Biologists crack centuries-old mystery of how cell growth triggers cell division

Sacharomyces cerevisiae cells in DIC microscopy. Credit: Wikipedia.

Cells were discovered in 1676, and almost immediately afterward scientists began wondering why cells are so perfectly small.

More than three centuries later, a team of Stanford biologists have zeroed in on a previously unknown mechanism within the cell growth cycle that controls cell size. The fundamental finding was made by studying yeast , but could provide insight to basic human biology as well as diseases such as cancer that thrive by manipulating this mechanism.

The finding is published in Nature.

Cells of all types seemingly "know" just how large to grow, and when they reach that determined size, they divide into new cells. With no clear answer for what triggers this cellular decision, Jan Skotheim, an associate professor of biology at Stanford, began searching for the mechanism nearly a decade ago.

The search started in yeast, and specifically in the molecular pathway controlling cell division. Cell size was known to affect the first part of the cell division pathway to control when cells begin to replicate their DNA, known as the G1/S transition. There are analogous pathways in most organisms, but yeast is relatively simple to manipulate, so if Skotheim and his colleagues could find the trigger in yeast, they could likely apply that knowledge to other species.

The obvious suspect was a protein called Cln3 – as the first protein in the chain of molecular events leading to the G1/S transition, it was the likely trigger to any change regarding cell size and, ultimately, the cell's decision to divide into two cells. But Skotheim's team found that the concentration of Cln3 stayed relatively constant during cell growth. There was no clear, characteristic spike or dip in its concentration to initiate the process.

This was perplexing. All known biologic pathways are initiated by some change or stimulus to the first molecule. In a combination of brilliance and frustration, a postdoctoral researcher in the group, Kurt Schmoller, had the idea to examine the concentrations of the other proteins involved in the pathway. This led them to Whi5, a protein smack in the middle of the pathway.

While the cell produced enough of the other proteins to keep their concentration constant as the cell grew, Whi5 concentration started out high but was continuously diluted as the cell became larger.

"This finding was extremely exciting because it immediately lead to a new idea of how size control could work," said Schmoller, the lead author on the study. "The inhibitor-dilution mechanism, where the cells dilute out an inhibitor of , is very elegant and, in retrospect, seems almost obvious."

To test whether Whi5 was somehow affecting cell size from the middle of the pathway, Skotheim's team began selectively dialing its concentration up and down, and leaving all other proteins as normal.

By lowering the concentration to a certain level, the researchers forced the cells to initiate division at a smaller-than-usual size. Similarly, boosting Whi5 allowed the cell to grow larger than normal before dividing.

This was a complete surprise to the researchers. Signaling pathways traditionally jump into action by stimulating the beginning of the pathway and then transmitting that information down the line in a chain reaction.

"We don't know of any other pathways that operate like this," Skotheim said. "This looks like a huge breakthrough for us to solve this really old problem."

Although the work was driven to solve a fundamental question in biology, the finding could eventually have far-reaching implications. The yeast pathway is analogous to a similar pathway in humans, and provides a good sketch for understanding human biology. For instance, diseases can manipulate that pathway, a prime example being cancerous cells that grow rapidly and proliferate.

In addition to thinking about these implications, Skotheim's group plans to conduct a genome-wide analysis to identify other biologic processes that might be impacted by cell size. Very little is known about how things like cell size and geometry affect signaling pathways, he said, but if some key protein concentrations change as cells grow, could affect anything.

"Tons of things have been learned from studying the yeast cell cycle that apply directly to human cells," Skotheim said. "Finding something like this that's so intuitively unlikely, I don't think we could have done it without the yeast work. But now we can test it, and we plan to apply these models to ."

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Yeast study yields insights into cell-division cycle

More information: "Dilution of the cell cycle inhibitor Whi5 controls budding-yeast cell size." Nature (2015) DOI: 10.1038/nature14908
Journal information: Nature

Citation: Biologists crack centuries-old mystery of how cell growth triggers cell division (2015, September 29) retrieved 16 September 2019 from
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Sep 29, 2015
Very, very interesting! This size control seems to be a co-option of a pathway that had an earlier role, implying a) it is rather young (but existent in the LECA at the very least) and b) something else was used earlier (though perhaps using the same dilution mechanism).

Sep 29, 2015
Sorry, TL. Meant that to be a 5..

Sep 29, 2015
Anyway. My question is - is the whi-5 actually being removed from the cell, or is the ratio just reducing as the cell grows. Or perhaps, it is being used to create other proteins...

Sep 29, 2015
All known biologic pathways are initiated by some change or stimulus to the first molecule.


Does anyone else think the stimulus-induced change could be nutrient-dependent and pheromone-controlled in species from yeasts to mammals via the conserved mechanisms of molecular epigenetics that we detailed in the section on molecular epigenetics in our 1996 Hormones and Behavior review article?

See: From Fertilization to Adult Sexual Behavior http://www.hawaii...ion.html

This size control seems to be a co-option of a pathway that had an earlier role

Where do you think that pathway came from. How did it evolve before or after the "last eukaryotic common ancestor" automagically emerged? What did it emerge from? When did the emergence occur that led to a pathway for evolution to follow that clearly links RNA-mediated amino acid substitutions to ecological adaptations in all living genera?

Sep 29, 2015
The "Nature" article authors conclude that inhibitor-dilution mechanisms may be used to control cell size.

When placed into the context of the nutrient-dependent pheromone-controlled physiology of reproduction in species from microbes to humans, cell size is biophysically constrained by the chemistry of RNA-mediated amino acid substitutions and protein folding in the context of nutrient stress and/or social stress.

Stress is linked via thermodynamic cycles of protein biosynthesis and degradation to all pathology. In the absence of epigenetic effects of stress on nutrient-dependent RNA-mediated protein folding, healthy longevity is manifested in morphological phenotypes and behavioral phenotypes.

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