Studying the machinery of cell division
Lunenfeld post-doctoral researcher and recent TD Bank Fellowship winner Dr. Nicole St-Denis is taking a systems biology approach to uncover the phosphatases involved in mitosis.
In an intricate series of coordinated events, cell division is normally tightly regulated, in large part though temporary, reversible modification of proteins involved in the process. The temporary modification of proteins underlying cell division is achieved by two sets of enzymes— kinases and phosphatases—that work in tandem to ensure proper cell division.
“Much is known about the specific kinases important in the regulation of cell division, and several targeted cancer therapies have been developed to modulate these enzymes. However, very little is known about the phosphatases involved in the process,” says Dr. Nicole St-Denis, a post-doctoral researcher at the Samuel Lunenfeld Research Institute who studies in the labs of Lunenfeld scientists Drs. Anne-Claude Gingras and Laurence Pelletier.
The image at left shows a cell in mitosis: the blue is DNA, green is the mitotic spindle, and the red dots are centrosomes.
“Because phosphatases balance the activities of kinases, they may also represent viable targets for new cancer therapeutics.” Dr. St-Denis notes that many of the chemotherapeutic drugs used today target the process of cell division. However, because healthy cells also divide, these drugs have toxic side effects that impact the quality of life of cancer patients. To develop more specific drugs and eliminate unwanted side effects, it is crucial to understand the exquisite details of cell division in healthy cells, as well as how control of cell division is disrupted in cancer cells.
Dr. St-Denis, who began studying at the Lunenfeld in 2010 after completing a PhD in Biochemistry at the University of Western Ontario, was recently awarded a prestigious and highly competitive TD Bank Fellowship to support her research into phosphatase regulation of mitosis.
“Nicole’s recent Fellowship is a testament to her dedication and innovative initiatives in the lab,” says Dr. Gingras. “She also has a positive outlook that enables her to take on challenges and reach her goals.”
Speaking about her work, Dr. St-Denis says that “Human cells have over 150 distinct protein phosphatases, many with no known function. This is a tremendously exciting area of research since so much is left to be discovered. The Lunenfeld is a perfect location to perform this work as we have the tools and expertise required to fill in the blanks in our understanding of phosphatase function and regulation.”
Her project is aimed at systematically examining human phosphatase regulation of mitosis. The project involves both high-resolution microscopic analysis (in the Pelletier lab) and proteomics approaches (in the Gingras lab). To identify phosphatases important for mitotic progression, Dr. St-Denis is performing a two-step, high-throughput RNA interference (RNAi) screen of all human protein phosphatases—the largest high-resolution screen ever conducted at the Lunenfeld.
“Importantly, this screen will enable both cell cycle analysis and evaluation of the mitotic machinery upon phosphatase depletion, providing a global view of phosphatase signalling not only in mitosis, but throughout the cell cycle,” says Dr. St-Denis.
In parallel, Dr. St-Denis is cataloging the interaction partners of every human phosphatase by systematically performing affinity purification coupled to mass spectrometry for phosphatases throughout the cell cycle. She is expecting her work to produce an “atlas” of phosphatase interactions and provide key insights into the various cellular roles of human phosphatases, many of which remain uncharacterized.
“We believe this project will greatly expand our understanding of mitosis and potentially uncover new druggable targets for the treatment of cancer.”
“After an extensive search of institutes where I thought I could perform the types of studies critical to my work, I found that the Lunenfeld offered a rare combination of expertise, equipment, and resources, as well as a collaborative approach to research,” says Dr. St-Denis. “This project could be done at few other research centres worldwide, and I believe this is a testament to what researchers at Mount Sinai are capable of.”