Disorder, oscillatory dynamics and state switching: The role of c-Myc

Nivedita Rangarajan, Zach Fox, Abhyudai Singh, Prakash Kulkarni, Govindan Rangarajan

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)105-114
Number of pages10
JournalJournal of Theoretical Biology
Volume386
DOIs
StatePublished - Dec 7 2015

Keywords

  • Cancer
  • Intrinsically disordered proteins
  • Myc
  • Oscillators
  • State-switching

ASJC Scopus subject areas

  • Statistics and Probability
  • Modeling and Simulation
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Agricultural and Biological Sciences(all)
  • Applied Mathematics

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