Proteasome inhibition in mammalian cells results in transcriptional upregulation of proteasome genes, thereby providing the cell with a homeostatic control mechanism to maintain proteasome levels. Preliminary studies indicated that this response was mediated by the transcription factor Nrf1 (also called Nfe2l1) and that knockdown of this factor sensitized cancer cells to proteasome inhibitor treatments. The overall goal of the current proposal is to further understand the mechanism behind this proteasome homeostatic pathway and to evaluate if inhibition of this pathway could be a viable anti-cancer strategy in vivo, especially when used in conjunction with proteasome inhibitors.
Specific Aims during the mentored phase are designed to understand the mechanism of Nrf1 activation following proteasome inhibition and to evaluate the utility of depleting Nrf1 in the treatment of mouse xenograft tumors with covalent proteasome inhibitors.
Specific Aims during the independent phase are designed to understand the role of p97/VCP and its co-factors in Nrf1 activation and to identify novel chemical inhibitors of the Nrf1-mediated proteasome recovery pathway. The proposed work has the potential to shed light on the functioning of the proteasome recovery pathway and also suggest strategies for the development of novel anti-cancer therapeutics that target the ubiquitin- proteasome system.

Public Health Relevance

Inhibition of protein degradation has recently emerged as an effective strategy against some forms of cancer. This proposal aims to further understand the mechanism by which the protein degradation machinery in the cells is induced. This knowledge can be useful in devising novel therapeutics that target this degradation machinery thereby expanding the repertoire of cancer types that can be treated.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Career Transition Award (K99)
Project #
5K99CA154884-02
Application #
8311632
Study Section
Subcommittee G - Education (NCI)
Program Officer
Schmidt, Michael K
Project Start
2011-08-03
Project End
2013-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
2
Fiscal Year
2012
Total Cost
$115,020
Indirect Cost
$8,520
Name
California Institute of Technology
Department
None
Type
Schools of Arts and Sciences
DUNS #
009584210
City
Pasadena
State
CA
Country
United States
Zip Code
91125