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Dr. William Crosby
2015 Progress Report (2014 Grant)

Posted on: January 19th, 2016
Dr. William Crosby

Dr. William Crosby

Dr. William Crosby

Department of Biological Sciences, University of Windsor

Systematic profiling of SCF E3 ligase regulatory attributes at play in cell cycle control and cancer

>Click for Project Overview

Co-Investigators and Collaborators:

  • Dr. Panayiotis Vacratsis, Department of Chemistry and Biochemistry, University of Windsor
  • Dr. Wade Harper, Department of Cell Biology, Harvard Medical School
  • Dr. Frank Sicheri, Lunenfeld-Tanenbaum, Research Institute, University of Toronto
  • Dr. Brian Raught, Ontario Cancer Institute; University of Toronto
  • EVIDENCE OF PROGRESS

    Proteins act as the building blocks of the cellular machinery thus playing an essential role in a wide array of the cellular processes including regulation of cellular division as an important feature of human cancers. Functional regulation of these proteins over time is vital to ensure the proper functioning of cells. This regulation is governed in part by the regulated but competing processes of protein production and destruction. Since the destruction of proteins in cells is strongly directed via the ubiquitin-proteasome system (UPS) machinery, it is no surprise that defects in genes encoding the UPS machinery components haven been widely implicated in the development of several human cancers including breast, cervical, colon, renal, and prostate, as well as other developmental defects.

    As components of the cellular UPS machinery, SCF complexes are responsible for targeting about about 20% of all proteins destined for controlled degradation, including onco-proteins and tumor suppressors. Aberrant regulation of SCF complexes is associated with the development of human cancers and other diseases, and as such, have become an established therapeutic target for treatment of cancer. In order to identify drug candidates with enhanced efficacy and reduced cytotoxicity, we need a better understanding of the regulatory mechanisms governing the activity of the UPS machinery in general, and SCF complexes in particular, as it relates to human cancer.

    In collaboration with labs at Harvard University and the University of Toronto, we have recently discovered that one of the main components of the SCF complex, Skp1, is heavily modified in human cells. We have shown that Skp1 modification plays a significant role in the regulation of SCF assembly and activity and the interplay between SCF and other UPS members. As a key regulator of the UPS, Skp1 not only governs accumulation and degradation of cell cycle regulators, but may also serve structural roles during in the regulation of chromosome instability – an important cellular feature of cancerous cells. We are investigating this novel functional role of Skp1 and its contribution to tumorigenesis. We anticipate that this study will shed new light on how protein abundance is ultimately regulated, thus offering novel therapeutic targets and approaches for the regulation of cell division and DNA repair as key processes in the development of human malignancies.

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