All Title Author
Keywords Abstract

Predicted Functions of MdmX in Fine-Tuning the Response of p53 to DNA Damage

DOI: 10.1371/journal.pcbi.1000665

Full-Text   Cite this paper   Add to My Lib


Tumor suppressor protein p53 is regulated by two structurally homologous proteins, Mdm2 and MdmX. In contrast to Mdm2, MdmX lacks ubiquitin ligase activity. Although the essential interactions of MdmX are known, it is not clear how they function to regulate p53. The regulation of tumor suppressor p53 by Mdm2 and MdmX in response to DNA damage was investigated by mathematical modeling of a simplified network. The simplified network model was derived from a detailed molecular interaction map (MIM) that exhibited four coherent DNA damage response pathways. The results suggest that MdmX may amplify or stabilize DNA damage-induced p53 responses via non-enzymatic interactions. Transient effects of MdmX are mediated by reservoirs of p53:MdmX and Mdm2:MdmX heterodimers, with MdmX buffering the concentrations of p53 and/or Mdm2. A survey of kinetic parameter space disclosed regions of switch-like behavior stemming from such reservoir-based transients. During an early response to DNA damage, MdmX positively or negatively regulated p53 activity, depending on the level of Mdm2; this led to amplification of p53 activity and switch-like response. During a late response to DNA damage, MdmX could dampen oscillations of p53 activity. A possible role of MdmX may be to dampen such oscillations that otherwise could produce erratic cell behavior. Our study suggests how MdmX may participate in the response of p53 to DNA damage either by increasing dependency of p53 on Mdm2 or by dampening oscillations of p53 activity and presents a model for experimental investigation.


[1]  Vogelstein B, Lane D, Levine AJ (2000) Surfing the p53 network. Nature 408: 307–310.
[2]  Ferbeyre G, Lowe SW (2002) The price of tumour suppression? Nature 415: 26–27.
[3]  Iwakuma T, Lozano G (2003) MDM2, an introduction. Mol Cancer Res 1: 993–1000.
[4]  Tiana G, Jensen MH, Sneppen K (2002) Time delay as a key to apoptosis induction in the p53 network. Eur Phys J B 29: 135–140.
[5]  Yan S, Zhuo Y (2006) A unified model for studying DNA damage-induced p53-Mdm2 interaction. Physica D: Nonlinear Phenomena 220: 157–162.
[6]  Wagner J, Ma L, Rice JJ, Hu W, Levine AJ, et al. (2005) p53-Mdm2 loop controlled by a balance of its feedback strength and effective dampening using ATM and delayed feedback. Syst Biol (Stevenage) 152: 109–118.
[7]  Monk NA (2003) Oscillatory expression of Hes1, p53, and NF-kappaB driven by transcriptional time delays. Curr Biol 13: 1409–1413.
[8]  Ma L, Wagner J, Rice JJ, Hu W, Levine AJ, et al. (2005) A plausible model for the digital response of p53 to DNA damage. Proc Natl Acad Sci U S A 102: 14266–14271.
[9]  Geva-Zatorsky N, Rosenfeld N, Itzkovitz S, Milo R, Sigal A, et al. (2006) Oscillations and variability in the p53 system. Mol Syst Biol 2: 2006 0033.
[10]  Ciliberto A, Novak B, Tyson JJ (2005) Steady states and oscillations in the p53/Mdm2 network. Cell Cycle 4: 488–493.
[11]  Zhang T, Brazhnik P, Tyson JJ (2007) Exploring mechanisms of the DNA-damage response: p53 pulses and their possible relevance to apoptosis. Cell Cycle 6: 85–94.
[12]  Chickarmane V, Ray A, Sauro HM, Nadim A (2007) A Model for p53 Dynamics Triggered by DNA Damage. SIAM Journal on Applied Dynamical Systems 6: 61–78.
[13]  Batchelor E, Mock CS, Bhan I, Loewer A, Lahav G (2008) Recurrent initiation: a mechanism for triggering p53 pulses in response to DNA damage. Mol Cell 30: 277–289.
[14]  Ramalingam S, Honkanen P, Young L, Shimura T, Austin J, et al. (2007) Quantitative Assessment of the p53-Mdm2 Feedback Loop Using Protein Lysate Microarrays. Cancer Res 67: 6247–6252.
[15]  Singh RK, Iyappan S, Scheffner M (2007) Hetero-oligomerization with MdmX rescues the ubiquitin/Nedd8 ligase activity of RING finger mutants of Mdm2. J Biol Chem 282: 10901–10907.
[16]  Gu J, Kawai H, Nie L, Kitao H, Wiederschain D, et al. (2002) Mutual dependence of MDM2 and MDMX in their functional inactivation of p53. J Biol Chem 277: 19251–19254.
[17]  Mancini F, Gentiletti F, D'Angelo M, Giglio S, Nanni S, et al. (2004) MDM4 (MDMX) overexpression enhances stabilization of stress-induced p53 and promotes apoptosis. J Biol Chem 279: 8169–8180.
[18]  Stad R, Little NA, Xirodimas DP, Frenk R, van der Eb AJ, et al. (2001) Mdmx stabilizes p53 and Mdm2 via two distinct mechanisms. EMBO Rep 2: 1029–1034.
[19]  Perry ME (2004) Mdm2 in the response to radiation. Mol Cancer Res 2: 9–19.
[20]  Toledo F, Wahl GM (2006) Regulating the p53 pathway: in vitro hypotheses, in vivo veritas. Nat Rev Cancer 6: 909–923.
[21]  Finch RA, Donoviel DB, Potter D, Shi M, Fan A, et al. (2002) mdmx is a negative regulator of p53 activity in vivo. Cancer Res 62: 3221–3225.
[22]  Migliorini D, Lazzerini Denchi E, Danovi D, Jochemsen A, Capillo M, et al. (2002) Mdm4 (Mdmx) regulates p53-induced growth arrest and neuronal cell death during early embryonic mouse development. Mol Cell Biol 22: 5527–5538.
[23]  Parant J, Chavez-Reyes A, Little NA, Yan W, Reinke V, et al. (2001) Rescue of embryonic lethality in Mdm4-null mice by loss of Trp53 suggests a nonoverlapping pathway with MDM2 to regulate p53. Nat Genet 29: 92–95.
[24]  Wang YV, Wade M, Wong E, Li Y-C, Rodewald LW, et al. (2007) Quantitative analyses reveal the importance of regulated Hdmx degradation for P53 activation. Proceedings of the National Academy of Sciences 104: 12365–12370.
[25]  Kohn KW (1999) Molecular interaction map of the mammalian cell cycle control and DNA repair systems. Mol Biol Cell 10: 2703–2734.
[26]  Kohn KW (2001) Molecular interaction maps as information organizers and simulation guides. Chaos 11: 84–97.
[27]  Kohn KW, Aladjem MI, Weinstein JN, Pommier Y (2006) Molecular interaction maps of bioregulatory networks: a general rubric for systems biology. Mol Biol Cell 17: 1–13.
[28]  Kitano H, Funahashi A, Matsuoka Y, Oda K (2005) Using process diagrams for the graphical representation of biological networks. Nat Biotechnol 23: 961–966.
[29]  Kohn KW, Riss J, Aprelikova O, Weinstein JN, Pommier Y, et al. (2004) Properties of switch-like bioregulatory networks studied by simulation of the hypoxia response control system. Mol Biol Cell 15: 3042–3052.
[30]  Orfanidis SJ (1985) Optimum signal processing: an introduction. xiii. New York: Macmillan. 349 p.
[31]  Clegg HV, Itahana K, Zhang Y (2008) Unlocking the Mdm2-p53 loop: ubiquitin is the key. Cell Cycle 7: 287–292.
[32]  Jian S, Harel W (2007) Toward realistic modeling of dynamic processes in cell signaling: Quantification of macromolecular crowding effects. The Journal of Chemical Physics 127: 155105.
[33]  Fernandez E, Schiappa R, Girault JA, Le Novere N (2006) DARPP-32 is a robust integrator of dopamine and glutamate signals. PLoS Comput Biol 2: e176.
[34]  Ferrell JE Jr, Machleder EM (1998) The biochemical basis of an all-or-none cell fate switch in Xenopus oocytes. Science 280: 895–898.
[35]  Ozbudak EM, Thattai M, Lim HN, Shraiman BI, Van Oudenaarden A (2004) Multistability in the lactose utilization network of Escherichia coli. Nature 427: 737–740.
[36]  Goldbeter A, Koshland DE Jr (1981) An amplified sensitivity arising from covalent modification in biological systems. Proc Natl Acad Sci U S A 78: 6840–6844.
[37]  Cherry JL, Adler FR (2000) How to make a Biological Switch. Journal of Theoretical Biology 203: 117–133.
[38]  Lahav G, Rosenfeld N, Sigal A, Geva-Zatorsky N, Levine AJ, et al. (2004) Dynamics of the p53-Mdm2 feedback loop in individual cells. Nat Genet 36: 147–150.
[39]  Lev Bar-Or R, Maya R, Segel LA, Alon U, Levine AJ, et al. (2000) Generation of oscillations by the p53-Mdm2 feedback loop: a theoretical and experimental study. Proc Natl Acad Sci U S A 97: 11250–11255.
[40]  Hamstra DA, Bhojani MS, Griffin LB, Laxman B, Ross BD, et al. (2006) Real-time evaluation of p53 oscillatory behavior in vivo using bioluminescent imaging. Cancer Res 66: 7482–7489.
[41]  Zhao BX, Chen HZ, Lei NZ, Li GD, Zhao WX, et al. (2006) p53 mediates the negative regulation of MDM2 by orphan receptor TR3. Embo J 25: 5703–5715.
[42]  Markevich NI, Hoek JB, Kholodenko BN (2004) Signaling switches and bistability arising from multisite phosphorylation in protein kinase cascades. J Cell Biol 164: 353–359.
[43]  Brazhnik P, Kohn KW (2007) HAUSP-regulated switch from auto- to p53 ubiquitination by Mdm2 (in silico discovery). Math Biosci 210: 60–77.
[44]  Jackson MW, Berberich SJ (2000) MdmX protects p53 from Mdm2-mediated degradation. Mol Cell Biol 20: 1001–1007.
[45]  Bakkenist CJ, Kastan MB (2003) DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 421: 499–506.
[46]  Atkinson KE (1989) An introduction to numerical analysis. xvi. New York: Wiley. 693 p.
[47]  Chen L, Gilkes DM, Pan Y, Lane WS, Chen J (2005) ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage. Embo J 24: 3411–3422.
[48]  Hu B, Gilkes DM, Farooqi B, Sebti SM, Chen J (2006) MDMX overexpression prevents p53 activation by the MDM2 inhibitor Nutlin. J Biol Chem 281: 33030–33035.


comments powered by Disqus

Contact Us


微信:OALib Journal