins and regulate transcription of multiple targets (5Sanidas I. Morris R. Fella K.A. Rumde P.H. Boukhali M. Tai E.C. Ting D.T. Lawrence M.S. Haas W. Dyson N.J. A code of mono-phosphorylation modulates the function of RB.Mol. Cell. 2019; 73: 985-1000.e1006Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar). As cells pass through G1, CDK2 phosphorylates RB on up to 14 sites to release E2F for cell cycle entry (5Sanidas I. Morris R. Fella K.A. Rumde P.H. Boukhali M. Tai E.C. Ting D.T. Lawrence M.S. Haas W. Dyson N.J. A code of mono-phosphorylation modulates the function of RB.Mol. Cell. 2019; 73: 985-1000.e1006Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 6Narasimha A.M. Kaulich M. Shapiro G.S. Choi Y.J. Sicinski P. Dowdy S.F. Cyclin D activates the Rb tumor suppressor by mono-phosphorylation.Elife. 2014; 3Crossref PubMed Google Scholar). Thus, the effect of phosphorylation on RB depends on the exact phosphorylation state and the specific RB-regulated activity in question. Cell cycle entry results in elevated rates of oxidative ATP synthesis, which generates reactive oxygen species (ROS) as a byproduct (7Sosa V. Moline T. Somoza R. Paciucci R. Kondoh H. ME L.L. Oxidative stress and cancer: An overview.Ageing Res. Rev. 2013; 12: 376-390Crossref PubMed Scopus (773) Google Scholar). Mechanisms to avoid cellular damage caused by ROS include superoxide dismutases, catalase, and a family of GSH peroxidases (GPX) (8Schieber M. Chandel N.S. ROS function in redox signaling and oxidative stress.Curr. Biol. 2014; 24: R453-R462Abstract Full Text Full Text PDF PubMed Scopus (3016) Google Scholar). When ROS generation outpaces antioxidant capacity, damage to membrane lipids and cell lysis occurs. In a number of biological systems, the process of ROS-mediated lipid peroxidation and cell lysis requires iron and has been called ferroptosis (9Yang W.S. Kim K.J. Gaschler M.M. Patel M. Shchepinov M.S. of by S. A. PubMed Scopus Google Scholar, R. Patel A.M. W.S. B. An form of cell Full Text Full Text PDF PubMed Scopus Google Scholar, S. B. S. P. W.S. of a state of cancer cells on a lipid PubMed Scopus Google Scholar). can induced by the of for the of a by to peroxidation of membrane lipids R. Patel A.M. W.S. B. An form of cell Full Text Full Text PDF PubMed Scopus Google Scholar, S. B. S. P. W.S. of a state of cancer cells on a lipid PubMed Scopus Google Scholar). can also induced by W.S. R. R. of ferroptotic cancer cell by 2014; Full Text Full Text PDF PubMed Scopus Google Scholar). cells a ROS generation via activity and antioxidant ROS to to in the regulation of ferroptosis by p53 and its pathways, this of is In p53 T. T. H. R. W. as a activity during PubMed Scopus Google Scholar, B. D. T. T. S. W. is for through a ferroptosis Cell Biol. 2019; PubMed Scopus Google suppresses A. p53 suppresses ferroptosis in cancer Full Text Full Text PDF PubMed Scopus Google Scholar, S. M. H. R. D. The tumor suppressor p53 ferroptosis by Full Text Full Text PDF PubMed Scopus Google ferroptosis under In p53 ferroptosis in cells A. p53 suppresses ferroptosis in cancer Full Text Full Text PDF PubMed Scopus Google Scholar). In studies p53 ferroptosis in multiple cell with inducible p53 Furthermore, we that which is to p53 inhibits ferroptosis by an is RB modulates ferroptosis with a potential C. I. H. C. C. D. V. B. A. The retinoblastoma ferroptosis induced by in human PubMed Scopus Google Scholar). Here, we show that p21, RB, and E2F modulate sensitivity to ferroptosis in a that can by of a pathway in E2F that is in cell cycle Thus, of ferroptosis to emanate from multiple points within the pathway. In a number of reports the of p53 on ferroptosis, For example, p53 found to induce ferroptosis through lipid peroxidation and T. T. H. R. W. as a activity during PubMed Scopus Google Scholar, B. D. T. T. S. W. is for through a ferroptosis Cell Biol. 2019; PubMed Scopus Google Scholar). In of p53 to ferroptosis in cell cells A. p53 suppresses ferroptosis in cancer Full Text Full Text PDF PubMed Scopus Google Scholar, S. M. H. R. D. The tumor suppressor p53 ferroptosis by Full Text Full Text PDF PubMed Scopus Google Scholar). the of p53 in ferroptosis, we multiple with inducible p53 of isogenic cells in p53 For of we a from a series of we have a I. R. V. Taylor W.R. cancer cells by reactive oxygen species in an Chem. PubMed Google Scholar, W.R. I. R. R. S. T. A. V. D. M.S. ferroptotic with potential to cancer 2019; PubMed Scopus Google Scholar). to of of cellular ROS and lipid peroxidation W.R. I. R. R. S. T. A. V. D. M.S. ferroptotic with potential to cancer 2019; PubMed Scopus Google Scholar). Cell is by iron and and is elevated in cancer cells I. R. V. Taylor W.R. cancer cells by reactive oxygen species in an Chem. PubMed Google Scholar, W.R. I. R. R. S. T. A. V. D. M.S. ferroptotic with potential to cancer 2019; PubMed Scopus Google Scholar). Thus, the show of the of inducing ferroptosis. of and that these the function of the In we with a inhibitor of also targets by binding to which to its to induce ferroptosis M. W.S. I. J.M. R. S. oxidative cell PubMed Scopus Google Scholar). also of studies with the inhibitor M. A. for p53 to PubMed Scopus Google to and A and we a human cell a p53 cells from a human cell from a with P. response of from with cancer to in Res. Google Scholar, S. in from with cancer and Res. Google Scholar). p53 a M.L. A. Taylor W.R. Stark G.R. p53 controls the and the cell cycle and growth arrest in human S. A. PubMed Scopus Google Scholar). cells for showed elevated p53 and p21 and enhanced ferroptosis to and a lipid ROS of cells by consistent with ferroptosis as a of in this cell of membrane lipid peroxidation the showed that of p53 in cells elevated membrane damage by and peroxidation is a of ferroptosis. these we cells from cell with an the to elevated p53 P. T. M.L. Stark G.R. Taylor W.R. during at Cell PubMed Scopus Google Scholar). of to cells for enhanced ferroptosis in response to and and induced by in cells with that this cell ferroptosis under these conditions and these show that ferroptosis induced by and is enhanced by As p53, and p21 elevated in cells to of cells to for caused a in the of p53 A and the of this to cells at points with The effect of with p53 levels levels and of and p53 in a that in p53 levels I. B. The to PubMed Scopus Google Scholar, by the Biol. PubMed Scopus Google Scholar). is a of p53 and an p53 for to the p53 response in cells is In a p53 found to ferroptosis in cells A. p53 suppresses ferroptosis in cancer Full Text Full Text PDF PubMed Scopus Google Scholar). In of p53 induced by the that to its with p53 B. D. C. C. In of the p53 pathway by of PubMed Scopus Google Scholar, C. B. H. W. p53 signaling in cancer: for S. A. 2006; PubMed Scopus Google Scholar). Our inducible to consistent with this we the effect of on sensitivity in the of p53, we cells a p53 B. M. Stark G.R. Taylor W.R. arrest in response to The of Res. Google and with cells with p53 the the sensitivity of cells to cells from this A and ferroptosis induced by in cell and enhanced in at the In cells at multiple of that ferroptosis in a the effect in cells the this we the effect of in an human cell from a with P. response of from with cancer to in Res. Google Scholar, S. in from with cancer and Res. Google Scholar). p53 a at and the other during of the cell p53 cell cycle control and inhibits gene in cells with p53 Full Text PDF PubMed Scopus Google Scholar). p53 is in this cell M.L. A. Taylor W.R. Stark G.R. p53 controls the and the cell cycle and growth arrest in human S. A. PubMed Scopus Google Scholar, A. M. S. A DNA damage is for p53 to Res. Google Scholar, T. S. M.L. T. in human cancer cells through PubMed Scopus Google Scholar, M.L. A. Taylor W.R. Chernova Stark G.R. A to cells from DNA damage in response to for S. A. 1998; PubMed Scopus Google Scholar). ferroptosis in cells with with and As showed p53 p21 in cells these results that inhibits ferroptosis in a of p53 and p21 in and of p53 and p21 of cells to for as a control for p53 and p21 to of and cells to for that and p53 and p21 in cells As we have p53 levels elevated in p21 levels B. M. Stark G.R. Taylor W.R. arrest in response to The of Res. Google Scholar). at a p21 still induced by in effect on p21 in these cells Our studies inducible that p53 ferroptosis. of p53, we cells a As a we the cells to ferroptosis cells A and Furthermore, effect on ferroptotic sensitivity in cells A and of p53 and p21 also that levels of p21 elevated in with the control the effect of CDKs on ferroptosis, we CDK2 and An as a ferroptosis induced by in and cells D and also ferroptosis in human overexpression suppressed cell in cells A and that effect on lipid peroxidation in cells CDK2 and In the of cells with cells and cells and Our results that elevated activity of from ferroptosis. this we a CDK4/6 inhibitor of cells with for to ferroptosis to Phosphorylation of RB at the effect of this on CDK activity the of the CDK2 and in from also elevated phosphorylation of RB of on in cells and show that elevated CDK activity suppresses ferroptosis. that the show increased of p21 with to ferroptosis In a p21 found to ferroptosis A. p53 suppresses ferroptosis in cancer Full Text Full Text PDF PubMed Scopus Google Scholar). 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Taylor W.R. cancer cells by reactive oxygen species in an Chem. PubMed Google Scholar). Cell induced by has of the of ferroptosis elevated lipid of and by ferroptotic and W.R. I. R. R. S. T. A. V. D. M.S. ferroptotic with potential to cancer 2019; PubMed Scopus Google Scholar, S. Taylor W.R. and of a inhibitor of Cell PubMed Scopus Google Scholar). of the studies the inhibitor and the ferroptosis a of inducible systems, we that p53 enhanced ferroptosis induced by effect in as as human of the cell we of and and cells cell to ferroptosis cells S. B. S. P. 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H. of the pathway is for CDK2 and entry in PubMed Scopus Google Scholar). p21 can ferroptosis A. p53 suppresses ferroptosis in cancer Full Text Full Text PDF PubMed Scopus Google Scholar). we also of ferroptosis by p21, p53 enhanced ferroptosis under Thus, p53 must also to regulate ferroptosis. Furthermore, p53 p21 under conditions where ferroptosis is we that signals from p53 must signals from p21. In the of p53 can cellular For example, of p53 single cell showed that of this in response to stress is I. B. The to PubMed Scopus Google Scholar, by the Biol. PubMed Scopus Google Scholar, A. C. of p53 in single Biol. PubMed Scopus Google Scholar, K.W. C. A. p53 control cell PubMed Scopus Google Scholar). The of the by Because p53 an that targets its p53 and the for I. B. The to PubMed Scopus Google Scholar, by the Biol. PubMed Scopus Google Scholar). Furthermore, cells that show p53 from DNA damage, cells that show of p53 K.W. C. A. p53 control cell PubMed Scopus Google Scholar). In of p21 to is of p21 in response to p53 is that the of p21 can ferroptotic we have to this Our of the of p53 in ferroptosis the cell with elevated p53 and increased ferroptosis. elevated ferroptosis in cells a D to the of in cancer cells with overexpression A. M. R. D. M. D. B. of a to the biological of Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The effect of elevated CDK activity by CDK2 and in cells and human Furthermore, cells to to the CDK4/6 inhibitor that CDK2 and CDK4/6 have a in sensitivity to ferroptosis. CDKs phosphorylate proteins in cell cycle progression with RB proteins of the S. P. and beyond cell cycle 2013; PubMed Scopus Google Scholar). In to cell cycle RB proteins modulate pathways to ROS and ferroptotic sensitivity M. P. R. and regulate Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, B. S. of by the tumor suppressor 2014; PubMed Scopus Google Scholar). that cells and and cells and to ferroptosis. Furthermore, with to control Taken together, these on ferroptosis by CDKs RB via phosphorylation. this the RB deletion from ferroptosis to CDK In RB family proteins a that RB deletion have as overexpression with to ferroptosis. this is RB family proteins show function as the of the E2F family (2Giacinti C. Giordano A. RB and cell cycle progression.Oncogene. 2006; 25: 5220-5227Crossref PubMed Scopus (756) Google Scholar, W. family 2006; 25: PubMed Scopus Google Scholar). In RB has binding in to Furthermore, on the of the cell multiple monophosphorylated of RB (5Sanidas I. Morris R. Fella K.A. Rumde P.H. Boukhali M. Tai E.C. Ting D.T. Lawrence M.S. Haas W. Dyson N.J. A code of mono-phosphorylation modulates the function of RB.Mol. Cell. 2019; 73: 985-1000.e1006Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 6Narasimha A.M. Kaulich M. Shapiro G.S. Choi Y.J. Sicinski P. Dowdy S.F. Cyclin D activates the Rb tumor suppressor by mono-phosphorylation.Elife. 2014; 3Crossref PubMed Google Scholar). Monophosphorylated RB still to of its binding and transcription of genes on the phosphorylation state (5Sanidas I. Morris R. Fella K.A. Rumde P.H. Boukhali M. Tai E.C. Ting D.T. Lawrence M.S. Haas W. Dyson N.J. A code of mono-phosphorylation modulates the function of RB.Mol. Cell. 2019; 73: 985-1000.e1006Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar). The of the pathway the to understanding these proteins regulate ferroptosis. we that the cell levels of p21 control cells CDK studies E2F binding sites in the p21 and of p21 by E2F H. A. of the inhibitor p21 gene during cell cycle progression is under the control of the transcription factor 1998; PubMed Scopus Google Scholar). cells elevated p21 as a of E2F activity to elevated RB In we of p21 levels Furthermore, to ferroptosis in cells p21 these proteins in this cellular to we also the that these proteins ferroptosis by p21, by CDKs still suppressed ferroptosis in cells to additional CDK RB In the pathway that cell is to the of these proteins in the regulation of ferroptosis. multiple and signals emanate from the components of this pathway show that p53 ferroptosis in a number of is that multiple and targets of p53 modulate ferroptotic The of p21 on ferroptosis to occur of its to CDK inhibitor also ferroptosis in this ferroptosis. Elevation of CDK activity ferroptosis, RB deletion enhanced ferroptosis. these is Elevation of E2F suppressed ferroptosis, and we show that this effect depends in part on p21. 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