title: Disorder, oscillatory dynamics and state switching: the role of c-Myc.
abstract: In this paper, using the intrinsically disordered oncoprotein Myc as an example, we present a mathematical model to help explain how protein oscillatory dynamics can influence state switching. Earlier studies have demonstrated that, while Myc overexpression can facilitate state switching and transform a normal cell into a cancer phenotype, its downregulation can reverse state-switching. A fundamental aspect of the model is that a Myc threshold determines cell fate in cells expressing p53. We demonstrate that a non-cooperative positive feedback loop coupled with Myc sequestration at multiple binding sites can generate bistable Myc levels. Normal quiescent cells with Myc levels below the threshold can respond to mitogenic signals to activate the cyclin/cdk oscillator for limited cell divisions but the p53/Mdm2 oscillator remains nonfunctional. In response to stress, the p53/Mdm2 oscillator is activated in pulses that are critical to DNA repair. But if stress causes Myc levels to cross the threshold, Myc inactivates the p53/Mdm2 oscillator, abrogates p53 pulses, and pushes the cyclin/cdk oscillator into overdrive sustaining unchecked proliferation seen in cancer. However, if Myc is downregulated, the cyclin/cdk oscillator is inactivated and the p53/Mdm2 oscillator is reset and the cancer phenotype is reversed.
authors.affiliation: Indian Institute of Science Education and Research, Pune, India.
authors.forename: Nivedita
authors.initials: N
authors.lastname: Rangarajan
authors.affiliation: Biomedical Engineering, University of Delaware, Newark, DE, USA.
authors.forename: Zach
authors.initials: Z
authors.lastname: Fox
authors.affiliation: Biomedical Engineering, University of Delaware, Newark, DE, USA; Electrical and Computer Engineering, University of Delaware, Newark, DE, USA.
authors.forename: Abhyudai
authors.initials: A
authors.lastname: Singh
authors.affiliation: Department of Urology and Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: pkulkar4@ibbr.umd.edu.
authors.forename: Prakash
authors.initials: P
authors.lastname: Kulkarni
authors.affiliation: Department of Mathematics, Indian Institute of Science, Bangalore, India; Centre for Neuroscience, Indian Institute of Science, Bangalore, India. Electronic address: rangaraj@math.iisc.ernet.in.
authors.forename: Govindan
authors.initials: G
authors.lastname: Rangarajan
mesh_terms: D001683:Biological Clocks / Q000502:physiology*; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D016213:Cyclins / Q000378:metabolism; D025461:Feedback, Physiological / Q000502:physiology; D006801:Humans; D008954:Models, Biological; D010641:Phenotype; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D016213:Cyclins; D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
keywords: Cancer; Intrinsically disordered proteins; Myc; Oscillators; State-switching