University of Arizona Cancer Center member Gregory Rogers, PhD, has recently published a paper in the journal Current Biology, highlighting his laboratory’s innovative work exploring the link between the Polo-like kinase 4 (Plk4) protein levels and chromosomal instability (CIN), which can contribute to the formation of cancer.
In this paper, titled “Polo-like Kinase 4 Autodestructs by Generating Its Slimb-Binding Phosphodegron,” Dr. Rogers and his team of researchers found that healthy Plk4 directly generates its own destruction and can do so without the assistance of other proteins. When protein levels are low and destroyed efficiently, cellular activity remains stable. Yet when this protein does not phosphorylate (i.e. destroy) itself properly, it leads to centrosome overduplication, which may lead to genetic instability and increased risk for cancer.
Charting this protein’s healthy, stable activity could potentially lead to breakthroughs in understanding these unhealthy, unstable activities, which could generate potential genetic interventions to prevent the formation of cancer.
Dr. Rogers’ paper appears in Current Biology at the same time as a parallel study conducted by Monica Bettencourt-Dias, whose lab was exploring this identical issue in Portugal.
“We ended up co-submitting our papers, because they were asking the exact same questions and coming to the exact same conclusions independently,” Dr. Rogers said. “We’ve been working on this study for about three-and-a-half years, and to see someone else on the other side of the globe asking the same questions, it let us know that we were all on the right path.”
This paper shows that the Plk4 protein promotes its own phosphorylation through homodimerization (the joining of two identical molecules). The only way it can promote its own destruction is to form this homodimer, and if that process is disrupted, then the protein levels run much higher than normal because the protein can no longer self destruct.
Dr. Rogers’ work studying chromosomal instability is among the centerpieces in the UACC’s “Phoenix Friends Project 2013-14.” His program, titled “Centrosome Surveillance in Cancer Progression: How stable are your chromosomes? The ‘CIN’ of cancer,” details how chromosomal instability is a hallmark of invasive cancers and how the discovery of early genetic markers and targets in aggressive cancers can lead to more precise, targeted tumor treatments.
In April, Dr. Rogers published a paper in the Journal of Cell Biology, highlighting his laboratory’s groundbreaking work in the field of chromosome territories. His paper, titled “SCFSlimb ubiquitin ligase suppresses condensin II–mediated nuclear reorganization by degrading Cap-H2,” finding that a mutation in the SCFSlimb gene caused cells to have too much condensin II activity, leading to cell instability and a distortion in the nuclear envelope — a set of circumstances that may leave a cell vulnerable to diseases such as Progeria (a rare genetic condition that produces rapid aging in children).
Dr. Rogers was previously featured in the Journal of Cell Biology with his article, titled “The Protein Phosphatase 2A regulatory subunit Twins stabilizes Plk4 to induce centriole amplification,” the first research paper that Dr. Rogers published since establishing his own lab at the Cancer Center more than four years ago. This paper helped Dr. Rogers land his first major grant in April 2012, courtesy of the National Science Foundation, to further his research on organelle biogenesis. The $660,000 grant will continue through 2016.
In 2009, Dr. Rogers published a manuscript, also in the Journal of Cell Biology, identifying the tumor suppressor serine/threonine kinase and PLK4 as a licensing factor that localizes to the mitotic centrioles and “primes” them to duplicate later during the cell cycle.
“Successful research is all about the questions you ask,” Dr. Rogers said. “Right now, I feel like our lab is asking the right questions, and we’re getting close to some big answers.”
-Nick Prevenas, Nov. 7, 2013