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One-way ticket through cell division

The long-held view that cells move through cell division in only one direction because of the irreversible degradation of certain key regulatory proteins has been challenged by a recent publication in Nature by Béla Novák, Professor for Systems Biology in the Department, Dr Frank Uhlmann at the Cancer Research UK London Research Institute and colleagues1.

‘Degradation takes place and it drives the process but this is not the important process which locks the cell out of mitosis.’

The eukaryotic cell passes through a number of different states during the cell division cycle: M (Mitosis), G1 (Gap 1), S (Synthesis), and G2 (Gap 2). Driving the transitions between states is a family of proteins known as Cdks (cyclin-dependent kinases) which are regulated by the availability and activity of other key proteins. The cell’s movement through these transitions is tightly controlled to ensure that it only passes one way through them.

For the cell to leave mitosis, for example, cdk partner proteins called cyclins have to be degraded. Cell biology textbooks state that protein degradation is thermodynamically irreversible and that this explains why cells can only move one way through the cell cycle.

But in 2007, Professor Novák and colleagues published a commentary in Nature Cell Biology challenging this fundamental dogma2. They proposed that irreversible cell cycle transitions cannot be attributed to a single molecule or reaction but derive instead from interactions between different molecular regulatory pathways.

They went on to argue that their theory, which could be applied to all the cell cycle transitions except one, could be supported by many experimental observations over the years.

Yeast cells moving in and out of mitosis

Yeast cells exit mitosis when cyclin degradation is turned on (left and middle). They can be made to move back into mitosis when degradation is turned off (right). The mitotic spindle, a marker for the mitotic state, is shown stained green, the spindle poles are stained red and the nucleus blue.

It was following discussions with Dr Uhlmann that an opportunity to test these ideas directly, using the model organism bakers' yeast, came about. Dr López-Avilés, a research fellow in Dr Uhlmann’s laboratory, carried out the work. The paper in Nature describes the key experiments that demonstrate that cyclin degradation is neither sufficient, nor necessary, to make exit from mitosis irreversible.

'Degradation takes place and it drives the process but this is not the important process which locks the cell out of mitosis,’ explains Professor Novák. He draws an analogy between the cell leaving a cell cycle state and being unable to go back, and someone leaving a room and being prevented from returning because the door closes behind them.

The group found that cells can be coaxed back into the mitotic state when cyclin is resynthesised following its destruction. Mitotic exit only becomes irreversible once a network of interacting regulatory pathways come into play to maintain the cell cycle in a new state. The process employed is known as a 'systems-level feedback'.

The Oxford group’s expertise in mathematical modelling was used to complement the experimental work and investigate how the regulatory pathways work together to hold the cell in its new state. The models, developed by Hungarian graduate student Orsolya Kapuy, simulate the levels and activities of cell cycle regulatory proteins in cells during mitotic exit and incorporate details of reactions and interactions based on experimental results in the literature.

Simulation of reversible mitotic exit experiments

Simulation of reversible mitotic exit experiments. The curves represent the relative concentration changes of four cell-cycle regulatory molecules.

As Professor Novák described in his 2007 paper, this process that may be happening at other cell cycle transitions. ‘There are many cell cycle transitions which are irreversible,’ he says. 'It's valid for G1-S and G2-M transitions.'

There is one exception to this feedback view of transitions. ‘One cell cycle transition where protein degradation makes the transition irreversible is anaphase,' he explains. This is because the sister chromatids of the newly replicated chromosomes are pulled apart during anaphase when proteins known as cohesins are destroyed, and no amount of cohesin ‘glue’ can stick these separated chromatids together again.

‘With all the other cell transitions, you have to think in dynamic terms,’ says Professor Novák, ‘Of course degradation destroys the protein but cells are synthesising, so the protein can be re-synthesised. Every process is counteracted by another one.'

How applicable is the phenomenon to other organisms? Professor Novák is working on modelling to prove that it is also true for mammalian cells. 'People are misinterpreting all of their experiments,' he thinks. 'Possibly the molecular details are different but the fundamental idea will apply.'

1. López-Avilés, S., Kapuy, O., Novák, B. and Uhlmann, F. Irreversibility of mitotic exit is the consequence of systems-level feedback. Nature 459, 592-595 (2009).

2. Novák, B., Tyson, J. J., Gyorffy, B. and Csikasz-Nagy, A. Irreversible cell-cycle transitions are due to systems-level feedback. Nature Cell Biol. 9, 724-728 (2007).



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