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August 22, 2005

New research unveils complex mechanisms that control cell growth and division

By Tim Stephens

Researchers studying the molecular mechanisms that control cell growth and division are piecing together a surprising and complicated regulatory system that offers promising targets for anticancer drugs.


The mutant yeast cells in this photo fail to properly coordinate cell growth and cell division.
Photo: Douglas Kellogg

A new study led by UCSC researchers has revealed the interactions between key regulatory proteins that determine when cells initiate the process of cell division.

The study, published August 11 in the journal Cell, represents an important step toward understanding the complex network of signals that controls the "cell cycle"--the orderly sequence of events that all cells pass through as they grow to a certain size, copy their chromosomes, and divide into two new cells.

"This discovery solves an important piece of the puzzle for understanding how cell division is initiated when cells reach a certain size," said Douglas Kellogg, professor of molecular, cell, and developmental biology and coauthor of the paper.

Cell cycle control is one of the hottest areas of biomedical research, in part because of the potential applications in fighting cancer, which results from uncontrolled proliferation of cells in the body. Enzymes called cyclin-dependent kinases are the basic regulators of the cell cycle, and they in turn are regulated by other proteins that inhibit or activate them.

The Cell paper describes the interactions of two proteins known as the Wee1 kinase and cyclin-dependent kinase 1 (Cdk1). Stacy Harvey, a graduate student in Kellogg's lab, is first author of the paper and carried out most of the experiments. The other coauthors are UCSC graduate student Alyson Charlet and Harvard Medical School researchers Wilhelm Haas and Steven Gygi.

Wee1 was already known to regulate Cdk1, inhibiting its activity and delaying the start of cell division until conditions are right. Harvey found that Cdk1 itself actually regulates Wee1, an unusual case of two proteins controlling each other's activity.

"This kind of reciprocal regulation is really surprising. It suggests that these two proteins act together as a dynamic sensor to control the initiation of cell division," Kellogg said.

Both proteins are kinases, a class of enzymes that "phosphorylate" or add phosphate groups to other proteins. Phosphorylation and dephosphorylation control the activity of many cellular enzymes. In this case, Cdk1 phosphorylates and activates Wee1, which then phosphorylates and inhibits Cdk1. If another enzyme dephosphorylates Cdk1, it becomes active and adds more phosphate groups to Wee1. This "hyperphosphorylation" of Wee1 inactivates it, and Cdk1 is then released from the inhibitory effect of Wee1 and can trigger cell division.

According to Kellogg, the phosphorylation of Wee1 by Cdk1 is counteracted by another enzyme that rapidly removes phosphate groups, so that Wee1 undergoes continuous rounds of phosphorylation and dephosphorylation. The balance between these processes then determines whether Wee1 is active or inactive.

"It's like an engine that is constantly running, so it's highly responsive to any change in the balance," Kellogg said.

Aside from its implications for cancer research, this study offers new insights into the mechanisms behind the incredible diversity in the sizes and shapes of cells. That diversity is the result of variations in the molecular mechanisms that link cell growth and cell division. Each cell type seems to know when to stop growing and when to divide.

"Understanding the mechanisms that determine cell size and shape is one of the long-term goals of this research. I think those mechanisms are going to be very complicated but also very beautiful," Kellogg said.

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