Frequency Domain Analysis Reveals External Periodic Fluctuations Can Generate Sustained p53 Oscillation 英文参考文献.docVIP

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Frequency Domain Analysis Reveals External Periodic Fluctuations Can Generate Sustained p53 Oscillation 英文参考文献.doc

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Frequency Domain Analysis Reveals External Periodic Fluctuations Can Generate Sustained p53 Oscillation 英文参考文献

FrequencyDomainAnalysisRevealsExternalPeriodic FluctuationsCanGenerateSustainedp53Oscillation Yong-JunShin1,BrandonHencey2,StevenM.Lipkin3,XilingShen1* 1ElectricalandComputerEngineering,CornellUniversity,Ithaca,NewYork,UnitedStatesofAmerica,2MechanicalandAerospaceEngineering,CornellUniversity,Ithaca, NewYork,UnitedStatesofAmerica,3DepartmentofMedicine,WeillCornellCollegeofMedicine,NewYork,NewYork,UnitedStatesofAmerica Abstract p53 is a well-known tumor suppressor protein that regulates many pathways, such as ones involved in cell cycle and apoptosis. The p53 levels are known to oscillate without damping after DNA damage, which has been a focus of many recentstudies.Anegativefeedbackloopinvolvingp53andMDM2hasbeenreportedtoberesponsibleforthisoscillatory behavior,butquestionsremainashowthedynamicsofthisloopalterinordertoinitiateandmaintainthesustainedor undamped p53 oscillation. Our frequency domain analysis suggests that the sustained p53 oscillation is not completely dictatedbythenegativefeedbackloop;instead,itislikelytobealsomodulatedbyperiodicDNArepair-relatedfluctuations thataretriggeredbyDNAdamage.Accordingtoouranalysis,thep53-MDM2feedbackmechanismexhibitsadaptabilityin different cellular contexts. It normally filters noise and fluctuations exerted on p53, but upon DNA damage, it stops performing the filtering function so that DNA repair-related oscillatory signals can modulate the p53 oscillation. Furthermore, it is shown that the p53-MDM2 feedback loop increases its damping ratio allowing p53 to oscillate at a frequency more synchronized with the other cellular efforts to repair the damaged DNA, while suppressing its inherent oscillation-generatingcapability.OuranalysissuggeststhattheoverexpressionofMDM2,observedinmanytypesofcancer, candisrupttheoperationof thisadaptive mechanism bymakingitless responsivetothemodulatingsignals after DNA damageoccurs. Citation: Shin Y-J, Hencey B, Lipkin SM, Shen X (2011) Frequency Domain Analysis Reveals External Period