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You searched for +publisher:"University of North Carolina" +contributor:("Mulvaney, Kathleen"). One record found.

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University of North Carolina

1. Mulvaney, Kathleen. PROTEOMIC DISSECTION OF KEAP1/NRF2 SIGNALING TO DETERMINE NEW PATHWAY INTERACTORS IN CANCER.

Degree: Cell Biology and Physiology, 2016, University of North Carolina

KEAP1/NRF2 signaling regulates intracellular reactive oxygen species and protects cells from reactive oxygen-induced damage. KEAP1 serves as the substrate adaptor for a CULLIN3-based E3 ubiquitin ligase (KEAP1-CUL3-RBX1). Under homeostatic conditions, the KEAP1-CUL3-RBX1 ligase targets its well-established substrate NFE2L2/NRF2 for rapid proteasomal degradation. During oxidative stress conditions, KEAP1 is inactivated, and NRF2 protein levels increase. NRF2 then drives the transcription of a battery of cytoprotective genes that ultimately mitigate the cellular stress that was sensed by KEAP1. This elegant signaling pathway has long been thought to be the primary function of the redox-sensitive KEAP1 E3 ligase complex. KEAP1/NRF2 signaling is the cell’s primary defense against reactive oxygen stress. Therefore, perturbations in this pathway are associated with a number of human pathologies, including cancer. The KEAP1/NRF2 pathway is frequently mutated in cancer, where NRF2-activating mutations correlate with disease progression and poor patient outcomes. In addition to somatic gene mutations in KEAP1, NRF2 or CUL3, we have demonstrated that NRF2 is activated at the protein level in tumors by a competitive binding method, underscoring the importance of understanding the protein-protein interactions within this pathway. Utilizing mass spectrometry-based approaches, we identified the KEAP1 protein interaction network under basal and proteasome-inhibited conditions. Coupling this screening with a candidate-based approach, MCM3 and NRF1 were identified as putative, novel KEAP1-CUL3-RBX1 substrates for ubiquitylation. MCM3, a subunit of the essential DNA replicative helicase, was validated as a KEAP1-CUL3-RBX1 substrate for ubiquitylation. We have characterized the binding and ubiquitylation of MCM3 by KEAP1 and determined that KEAP1 does not regulate MCM3 protein stability. Rather, we propose a model where KEAP1 ubiquitylates MCM3 to regulate its function within the replicative helicase. We demonstrate that KEAP1 associates with chromatin in a cell cycle-dependent fashion with kinetics similar to MCM3 and is thus poised to affect MCM3 function. We also demonstrate that loss of KEAP1 affects cell cycle progression and proliferation in normal cells. Therefore, we have found previously unappreciated roles for KEAP1 in cell cycle progression and chromatin dynamics. Advisors/Committee Members: Mulvaney, Kathleen, Major, Michael, Cook, Jean, Cyr, Douglas, Vaziri, Cyrus, Baldwin, Albert, Mulvaney, Michael.

Subjects/Keywords: School of Medicine; Department of Cell Biology and Physiology

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APA (6th Edition):

Mulvaney, K. (2016). PROTEOMIC DISSECTION OF KEAP1/NRF2 SIGNALING TO DETERMINE NEW PATHWAY INTERACTORS IN CANCER. (Thesis). University of North Carolina. Retrieved from https://cdr.lib.unc.edu/record/uuid:6a38b6e9-c9a6-4280-9816-da904d71b6d0

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16th Edition):

Mulvaney, Kathleen. “PROTEOMIC DISSECTION OF KEAP1/NRF2 SIGNALING TO DETERMINE NEW PATHWAY INTERACTORS IN CANCER.” 2016. Thesis, University of North Carolina. Accessed September 26, 2020. https://cdr.lib.unc.edu/record/uuid:6a38b6e9-c9a6-4280-9816-da904d71b6d0.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7th Edition):

Mulvaney, Kathleen. “PROTEOMIC DISSECTION OF KEAP1/NRF2 SIGNALING TO DETERMINE NEW PATHWAY INTERACTORS IN CANCER.” 2016. Web. 26 Sep 2020.

Vancouver:

Mulvaney K. PROTEOMIC DISSECTION OF KEAP1/NRF2 SIGNALING TO DETERMINE NEW PATHWAY INTERACTORS IN CANCER. [Internet] [Thesis]. University of North Carolina; 2016. [cited 2020 Sep 26]. Available from: https://cdr.lib.unc.edu/record/uuid:6a38b6e9-c9a6-4280-9816-da904d71b6d0.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Mulvaney K. PROTEOMIC DISSECTION OF KEAP1/NRF2 SIGNALING TO DETERMINE NEW PATHWAY INTERACTORS IN CANCER. [Thesis]. University of North Carolina; 2016. Available from: https://cdr.lib.unc.edu/record/uuid:6a38b6e9-c9a6-4280-9816-da904d71b6d0

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

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