| RESEARCH SUMMARY:
The 26S proteasome is a highly conserved ATP-dependent protease
that has a central role in the control of protein stability
in all eukaryotic organisms. Among the key biological processes
that are controlled by the 26S proteasome are the cell division
cycle, cell growth and differentiation, signal transduction,
gene expression, DNA repair, stress and immunological responses,
and function of the nervous system (circadian rhythms and
acquisition of memory). Perturbations of the 26S proteasome-dependent
protein degradation pathway are implicated in the pathogenesis
of cancer, senescence, viral infection, and major neurodegenerative
diseases.
My lab is broadly interested in understanding the molecular
mechanism by which the 26S proteasome recruits substrates
and initiates their destruction. We currently address this
goal by biochemical dissection of protein ubiquitination and
degradation in vitro, using purified substrates and components
of the SCF ubiquitination pathway of yeast S. cerevisiae (Skowyra
et al. 1997, Skowyra et al. 1999). This pathway is conserved
and controls degradation of major G1 cell cycle regulatory
proteins and signaling molecules in all organisms, from yeast
to humans. The knowledge obtained with yeast is therefore
directly relevant to the understanding of SCF-mediated proteolysis
in human cells. In our studies, we seek to uncover features
of the proteasome that could serve as targets for pharmacological
regulation of its activity at the steps of substrate recognition
and its processing for degradation, but not the degradation
itself. This knowledge may be of a considerable significance
for development of novel strategies for targeting the proteasome
in cancer and other diseases linked to abnormal protein degradation.
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