Rapid changes in cell physiology during cell cycle transitions or in response to changes in external conditions are often mediated by the degradation of regulatory molecules. These changes are typically directed by the modification of protein targets with chains of the small protein ubiquitin. Ubiquitinization is carried out by a series of three enzymes, sometimes referred to as E1, E2 and E3, which function in tandem to transfer ubiquitin to a substrate. Substrate specificity is usually mediated by the E3 complex, also called an ubiquitin ligase. The SCF and the APC represent two highly conserved multi-subunit ubiquitin ligases important for both cell cycle progression and the regulation of many aspects of cellular physiology. We will examine mechanisms of APC regulation, and also identify the substrates other ubiquitin ligases using a biochemical technique that we have recently developed. Finally, we will explore the turnover of one ubiquitin ligase substrate, a G1 cyclin, in greater detail.

Public Health Relevance

Cancer is the result of uncontrolled cell division. In this proposal, we outline experiments that characterize proteins responsible for the regulation of cell division. In doing this, we can better understand how cancers arise and the characteristics of tumors that can be used to selectively target them.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM070539-10
Application #
8510654
Study Section
Cellular Signaling and Regulatory Systems Study Section (CSRS)
Program Officer
Hamlet, Michelle R
Project Start
2004-06-01
Project End
2016-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
10
Fiscal Year
2013
Total Cost
$325,933
Indirect Cost
$114,308
Name
University of California San Francisco
Department
None
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Mark, Kevin G; Simonetta, Marco; Maiolica, Alessio et al. (2014) Ubiquitin ligase trapping identifies an SCF(Saf1) pathway targeting unprocessed vacuolar/lysosomal proteins. Mol Cell 53:148-61
Benanti, Jennifer A; Matyskiela, Mary E; Morgan, David O et al. (2009) Functionally distinct isoforms of Cik1 are differentially regulated by APC/C-mediated proteolysis. Mol Cell 33:581-90
Benanti, Jennifer A; Toczyski, David P (2008) Cdc20, an activator at last. Mol Cell 32:460-1
Vega, Leticia R; Phillips, Jane A; Thornton, Brian R et al. (2007) Sensitivity of yeast strains with long G-tails to levels of telomere-bound telomerase. PLoS Genet 3:e105