A mathematical model of P53 gene regulatory networks under radiotherapy

Abstract P53, a vital anticancer gene, controls the transcription and translation of a series of genes, and implement the cell cycle arrest and cell apoptosis by regulating their complicated signal pathways. Under radiotherapy, cell can trigger internal self-defense mechanisms in fighting against genome stresses induced by acute ion radiation (IR). To simulate the investigating of cellular responding acute IR at single cell level further, we propose a model of P53 gene regulatory networks under radiotherapy. Our model can successfully implement the kinetics of double strand breaks (DSBs) generating and their repair, ataxia telangiectasia mutated (ATM) activation, as well as P53-MDM2 feedback regulating. By comparing simulations under different IR dose, we can try to find the optimal strategy in controlling of IR dose and therapy time, and provide some theoretical analysis to obtain much better outcome of radiotherapy further.

[1]  M. Oren,et al.  Decision making by p53: life, death and cancer , 2003, Cell Death and Differentiation.

[2]  K. Chou,et al.  Role of the protein outside active site on the diffusion-controlled reaction of enzymes , 1982 .

[3]  Meng Wang,et al.  A new nucleotide-composition based fingerprint of SARS-CoV with visualization analysis. , 2005, Medicinal chemistry (Shariqah (United Arab Emirates)).

[4]  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.

[5]  W Düchting,et al.  Cancer: a challenge for control theory and computer modelling. , 1996, European journal of cancer.

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

[7]  C C Ling,et al.  Radiation-induced apoptosis: relevance to radiotherapy. , 1995, International journal of radiation oncology, biology, physics.

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

[9]  M. Story,et al.  Cellular responses to ionizing radiation damage. , 2001, International journal of radiation oncology, biology, physics.

[10]  Kai Rothkamm,et al.  A Double-Strand Break Repair Defect in ATM-Deficient Cells Contributes to Radiosensitivity , 2004, Cancer Research.

[11]  R. Bristow,et al.  The p53 protein family and radiation sensitivity: Yes or no? , 2004, Cancer and Metastasis Reviews.

[12]  J. Levine,et al.  Surfing the p53 network , 2000, Nature.

[13]  Gilbert Chu,et al.  Processing of DNA for nonhomologous end‐joining by cell‐free extract , 2005, The EMBO journal.

[14]  M. Ritter,et al.  The role of p53 in radiation therapy outcomes for favorable-to-intermediate-risk prostate cancer. , 2002, International journal of radiation oncology, biology, physics.

[15]  Fayza Daboussi,et al.  DNA double-strand break repair signalling: the case of RAD51 post-translational regulation. , 2002, Cellular signalling.

[16]  Kai Rothkamm,et al.  Evidence for a lack of DNA double-strand break repair in human cells exposed to very low x-ray doses , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[17]  Yves Pommier,et al.  Molecular interaction map of the p53 and Mdm2 logic elements, which control the Off-On switch of p53 in response to DNA damage. , 2005, Biochemical and biophysical research communications.

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

[19]  Arnold Kristjuhan,et al.  ARF and ATM/ATR cooperate in p53-mediated apoptosis upon oncogenic stress. , 2005, Biochemical and biophysical research communications.

[20]  Kai Rothkamm,et al.  Pathways of DNA Double-Strand Break Repair during the Mammalian Cell Cycle , 2003, Molecular and Cellular Biology.

[21]  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.

[22]  K. Chou.  Structural bioinformatics and its impact to biomedical science. , 2004, Current medicinal chemistry.

[23]  A. Brahme,et al.  Principles and Practice of Radiation Oncology , 1992 .

[24]  Karl Otto Greulich,et al.  After double-strand break induction by UV-A, homologous recombination and nonhomologous end joining cooperate at the same DSB if both systems are available , 2004, Journal of Cell Science.

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

[26]  Michael Weller,et al.  Predicting response to cancer chemotherapy: the role of p53 , 1998, Cell and Tissue Research.

[27]  S. Tribius,et al.  ATM protein expression correlates with radioresistance in primary glioblastoma cells in culture. , 2001, International journal of radiation oncology, biology, physics.

[28]  G. Zhou,et al.  An extension of Chou's graphic rules for deriving enzyme kinetic equations to systems involving parallel reaction pathways. , 1984, The Biochemical journal.

[29]  Yongsheng Ding,et al.  An application of gene comparative image for predicting the effect on replication ratio by HBV virus gene missense mutation. , 2005, Journal of theoretical biology.

[30]  Zeljko Bajzer,et al.  Mathematical modeling of cancer radiovirotherapy. , 2006, Mathematical biosciences.

[31]  Paul Van Houtte,et al.  NF-kappaB modulation and ionizing radiation: mechanisms and future directions for cancer treatment. , 2006, Cancer letters.