A theoretical model for p53 dynamics: Identifying optimal therapeutic strategy for its activation and stabilization

The activation and stabilization of tumor suppressor p53 are very important in preventing cells from becoming cancerous. Hence, many experimental works have been carried out to investigate p53’s dynamics through its interactions with other proteins and its therapeutic applications for the treatment of cancers. In this work, by analyzing a theoretical model, we attempt to search for an optimal therapeutic strategy that guarantees the activation and stabilization of p53. For this purpose, we introduce a new mathematical model including oncogene activation and ARF, which are recognized as crucial for tumor suppression but have not yet been considered in most theoretical works. Through mathematical modeling and numerical simulations, we confirm several important properties of p53 dynamics: the role of the oncogene-mediated activation of ARF as an important factor for the activation and stabilization of p53, the necessity of time delays in negative feedback loops to guarantee sustained p53 oscillations, and the digital behavior of p53 pulses. Furthermore, we propose that the binding of ARF to Mdm2 and enhancing the degradation of Mdm2 is an efficient strategy for therapeutic targeting, which may assure the activation and stabilization of p53.

[1]  K. Wiman,et al.  Strategies for therapeutic targeting of the p53 pathway in cancer , 2006, Cell Death and Differentiation.

[2]  J L Cleveland,et al.  Myc signaling via the ARF tumor suppressor regulates p53-dependent apoptosis and immortalization. , 1998, Genes & development.

[3]  T. Ørntoft,et al.  DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis , 2005, Nature.

[4]  C. Sherr.  The Pezcoller lecture: cancer cell cycles revisited. , 2000, Cancer research.

[5]  P. Chène.  Inhibiting the p53–MDM2 interaction: an important target for cancer therapy , 2003, Nature Reviews Cancer.

[6]  Stephen N. Jones,et al.  Regulation of p53 stability by Mdm2 , 1997, Nature.

[7]  R. Honda,et al.  Association of p19ARF with Mdm2 inhibits ubiquitin ligase activity of Mdm2 for tumor suppressor p53 , 1999, The EMBO journal.

[8]  G. Wahl,et al.  c-Myc can induce DNA damage, increase reactive oxygen species, and mitigate p53 function: a mechanism for oncogene-induced genetic instability. , 2002, Molecular cell.

[9]  John T. Powers,et al.  ATM promotes apoptosis and suppresses tumorigenesis in response to Myc , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[10]  John Jeremy Rice,et al.  A plausible model for the digital response of p53 to DNA damage. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[11]  Carole J. Proctor,et al.  Explaining oscillations and variability in the p53-Mdm2 system , 2008, BMC Systems Biology.

[12]  Muyang Li,et al.  Mono- Versus Polyubiquitination: Differential Control of p53 Fate by Mdm2 , 2003, Science.

[13]  A. Levine,et al.  Surfing the p53 network , 2000, Nature.

[14]  Alexei Vazquez,et al.  The genetics of the p53 pathway, apoptosis and cancer therapy , 2008, Nature Reviews Drug Discovery.

[15]  P. Chène.  Inhibition of the p53-hdm2 Interaction with Low Molecular Weight Compounds , 2004, Cell cycle.

[16]  S. Elledge,et al.  DNA damage-induced activation of p53 by the checkpoint kinase Chk2. , 2000, Science.

[17]  K. Sneppen,et al.  Time delay as a key to apoptosis induction in the p53 network , 2002, cond-mat/0207236.

[18]  Y. Haupt,et al.  p53: An Internal Investigation , 2002, Cell cycle.

[19]  M. Oren,et al.  mdm2 expression is induced by wild type p53 activity. , 1993, The EMBO journal.

[20]  Mei-Ling Kuo,et al.  N-terminal polyubiquitination and degradation of the Arf tumor suppressor. , 2004, Genes & development.

[21]  A. Levine,et al.  The p53 pathway: positive and negative feedback loops , 2005, Oncogene.

[22]  G. Peters,et al.  Stabilization of p53 by p14ARF without relocation of MDM2 to the nucleolus , 2001, Nature Cell Biology.

[23]  C. Sherr.  Divorcing ARF and p53: an unsettled case , 2006, Nature Reviews Cancer.

[24]  Shaomeng Wang,et al.  Small-molecule inhibitors of the MDM2-p53 protein-protein interaction to reactivate p53 function: a novel approach for cancer therapy. , 2009, Annual review of pharmacology and toxicology.

[25]  D. Lane,et al.  An N-terminal p14ARF peptide blocks Mdm2-dependent ubiquitination in vitro and can activate p53 in vivo , 2000, Oncogene.

[26]  R. Milo,et al.  Oscillations and variability in the p53 system , 2006, Molecular systems biology.

[27]  Xiongbin Lu,et al.  The Wip1 Phosphatase acts as a gatekeeper in the p53-Mdm2 autoregulatory loop. , 2007, Cancer cell.

[28]  M. Fiscella,et al.  Wip1, a novel human protein phosphatase that is induced in response to ionizing radiation in a p53-dependent manner. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[29]  F. Zindy,et al.  Functional and physical interactions of the ARF tumor suppressor with p53 and Mdm2. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[30]  M. Serrano,et al.  p19ARF links the tumour suppressor p53 to Ras , 1998, Nature.

[31]  U Alon,et al.  Generation of oscillations by the p53-Mdm2 feedback loop: a theoretical and experimental study. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[32]  Samuel Bottani,et al.  Analysis of a minimal model for p53 oscillations. , 2007, Journal of theoretical biology.

[33]  Y Taya,et al.  Activation of the ATM kinase by ionizing radiation and phosphorylation of p53. , 1998, Science.

[34]  N. Monk.  Oscillatory Expression of Hes1, p53, and NF-κB Driven by Transcriptional Time Delays , 2003, Current Biology.

[35]  G. Lahav,et al.  Recurrent initiation: a mechanism for triggering p53 pulses in response to DNA damage. , 2008, Molecular cell.

[36]  Galina Selivanova,et al.  Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound , 2002, Nature Medicine.

[37]  N. Onishi,et al.  Regulation of the antioncogenic Chk2 kinase by the oncogenic Wip1 phosphatase , 2006, Cell Death and Differentiation.

[38]  C. Marth,et al.  Why did p53 gene therapy fail in ovarian cancer? , 2003, The Lancet. Oncology.

[39]  Marie-Claude Marsolier-Kergoat,et al.  The Wip1 phosphatase (PPM1D) antagonizes activation of the Chk2 tumour suppressor kinase , 2007, Oncogene.

[40]  G. Peters,et al.  Regulation of the INK4b–ARF–INK4a tumour suppressor locus: all for one or one for all , 2006, Nature Reviews Molecular Cell Biology.

[41]  L. Vassilev.  Small-Molecule Antagonists of p53-MDM2 Binding: Research Tools and Potential Therapeutics , 2004, Cell cycle.

[42]  Peter A. Jones,et al.  The Human ARF Cell Cycle Regulatory Gene Promoter Is a CpG Island Which Can Be Silenced by DNA Methylation and Down-Regulated by Wild-Type p53 , 1998, Molecular and Cellular Biology.

[43]  S. Elledge,et al.  Ataxia telangiectasia-mutated phosphorylates Chk2 in vivo and in vitro. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[44]  Y. Shiloh,et al.  Rapid ATM-dependent phosphorylation of MDM2 precedes p53 accumulation in response to DNA damage. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[45]  Dahai Zhu,et al.  ATM activity contributes to the tumor-suppressing functions of p14ARF , 2004, Oncogene.

[46]  Jiri Bartek,et al.  Chk1 and Chk2 kinases in checkpoint control and cancer. , 2003, Cancer cell.

[47]  M. Kastan,et al.  DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation , 2003, Nature.

[48]  Andrea Ciliberto,et al.  Steady States and Oscillations in the p53/Mdm2 Network , 2005, Cell cycle.

[49]  M. Widschwendter,et al.  New insights into p53 regulation and gene therapy for cancer. , 2000, Biochemical pharmacology.

[50]  L. Donehower,et al.  PPM1D dephosphorylates Chk1 and p53 and abrogates cell cycle checkpoints. , 2005, Genes & development.

[51]  A. Levine,et al.  The p53-mdm-2 autoregulatory feedback loop. , 1993, Genes & development.

[52]  Hui Wang,et al.  Antisense anti-MDM2 oligonucleotides as a novel therapeutic approach to human breast cancer: in vitro and in vivo activities and mechanisms. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[53]  Yue Xiong,et al.  ARF Promotes MDM2 Degradation and Stabilizes p53: ARF-INK4a Locus Deletion Impairs Both the Rb and p53 Tumor Suppression Pathways , 1998, Cell.

[54]  A. Efeyan,et al.  Tumour biology: Policing of oncogene activity by p53 , 2006, Nature.

[55]  Richard A. Ashmun,et al.  Tumor Suppression at the Mouse INK4a Locus Mediated by the Alternative Reading Frame Product p19 ARF , 1997, Cell.

[56]  L. Vassilev,et al.  In Vivo Activation of the p53 Pathway by Small-Molecule Antagonists of MDM2 , 2004, Science.

[57]  I. Verma,et al.  Gene therapy - promises, problems and prospects , 1997, Nature.

[58]  S. T. Kim,et al.  ATM-dependent phosphorylation of Mdm2 on serine 395: role in p53 activation by DNA damage. , 2001, Genes & development.

[59]  G. Wahl,et al.  Accelerated MDM2 auto‐degradation induced by DNA‐damage kinases is required for p53 activation , 2004, The EMBO journal.

[60]  D. Felsher,et al.  Defective double-strand DNA break repair and chromosomal translocations by MYC overexpression , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[61]  Brian A. Smith,et al.  DNA damage disrupts the p14ARF-B23(nucleophosmin) interaction and triggers a transient subnuclear redistribution of p14ARF. , 2005, Cancer research.

[62]  Y Taya,et al.  Enhanced phosphorylation of p53 by ATM in response to DNA damage. , 1998, Science.

[63]  M. Roussel,et al.  Disruption of the ARF-Mdm2-p53 tumor suppressor pathway in Myc-induced lymphomagenesis. , 1999, Genes & development.

[64]  Manuel Serrano,et al.  p53: Guardian of the Genome and Policeman of the Oncogenes , 2007, Cell cycle.

[65]  D. Lane,et al.  p53, guardian of the genome , 1992, Nature.

[66]  Uri Alon,et al.  Dynamics of the p53-Mdm2 feedback loop in individual cells , 2004, Nature Genetics.

[67]  A. Levine,et al.  p53-Mdm2 loop controlled by a balance of its feedback strength and effective dampening using ATM and delayed feedback. , 2005, Systems biology.

[68]  D. Lane,et al.  Updates on p53: modulation of p53 degradation as a therapeutic approach , 2008, British Journal of Cancer.

[69]  S. Lowe,et al.  Oncogenic ras Provokes Premature Cell Senescence Associated with Accumulation of p53 and p16INK4a , 1997, Cell.

[70]  Dimitris Kletsas,et al.  Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions , 2005, Nature.

[71]  Kevin Ryan,et al.  The alternative product from the human CDKN2A locus, p14ARF, participates in a regulatory feedback loop with p53 and MDM2 , 1998, The EMBO journal.

[72]  Paul Brazhnik,et al.  Exploring Mechanisms of the DNA-Damage Response: p53 Pulses and their Possible Relevance to Apoptosis , 2007, Cell cycle.

[73]  N. Gueven,et al.  The complexity of p53 stabilization and activation , 2006, Cell Death and Differentiation.

[74]  M. Oren,et al.  Mdm2 promotes the rapid degradation of p53 , 1997, Nature.

[75]  E. Appella,et al.  Wip1 phosphatase modulates ATM-dependent signaling pathways. , 2006, Molecular cell.

[76]  G. Evan,et al.  The pathological response to DNA damage does not contribute to p53-mediated tumour suppression , 2006, Nature.

[77]  M. E. Perry,et al.  The p53 Tumor Suppressor Protein Does Not Regulate Expression of Its Own Inhibitor, MDM2, Except under Conditions of Stress , 2000, Molecular and Cellular Biology.

[78]  Jiandong Chen,et al.  Synergistic activation of p53 by inhibition of MDM2 expression and DNA damage. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[79]  Petra de Graaf,et al.  Phosphorylation of Hdmx mediates its Hdm2- and ATM-dependent degradation in response to DNA damage. , 2005, Proceedings of the National Academy of Sciences of the United States of America.