Positive-feedback System Ensures That Cells Divide Print E-mail
Science - Biological Sciences
Written by TS-Si News Service   
Sunday, 17 August 2008 16:30
Synchronization. When cells begin division, hundreds of genes and proteins must be coordinately regulated. A positive-feedback loop involving two G1 cyclins, Cln1 and Cln2 (green), help keep events in sync.
TS-Si Biological Sciences
New York, NY, USA. Cell division in humans is a process by which a parent cell divides into two or more daughter cells. There is a point of no return in the life of every cell. Once it enters the cell cycle and passes a checkpoint known as Start, a cell will follow defined steps to divide — no matter what changes occur in its environment.
 
The process executes with comparatively high reliability, marked by few errors. However, errors can and do happen. A good start on understanding how cell division proceeds, including any missteps, is to identify the mechanisms that ensure overall reproducibility and reliability.
 
Positive feedback of G1 cyclins ensures coherent cell cycle entry. Jan M. Skotheim, Stefano Di Talia, Eric D. Siggia and Frederick R. Cross. Nature 454(7202) 291-296. doi: 10.1038 / nature07118
 
Scientists have now shown how a positive-feedback system ensures that a cell can reach Start, then finish the process, allowing cells to adapt to changes in their environment rapidly and efficiently.
 
Postdoc Jan Skotheim, The Rockefeller University, collaborated on the research with Frederick Cross, head of the Laboratory of Yeast Molecular Genetics, and Eric Siggia, head of the Laboratory of Theoretical Condensed Matter Physics. Their findings appear in Nature.
 
Part of the decision process includes the simultaneous activation of more than 200 genes, a formidable problem considering the noisy environment of the cell. “Given how difficult it is for a cell to activate just one gene, activating 200 at the same time seems like a very difficult task,” says Skotheim. Skotheim says the “… way the cell solves this challenge is through positive feedback. It keeps all these events in sync.” 
 
In the case of cell division, the key is a pair of molecules called Cln1 and Cln2, part of a family of proteins known as G1 cyclins. Skotheim and his colleagues, including graduate student Stefano DiTalia, show that when budding yeast (Saccharomyces cerevisiae) cells sense that they are big enough to divide, they synthesize an activator molecule that triggers a positive feedback system in which Cln1 and Cln2 advance their own expression.
 
“So what happens is that the very rapid ramp-up of the G1 cyclins during Start lead to all those target genes getting fired synchronously,” says Skotheim. “It’s a function of positive feedback that hasn’t been thought of before: synchrony and coherence.”
  • For the genes to be fired synchronously, a protein called Whi5 must be exported from the nucleus, and kept out until the two daughter cells are born.
     
  • During Start, which lasts approximately three minutes, Cln1, Cln2 and the activator molecule all collaborate to kick out Whi5. Once out, Cln1 and Cln2 must continue to advance their own expression in order to keep Whi5 out.
     
  • Then, the moment the two daughter cells separate, the G1 cyclins are inactivated, Whi5 enters back into the nucleus and the complex detaches.
In previous work, the team showed that the export of Whi5 is the molecular event that signals Start. Now they show that a positive-feedback mechanism is what drives it.
 
In the past, when scientists tested the possibility that positive feedback could be behind cell division, the results always came out negative. But Skotheim took a different approach from that of his predecessors. Instead of averaging the results across many cells, he looked at data from individual cells, an approach that minimizes data loss.
 
Working with two strains of single-celled budding yeast, only one of which had Cln1 and Cln2, the researchers observed that most cells without the two molecules had less predictable divisions. They took longer to start dividing, and when they finally passed Start, the time it took them to complete the process varied considerably. In fact, some cells didn’t bud at all.
 
“By looking at averages, previous attempts to find a potential positive-feedback loop had obscured what was going on,” explains Skotheim.
 
“By studying single cells, we regained the lost information and found the opposite of what others had found: that positive feedback drives and coordinates a cell’s commitment to divide.”
 


Positive feedback of G1 cyclins ensures coherent cell cycle entry. Jan M. Skotheim, Stefano Di Talia, Eric D. Siggia and Frederick R. Cross. Nature 454(7202) 291-296. doi: 10.1038 / nature07118

Abstract

In budding yeast, Saccharomyces cerevisiae, the Start checkpoint integrates multiple internal and external signals into an all-or-none decision to enter the cell cycle. Here we show that Start behaves like a switch due to systems-level feedback in the regulatory network. In contrast to current models proposing a linear cascade of Start activation, transcriptional positive feedback of the G1 cyclins Cln1 and Cln2 induces the near-simultaneous expression of the 200-gene G1/S regulon. Nuclear Cln2 drives coherent regulon expression, whereas cytoplasmic Cln2 drives efficient budding. Cells with the CLN1 and CLN2 genes deleted frequently arrest as unbudded cells, incurring a large fluctuation-induced fitness penalty due to both the lack of cytoplasmic Cln2 and insufficient G1/S regulon expression. Thus, positive-feedback-amplified expression of Cln1 and Cln2 simultaneously drives robust budding and rapid, coherent regulon expression. A similar G1/S regulatory network in mammalian cells, comprised of non-orthologous genes, suggests either conservation of regulatory architecture or convergent evolution.

 
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Last Updated on Sunday, 17 August 2008 15:17