NSF ChemGen IGERT Program Associate Director
Mailing Address:Botany and Plant Sciences
Genomics Building /3119A
University of California
Riverside, CA 92521
Phone: (951) 827-6990
Fax: (951) 827-4437
Degree(s):PhD 2001 Stanford University
MS 1995 University of Toronto
BA 1991 University of Toronto
College/Division Affiliation:College of Natural and Agricultural Sciences
Center/Inst Affiliation(s):Center for Plant Cell Biology
Areas Of Expertise:Chemical Genomics; Analysis and Exploitation of Natural Variation Using Small Molecules
Awards / Honors:
2010 ScienceWatch Interview: Fast Breaking Papers 2010
2009 Top 10 Breakthrough List, Science
Canadian Research Chair in Plant Functional Genomics
Research in the Cutler lab is focused on two interrelated research interests– the use of chemical genetics to identify new factors that regulate Arabidopsis cell expansion and the analysis and exploitation of natural variation using small molecules. Both of these goals have been pursued in parallel using a collection of ~1000 small molecule cell expansion inhibitors that the lab identified in several small molecule screens for new inhibitors of etiolated hypocotyl cell expansion. To harness the power of natural variation, the lab's screens incorporated parallel assays that used multiple ecotypes and this demonstrated that variation in sensitivity to small molecules is pervasive between Arabidopsis isolates. This variation can be used to identify natural drug-resistance and drug-hypersensitivity alleles (Figure 1) and provided evidence for an unusual mechanism of pro-drug activation through glucosylation. This pathway uses enzymes that are homologous to human drug metabolism enzymes (UGTs) and thus showed that natural variation in the same enzyme families can create pharmacogenetic variation across biological kingdoms.
The lab’s efforts have recently focused on understanding the mechanism of action of a newly isolated agonist of the Abscisic Acid (ABA) signal transduction pathway named Pyrabactin (Figure 2). Pyrabactin was identified as a germination inhibitor in our original screen and a combination of genetic, transcriptomic and physiological evidence show that Pyrabactin activates the ABA pathway in a manner very similar to ABA and does not do so by increasing ABA biosynthesis. As such, Pyrabactin is the first ABA agonist that is not an ABA analog. In addition, Pyrabactin shows intriguing selectivity for the seed ABA signaling pathway; thus our characterization of Pyrabactin will provide new insight into the ABA signal trasnduction pathway and its developmental regulation.
Figure 1. Natural variation in drug sensitivity is mediated by the UDP-Glucosyltransferase HYR1. In the left panel, the difference in sensitivity between Columbia and Landsberg to the cell expansion inhibitor hypoststatin in shown. Our genetic and chemical analyses of hypostatin have shown that hypostatin is a pro-drug that is activated in vivo by HYR1 mediated glucosylation revealing an unusual case of pro-drug activation via glycosylation.
Figure 2. Pyrabactin: a small molecule agonist of the ABA signal transduction pathway. Shown are whole genome microarray profiles of ABA and Pyrabactin treated seeds. Plotted are log transformed data for any transcript showing a significant response to either ABA or Pyrabactin. The similar transcriptional responses (r = 0.91) )induced by ABA and Pyrabactin suggests that it activates the ABA signaling pathway, a conclusion that is additionally supported by genetic evidence .
Lab Personnel: +
- Alfred, Simon
- Junior Specialist — Chemical Genetic Polarized Cytokinesis Inhibitors; ER Morphology
- Li, Xiaofei
- Junior Specialist — Genetic-based Small Molecule Target Identification
- Park, Sang
- Assistant Specialist — Molecular Mechanism of Pyrabactin Action
- Defries, Andrew
- Graduate Student Researcher — Chemical Genetics