UCSF

Daniel Gray receives Krevans Award for Outstanding Dissertation

Daniel Gray, PhD, is the recipient of the 2011 Julius R. and Patricia A. Krevans Distinguished Dissertation Award. The award, which honors the most outstanding doctoral dissertation by graduate department nominees who completed their PhDs at UCSF during the past year, is named for UCSF Chancellor Emeritus Krevans and his wife, and comes with a cash prize.

Gray recently earned his doctorate from UCSF’s Chemistry and Chemical Biology (CCB) graduate program. He did his award-winning research in the lab of Professor James Wells, PhD, chair of the UCSF School of Pharmacy’s Department of Pharmaceutical Chemistry, which is the administrative home to the CCB graduate program.

Gray’s thesis focused on annotating the distinct roles played by specific caspases—a family of protease enzymes (enzymes that cleave proteins and enzymes) vital to the normal cellular self-demolition known as apoptosis, which fails to occur in cancers or occurs too much in inflammation and neurodegenerative diseases.

Parsing the “executioners”

In particular, Gray was able to parse the roles played by caspase-3, -6, and -7—known as “executioners” for being the final transformative players in the apoptotic cascade. Normally, yet another subset of caspases activates the inert pro-enzyme forms of these three executioners.

Gray developed a way to activate each caspase isoform in a precisely controlled manner. He used a protease from a tobacco etch virus (TEV) that’s inactivated when split in two and altered it so that the two halves could only re-combine when he added another small molecule—the drug rapamycin. Then he replaced each caspase isoform’s cleavage site with TEV target sites.

In a 2010 paper published in Cell, which was co-authored with Wells and postdoctoral fellow Sami Mahrus, PhD, Gray showed that activation of either casapse-3 or -7 alone was sufficient to induce cell apoptosis but not caspase-6.

Caspases vs. proteasomes

The same paper also proposed “a model of proteolytic reciprocal negative regulation” —in other words, while the cell-demolishing caspases are themselves broken down by proteasomes (protein complexes that act like shredders of unwanted proteins inside cells), the caspases, in turn, cleave and break 0down the proteasomes.

This explains how caspases’ demolition work can be turned off during non-apoptotic bursts of “remodeling” in cellular differentiation. It also predicts that drugs that activate the caspases—to induce apoptosis in cancer treatment—will synergize with proteasome inhibitor meds.

In his letter nominating Gray for the Krevans Award, Wells noted that the ability to selectively cleave any protein in the cell using the technology Gray developed—which is dubbed SNIPer for Single Nick in Proteome—has launched a half-dozen new projects in his lab as well as several with other collaborators at UCSF. Also, SNIPer reagents have already been sent out to more than 25 labs outside the university.

Gray, who was also named the top CCB teaching assistant in his year, plans to pursue a career in the biotechnology industry.


About the School: The UCSF School of Pharmacy is a premier graduate-level academic organization dedicated to improving health through precise therapeutics. It succeeds through innovative research, by educating PharmD health professional and PhD science students, and by caring for the therapeutics needs of patients while exploring innovative new models of patient care. The School was founded in 1872 as the first pharmacy school in the American West. It is an integral part of UC San Francisco, a leading university dedicated to promoting health worldwide.