Cell Division the Outcome of an Adversarial Process

Two mutually antagonistic protein complexes have been found to duel on the precipice of cell division. Whichever one prevails determines whether the cell remains in the G1 phase (where the focus is on growth) or enters the S phase (where the focus is on chromosome duplication and separation). It has long been known that one of these protein complexes, anaphase-promoting complex/cyclosome (APC/C), needs to be shut down for the S phase to commence. But it was not known that APC/C has what amounts to a rival, a sort of Spy vs. Spy counterpart. This rival complex, which recently stepped from the shadows in a study conducted at the University of North Carolina (UNC), turns out to be SCF (Skp1-Cul1-F box)/cyclin F.

Unlike the original Spy vs. Spy antagonists, which forever sought to blow each other up, the dueling protein complexes merely mark each other for recycling, applying tags that attract the proteasome. For example, APC/C teams up with a protein called Cdh1 to grab a bunch of other proteins in the cell and tag them (with enzymes) for disposal. Cells commonly use tagging-for-disposal complexes like APC/C—which are known as E3 ubiquitin ligases—to regulate the amounts of specific proteins. The proteins that APC/C suppresses include many that would facilitate the cell’s entry into S phase. Thus, while APC/C remains active, the cell cannot move into S phase.

APC/C inactivation was studied by a team of UNC scientists led by Michael J. Emanuele, Ph.D., an assistant professor of pharmacology. The team knew it was on to something when it discovered that APC/C and Cdh1 target a protein called cyclin F. The finding was interesting because cyclin F does what Cdh1 does: it serves as a target-recognition device for another disposal-tagging E3 ubiquitin ligase, in this case one called SCF. Thus, one big ubiquitin ligase, APC/C-Cdh1, effectively shuts down SCF/cyclin F.

Dr. Emanuele and his team soon found hints that SCF/cyclin F returns the favor. “When we looked at cells going through the cell cycle, we saw cyclin F levels starting to increase right at the G1/S transition, and at the same time the levels of Cdh1 were decreasing. The timing was perfect,” Dr. Emanuele said. “Then, when we put the protein complexes in cells at the same time, the levels of both went down, as if they were targeting each other.”

The team presented its results September 20 in the journal Cell Reports, in an article entitled, “APC/C and SCF^{cyclin F} Constitute a Reciprocal Feedback Circuit Controlling S-Phase Entry.” This article suggests that the APC/C and SCF/cyclin F complexes together constitute a sort of molecular switch—when it flips, the cell cycle enters S phase.

“Cyclin F loss impairs Cdh1 degradation and delays S-phase entry, and this delay is reversed by simultaneous removal of Cdh1,” wrote the article’s authors. “These data indicate that the coordinated, temporal ordering of cyclin F and Cdh1 degradation, organized in a double-negative feedback loop, represents a fundamental aspect of cell-cycle control.”

While the study performs the useful service of clarifying how cell division works, it has other implications. The study, for example, describes a kind of mutual antagonism that could be a feature of oscillating systems other than the cell-cycle oscillator.

“To the best of our knowledge nobody else has described a system involving direct antagonism between two E3 ubiquitin ligases,” noted Dr. Emanuele. “It suggests the possibility that similar mutually antagonistic pairs of E3s regulate other oscillating systems in biology.”

The study also raises the possibility that future drugs could target the switch, or elements of the switch, to help stop the uncontrolled division of cancerous cells. “Our work describes a key piece of the puzzle for how this fundamental process works,” concluded Dr. Emanuele. “We did not focus on suppressing cancer cell division in this study, but given what we’ve found we think it’s definitely worth investigating further.”

“Cdh1 is a largely under-appreciated tumor suppressor,” Dr. Emanuele added. “Although it blocks S phase, Cdh1 isn’t mutated in cancers. One of the implications of our data, however, is that Cdh1 is degraded at this critical G1/S juncture. It could be that in some cases, too much Cdh1degradation is all that’s needed to promote cancerous growth.”

Dr. Emanuele suspects that phosphorylation or some similar modification may be what triggers the ascendancy of each of the ubiquitin ligases in turn. “That’s something we’re working on now,” he said.