Hysteresis and Cell Cycle Transitions: How Crucial is it?

¹ University of California, Los Angeles
² UCLA School of Medicine Cardiovascular Research Laboratory

^* To whom correspondence should be addressed. E-mail: zqu{at}mednet.ucla.edu.

Submitted on September 15, 2004
Revised on October 6, 2004
Accepted on 16 December 2004

	Abstract

Recently, experiments have shown that cyclin-dependent kinase (CDK) activity exhibits hysteresis in its response to total cyclin when cyclin is made non-degradable and controlled externally. This observation was taken to support mathematical modeling predictions regarding the underlying dynamics of the cell cycle. However, cell cycle dynamics can also be generated by other non-hysteretic mechanisms. To examine the robustness of the hysteretic response of CDK activity to total cyclin, we simulated various cell cycle signal transduction networks, and correlated the dynamics to the response function of CDK activity versus total cyclin. By randomly searching parameter space, we assessed robustness by estimating the frequency of hysteretic versus non-hysteretic dynamical mechanisms. When the dynamical instabilities were caused by feedback loops in CDK phosphorylation and dephosphorylation or by feedback between cyclin and the CDK inhibitor, the response function of CDK activity versus total cyclin correlated well with the dynamical instabilities. However, when the dynamical instabilities originated from feedback between cyclin and APC-CDH1 or RB-E2F, the response function did not correlate with dynamical instabilities. Thus, although a hysteretic response is neither necessary nor sufficient, it is in general a much more robust mechanism for generating cell cycle dynamics than non-hysteretic mechanisms.

Key Words: bistability, cyclin, cyclin-depedent kinase, dynamics, simulation

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