New insights into orderly cell-cycle transitions
Research described in a recent paper from Professor Bela Novak and colleagues in the department together with researchers in France, is helping to broaden our understanding of how cells ensure that they follow through the different phases of the cell cycle in the correct order (1).
A schematic diagram showing some of the key protein components of the cell cycle and how they interact with each other. PP2A is the MPP (Click to enlarge)
The research demonstrates that the balance between the activity of two cell-cycle enzymes – the cyclin-dependent kinase 1 (CDK1) and the mitosis-regulating protein phosphatase (MPP) – is crucial in controlling whether the cell undergoes DNA replication or mitosis.
The cell cycle – whether in simple eukaryotes such as yeast, or complex organisms like mammals – is driven by the activity of cyclin-dependent protein kinases (CDK). These act in partnership with a group of proteins called cyclins which oscillate during the cell cycle. By phosphorylating key substrates, the CDK-cyclin complexes trigger first DNA replication and then mitosis.
But layered on top of this is an additional regulatory mechanism. Countering the phosphorylation activities of the kinase is the mitosis-regulating protein phosphatase (MPP) which dephosphorylates substrates. The activity of both the CDK and MPP is regulated. For DNA replication to take place, the MPP activity must trump the CDK activity, whereas entering into mitosis requires the inactivation of the MPP.
Professor Novak and colleagues have been using mathematical modelling, based on experiments described in research papers, to understand the complex relationship between the competing kinase and phosphatase activities. Their models indicated that the CDK and MPP are antagonistic – that CDK inhibits MPP and vice versa.
Through discussions with other cell cycle researchers, Professor Novak was put in contact with Dr Daniel Fisher at the Institut de Génétique Moléculaire in Montpellier who was working on the experimental side of the problem using extract from Xenopus eggs.
These eggs are an ideal system for studying the cell cycle as they undergo a series of fast cell cycles, alternating between DNA replication and mitosis. All the cell cycle components found in Xenopus eggs are conserved in mammalian cells.
Bringing together modeller and experimentalist proved to be a success. ‘Our model provided a theoretical foundation for Daniel’s data, making sense of the data,’ says Professor Novak.
This and other work has ignited interest in the mitotic phosphatases which have been overshadowed by the kinases and whose regulation was largely unknown. In part, this has been due to the difficulty in carrying out biochemical studies on the phosphatases.
‘We’re reaching a threshold in cell cycle research and a new picture is emerging,’ explains Professor Novak. ‘We’re realising that the phosphatases are equally important as the kinases.’
‘If you put all the pieces on the table, it’s actually incredibly complicated,’ says Professor Novak. ‘It’s just like a social network, with everybody contacting each other, and it’s very difficult to work out who is the director of the system.’
With the story getting more complex all the time, mathematical models in combination with experimental work offer an attractive way of gaining a deeper understanding of this fundamental biological process.