MicroRNA-16 feedback loop with p53 and Wip1 can regulate cell fate determination between apoptosis and senescence in DNA damage response

Cell fate regulation is an open problem whose comprehension impacts several areas of the biosciences. DNA damage induces cell cycle checkpoints that activate the p53 pathway to regulate cell fate mechanisms such as apoptosis or senescence. Experiments with different cell types show that the p53 pathway regulates cell fate through a switch behavior in its dynamics. For low DNA damage the pathway presents an oscillatory pattern associated with intense DNA damage repair while for high damage there are no oscillations and either p53 concentration increases inducing apoptosis or the cell enters a senescence state. Apoptosis and senescence phenotypes seem to have compensatory functions in tissues and the microRNA 16–1 (miR-16) is involved in the regulation of the fate between both phenotypes in cancer cells. To investigate the regulation of cell fate we developed a logical model of the G1/S checkpoint in DNA damage response that takes into account different levels of damage and contemplates the influence of miR-16 through its positive feedback loop formed with p53 and Wip1. The model reproduces the observed cellular phenotypes in experiments: oscillatory (for low DNA damage) regulated by negative feedback loops involving mainly p53 and Mdm2 and apoptotic or senescent (for high DNA damage) regulated by the positive p53/Wip1/miR-16 feedback loop. We find good agreement between the level of DNA damage and the probability of the phenotype produced according to experiments. We also find that this positive feedback makes senescent and apoptotic phenotypes to be determined stochastically (bistable), however controlling the expression level of miR-16 allows the control of fate determination as observed experimentally.

[1]  Denis Thieffry,et al.  Dynamical roles of biological regulatory circuits , 2007, Briefings Bioinform..

[2]  Zengrong Liu,et al.  Dynamical Behaviors of Rb-E2F Pathway Including Negative Feedback Loops Involving miR449 , 2012, PloS one.

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

[4]  Xin Lu,et al.  RB regulates the stability and the apoptotic function of p53 via MDM2. , 1999, Molecular cell.

[5]  R. Medema,et al.  Checkpoint control and cancer , 2012, Oncogene.

[6]  M. Malumbres,et al.  MicroRNAs and the cell cycle. , 2011, Biochimica et biophysica acta.

[7]  N. Mailand,et al.  The ATM–Chk2–Cdc25A checkpoint pathway guards against radioresistant DNA synthesis , 2001, Nature.

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

[9]  R. Abraham.  Cell cycle checkpoint signaling through the ATM and ATR kinases. , 2001, Genes & development.

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

[11]  Stephen J. Elledge,et al.  p53-dependent inhibition of cyclin-dependent kinase activities in human fibroblasts during radiation-induced G1 arrest , 1994, Cell.

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

[13]  N. Novère.  Quantitative and logic modelling of molecular and gene networks , 2015, Nature Reviews Genetics.

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

[15]  A. Levine,et al.  Functions of the MDM2 oncoprotein , 1999, Cellular and Molecular Life Sciences CMLS.

[16]  Haoming Zhang,et al.  miR-16 family induces cell cycle arrest by regulating multiple cell cycle genes , 2008, Nucleic acids research.

[17]  Cellular senescence and cancer , 1999, The Journal of pathology.

[18]  M. Kitagawa,et al.  Enhanced Mdm2 activity inhibits pRB function via ubiquitin‐dependent degradation , 2005, The EMBO journal.

[19]  Jeremy E. Purvis,et al.  p53 Dynamics Control Cell Fate , 2012, Science.

[20]  Denis Thieffry,et al.  Logical Modeling and Dynamical Analysis of Cellular Networks , 2016, Front. Genet..

[21]  W. Sellers,et al.  Interaction between the retinoblastoma protein and the oncoprotein MDM2 , 1995, Nature.

[22]  H. Hirai,et al.  Cdk-mediated phosphorylation of pRB regulates HDAC binding in vitro. , 2004, Biochemical and biophysical research communications.

[23]  P. Bastiaens,et al.  Single Particle Tracking Reveals that EGFR Signaling Activity Is Amplified in Clathrin-Coated Pits , 2015, PloS one.

[24]  C. Croce,et al.  miR-15 and miR-16 induce apoptosis by targeting BCL2. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[25]  Denis Thieffry,et al.  Integrative Modelling of the Influence of MAPK Network on Cancer Cell Fate Decision , 2013, PLoS Comput. Biol..

[26]  J. Campisi.  Aging, cellular senescence, and cancer. , 2013, Annual review of physiology.

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

[28]  Y Taya,et al.  A role for ATR in the DNA damage-induced phosphorylation of p53. , 1999, Genes & development.

[29]  H. Tagawa,et al.  MicroRNA-16 mediates the regulation of a senescence–apoptosis switch in cutaneous T-cell and other non-Hodgkin lymphomas , 2016, Oncogene.

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

[31]  Maria Thanasoula,et al.  ATM/ATR checkpoint activation downregulates CDC25C to prevent mitotic entry with uncapped telomeres , 2012, The EMBO journal.

[32]  C. Franceschi,et al.  MicroRNAs linking inflamm-aging, cellular senescence and cancer , 2013, Ageing Research Reviews.

[33]  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.

[34]  J. Nevins,et al.  Selective induction of E2F1 in response to DNA damage, mediated by ATM-dependent phosphorylation. , 2001, Genes & development.

[35]  M. Donzelli,et al.  Regulating mammalian checkpoints through Cdc25 inactivation , 2003, EMBO reports.

[36]  J. Campisi,et al.  Senescence and apoptosis: dueling or complementary cell fates? , 2014, EMBO reports.

[37]  Manuel Serrano,et al.  Cellular senescence: from physiology to pathology , 2014, Nature Reviews Molecular Cell Biology.

[38]  Jun Cui,et al.  A plausible model for bimodal p53 switch in DNA damage response , 2014, FEBS letters.

[39]  Hiroshi I. Suzuki,et al.  Modulation of microRNA processing by p53 , 2009, Nature.

[40]  S. Elledge,et al.  Inhibition of cyclin-dependent kinases by p21. , 1995, Molecular biology of the cell.

[41]  A. Bardia,et al.  Targeting the cyclin D-cyclin-dependent kinase (CDK) 4/6-retinoblastoma pathway with selective CDK 4/6 inhibitors in hormone receptor-positive breast cancer: rationale, current status, and future directions. , 2016, Discovery medicine.

[42]  M. Soleimani,et al.  Overexpression of microRNA-16 declines cellular growth, proliferation and induces apoptosis in human breast cancer cells , 2015, In Vitro Cellular & Developmental Biology - Animal.

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

[44]  Claudine Chaouiya,et al.  Quantification of reachable attractors in asynchronous discrete dynamics , 2014, ArXiv.

[45]  G. Castellani,et al.  A simple stochastic model for the feedback circuit between p16INK4a and p53 mediated by p38MAPK: implications for senescence and apoptosis. , 2015, Molecular bioSystems.

[46]  A. Galbiati,et al.  Interplays between ATM/Tel1 and ATR/Mec1 in sensing and signaling DNA double-strand breaks. , 2013, DNA repair.

[47]  Claudine Chaouiya,et al.  Modelling the onset of senescence at the G1/S cell cycle checkpoint , 2014, BMC Genomics.

[48]  Joseph R. Nevins,et al.  The E2F transcription factor is a cellular target for the RB protein , 1991, Cell.

[49]  Yi-Song Wang,et al.  WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis. , 1994, Cancer research.

[50]  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.

[51]  D. Ginsberg,et al.  ATM is a target for positive regulation by E2F-1 , 2003, Oncogene.

[52]  Zhang,et al.  Oncogenic Wip1 Phosphatase Is Inhibited by miR-16 in the DNA Damage Signaling Pathway , 2010 .

[53]  Denis Thieffry,et al.  Discovery of Drug Synergies in Gastric Cancer Cells Predicted by Logical Modeling , 2015, PLoS Comput. Biol..

[54]  Xinbin Chen,et al.  MDM 2 Is a Negative Regulator of p 21 WAF 1 / CIP 1 , Independent of p 53 * , 2004 .

[55]  D. Ginsberg,et al.  p53 and E2f: partners in life and death , 2009, Nature Reviews Cancer.

[56]  Xi Chen,et al.  DNA damage strength modulates a bimodal switch of p53 dynamics for cell-fate control , 2013, BMC Biology.

[57]  Xinbin Chen,et al.  MDM2 Is a Negative Regulator of p21WAF1/CIP1, Independent of p53* , 2004, Journal of Biological Chemistry.

[58]  M. Fiscella,et al.  Wip 1 , a novel human protein phosphatase that is induced in response to ionizing radiation in a p 53-dependent manner , 1997 .

[59]  A. Sancar,et al.  Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. , 2004, Annual review of biochemistry.

[60]  R. Sachidanandam,et al.  A threshold mechanism mediates p53 cell fate decision between growth arrest and apoptosis , 2013, Cell Death and Differentiation.

[61]  Masaaki Adachi,et al.  p53‐inducible Wip1 phosphatase mediates a negative feedback regulation of p38 MAPK‐p53 signaling in response to UV radiation , 2000, The EMBO journal.

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

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

[64]  M. Yamakuchi,et al.  MiR-34, SIRT1, and p53: The feedback loop , 2009, Cell cycle.

[65]  José C. M. Mombach,et al.  A Model for p38MAPK-Induced Astrocyte Senescence , 2015, PloS one.