Written by: Rob Levy

Medically Reviewed By: Dipanjan Chowdhury, PhD

• Dana-Farber Cancer Institute researchers have found that CDK5, previously thought unrelated to cell division, plays a critical role in mitosis.
• The study shows that CDK5 is produced in excess in fast-growing cancer cells, presenting a potential target for cancer therapies.
• CDK5 binds to cyclin B1, offering new insights into its involvement in the cell cycle.

In the family of cyclin-dependent kinase (CDK) proteins, CDK5 always seemed to be a misfit. Despite being structurally similar to other CDKs, and despite the “cyclin” in its name, it did not participate in the family business of ushering cells through the cycle of growth and division. 

Or so scientists thought, and textbooks said. 

In a recent study in the journal Nature, Dana-Farber scientists show that CDK5 leads a kind of double life: in addition to its well-described role in brain development, it also plays a part in the cell cycle, specifically in mitosis, the process of forming two identical cells from a single parent cell. 

The discovery is significant not only for revealing a new aspect of CDK5’s repertoire. The researchers also found that CDK5 is overexpressed – produced to excess – in fast-dividing cells, which make up the vast majority of cancers. The implication is that targeting CDK5 in these cancers may offer a way to foil their rampant growth. 

“Of the more than 20 known CDKs, the one designated ‘CDK1’ is the only one that’s essential to mitosis,” says Dana-Farber’s Dipanjan Chowdhury, PhD, senior author of the new study. “Without it, cells cannot divide and an organism dies. What we’ve shown is that CDK5 acts in a way that complements or supplements CDK1’s role in mitosis." 

One reason CDK5 was considered an outlier in the CDK clan was because of the proteins it partners with – or, to be precise, doesn’t partner with. CDKs are like wallflowers at a dance – idle until they find a partner. Only when they join to a cyclin protein do they push the cell cycle along, hence the name cyclin-dependent kinases. CDK1, for example, gets involved in cell cycle progression by binding to cyclin B1. 

CDK5 was an anomaly. It binds to a protein called p25 to participate in brain development but wasn’t thought to bind to a cyclin. “It was known as a cyclin-dependent kinase without a cyclin,” Chowdhury remarks. 

That, too, proved to be mistaken, as Chowdhury and his colleagues show in the new paper. 

Serendipitous start 

The researchers’ attention was drawn to CDK5 as a result of a chance finding in an earlier study. The study was examining how cells repair DNA during mitosis when they saw signs that CDK5 was active as mitosis progressed. 

Chowdhury, the leader of that study, told his Dana-Farber colleague Alexander Spektor, MD, PhD, an expert in mitosis, about the finding. Together with co-first authors Xiao-Feng Zheng, PhD, and Anniruddha Sarkar, PhD, of Dana-Farber, they undertook a series of experiments to ferret out CDK5’s role in mitosis. 

They did so in classic scientific fashion: to determine what part a protein plays in a biological process, researchers explore what happens when that protein is removed. That proved especially challenging in the case of CDK5: molecules capable of blocking CDK5 often interfere with other proteins as well, making it difficult to isolate CDK5’s specific involvement in mitosis; and cells may compensate for the loss of CDK5 by switching on other protein circuits. 

The researchers overcame that difficulty by tweaking the structure of CDK5 so it could be inhibited by certain molecules. They then ran two sets of experiments that inactivated CDK5 just before cells entered mitosis. The first experiments used a molecule to inhibit CDK5, the second degraded CDK5 so it could no longer function. 

Both sets of experiments yielded the same conclusion: CDK5 plays a role in the regulation of the mitotic spindle – a group of fibers that extend from one end of a dividing cell to the other, resembling the long arcing lines on a football. The spindle, which is made of elongated proteins called microtubules, comes into play after a cell has duplicated its chromosomes in preparation for division. Each chromosome is joined to its newly made twin. The spindle fibers reach out from opposite ends of the cell and attach to the chromosome pairs. Once all attachments are made and the chromosome pairs align in the middle of the cell, the pairs separate and the spindle fibers tug each chromosome to the far ends of the cell, which has taken an oblong shape as it gets ready to separate into two daughter cells. In this way, each of the two daughter cells receives the exact same set of genetic instructions. 

“When we looked at cells that lacked functional CDK5, we saw a variety of abnormalities in the spindle,” Spektor relates. The spindle, as scientists have long known, is a supple structure: at the same time that spindle fibers are attaching to chromosomes, complex cellular machinery is making sure they’re attaching properly. When an incorrect attachment is found, it needs to be detached. Failure to make these kinds of revisions can result in a host of problems – daughter cells with extra or missing chromosomes, abnormal or mishappen nuclei, even cell death. 

“In cells where CDK5 was absent, we found the microtubules within the spindle to be overly stable,” Spektor remarks, adding that while stability is usually considered a positive quality, excessive stability within a spindle can have adverse consequences. “If the microtubules are too stable, improper attachments might not be detachable,” Spektor says. “Our findings demonstrate that CDK5 has an important role in fine-tuning the spindle so it’s optimally able to correct errors.” 

Fast-dividing cancer cells, where CDK5 is often overabundant, show the consequences of abnormal spindles. Too-weak attachments between spindles and chromosomes can be as harmful as too-strong ones. 

From a cancer cell’s point of view, CDK5 is an attractive resource for rapid growth, Chowdhury explains. “Unlike CDK1, CDK5 is not essential for mitosis, but if a cell wants to divide quickly after duplicating its DNA, CDK5 offers a way to power through mitosis without slowing down.” 

The researchers also found that CDK5’s involvement in mitosis comes about by binding to the cyclin B1 protein. This again was a surprise, as cyclin B1 had been shown to work with CDK1 but no other CDK.  

The discovery that CDK5 is, despite what the textbooks say, a participant in mitosis raises the possibility that other, less well-studied CDKs may play a role in regulating the cell cycle as well, researchers say. And the fact that fast-dividing cancer cells are abnormally dependent on CDK5 makes it an inviting target for future therapies. 

“In retrospect, the fact that CDK5 plays a role in mitosis shouldn’t come as a surprise,” Chowdhury says. “Nature is very economical. It doesn’t make sense that it would create a protein that’s very similar to other proteins and not have it fill a similar function.”