Title

FRET-based Assay for Small Ubiquitin-like Modifier (SUMO)-specific Protease Inhibitors Screening

Authors

Ann Gregory

Document Type

Article

Publication Date

2009

Abstract

This summer I continued my project from last summer of screening for small ubiquitin-like modifier (SUMO)-specific protease inhibitors. Small ubiquitin-like modifier (SUMO) becomes covalently conjugated to target proteins in a process called sumoylation. Desumoylation involves removal of the SUMO-moiety from target proteins. In higher eukaryotes, there are three related SUMO: SUMO-1, -2 & -3. Sumoylation modifies the physical properties and the cellular functions of the target proteins. These modifications affect intracellular localization, protein-protein interactions, and other post-translational processes. These changes in turn affect gene expression, genomic and chromosomal stability and integrity, and signal transduction. In humans, sumo-specific proteases (SENPs) are necessary for the sumoylation-desumoylation cycle. SENP cleaves a peptide bond within the SUMO protein to active and prepare it for conjugation. In addition, SENP cleaves the SUMO-moiety from SUMO-modified target proteins to reverse the sumoylation process. There are seven known human SENPs. SENPs are cysteine proteases which share a common catalytic mechanism: using a nucleophilic cysteine thiol in a catalytic triad to cleave peptide bonds. In this study, we focused on SENP1 and SUMO-1. Recent research identified two links between SENP1 and cancer. One study showed that androgen receptor (AR) sumoylation is dynamic and reversed by SENP1 and that desumoylation promotes AR-dependent transcription in prostate cancer cells. Another study examining SENP1-/- mice embryos found that SENP1 regulates the stability of hypoxia-inducible factor 1α (HIF1α) during hypoxia. Thus, by finding inhibitors for SENP1 we may be able to modulate AR-dependent transcription in prostate cancer cells and/or regulate HIF1α stability, which is important in multiple solid tumors. This summer we screened 30,000 compounds.

Advisor

Dr. Richard Yip, City of Hope

Department

biochem

Support

Howard Hughes Medical Institute Undergraduate Science Education Grant



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