Biological Sciences

Events and seminars

WT PhD Programme Seminar - Cell cycle regulation by systems-level feedback controls

Bèla Novàk, Department of Biochemistry, University of Oxford

10th May 2017 at 12:00pm [Download iCalendar / .ics file]

Daniel Rutherford, G.27, LT1

In order to maintain genome integrity and an effective nucleocytoplasmic ratio from one generation to the next, cells carefully monitor progression through their replication-division cycle and fix any errors before they jeopardize the progeny of the cellular reproduction process. These error surveillance and correction mechanisms operate at distinct ‘checkpoints’ in the cell division cycle, where a growing cell must ‘decide’ whether it must wait for errors to be corrected or it may proceed to the next phase of the cell cycle. Once a decision is made to proceed, the cell unequivocally enters into a qualitatively different biochemical state, which makes cell cycle transitions switch-like and irreversible. These characteristics of cell cycle transitions are best explained by bistable switches with different activation and inactivation thresholds, resulting in a hysteresis effect. Almost 25 years ago, John Tyson and I proposed that the activity of the mitosis-inducing protein kinase, Cdk1:CycB, is controlled by an underlying bistable switch generated by positive feedbacks involving inhibitory phosphorylations of the kinase subunit. Numerous predictions of this model were experimentally verified by different groups, and bistability has become a paradigm of cell cycle transitions. The phosphorylation of mitotic proteins by Cdk1:CycB is counteracted by a protein phosphatase, PP2A:B55, which is inhibited during mitosis by a stoichiometric binding partner, ENSA-P, which is itself activated by Greatwall-kinase. Using mathematical modelling guided by biochemical reconstitution experiments, we showed recently that the BEG (B55-ENSA-Greatwall) pathway also represents a bistable, hysteretic switch controlled by the activity of Cdk1:CycB. Bistable regulation of the kinase (Cdk1:CycB) and the phosphatase (PP2A:B55) makes hysteresis a robust property of mitotic control, with suppression of futile cycling of protein phosphorylation and dephosphorylation during M phase.  These considerations show that both entry into and exit from mitosis are controlled by bistable switches intimately connected to the activities of the major mitotic kinase, Cdk1:CycB, and phosphatase, PP2A:B55. Intriguingly, the ‘design principle’ of the BEG pathway is operative as well at two other cell cycle checkpoints, as will be discussed.

Host Adele Marston

ical_icon_40px.png iCalendar / ICS feed

Seminars are available in .ics format utilised by various calendar and email programs including Google Calendar, Apple iCal, and Microsoft Outlook.

rss_icon_med_40px.gif RSS Feeds from Biology

Events and seminars are available via an RSS feed. Please click the link below to subscribe.