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Thermodynamic, Structural, and Functional Characterization of MINT: A Notch Signaling Corepressor

VanderWielen, Bradley D

Abstract Details

2013, PhD, University of Cincinnati, Medicine: Molecular Genetics, Biochemistry, and Microbiology.
The Notch pathway is a cell-to-cell signaling mechanism conserved in multicellular organisms that plays a vital role in cellular development, differentiation and homeostasis. Biological and experimental evidence has shown that improper regulation leads to disease states such as kidney disease, stroke, and cancer. A properly regulated Notch signal effects transcriptional regulation of target genes through coregulator interactions with the nuclear effector CSL (CBF-1, Su(H), Lag-1). CSL functions as an activator when the intracellular domain of Notch is bound; however, in the absence of Notch, corepressors that mediate transcriptional repression bind CSL. This opposing regulatory role of the nuclear effector underscores the importance of understanding the molecular details of the protein-protein interactions that mediate both activation and repression. The work described in the following chapters characterizes the molecular details of CSL interacting with the corepressor MINT. Chapter 1 reviews Notch signaling. In Chapter 2, the quantified thermodynamic details of the MINT:CSL interaction is described. Based on these findings we determine the minimum binding constructs of MINT required to bind to CSL as well as the domains of CSL required to bind to MINT. In Chapter 3, the X-ray crystallographic structure of MINT bound to CSL is determined. Here I use mutational studies to validate the structure. In Chapter 4, I summarize the work presented here on the MINT:CSL interaction and postulate about further experiments to fully delineate the molecular mechanisms of Notch signaling transcriptional regulation.
Rhett Kovall, Ph.D. (Committee Chair)
Gary Dean, Ph.D. (Committee Member)
Andrew Herr, Ph.D. (Committee Member)
Thomas Thompson, Ph.D. (Committee Member)
Pearl Tsang, Ph.D. (Committee Member)
246 p.

Recommended Citations

Citations

  • VanderWielen, B. D. (2013). Thermodynamic, Structural, and Functional Characterization of MINT: A Notch Signaling Corepressor [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1377868739

    APA Style (7th edition)

  • VanderWielen, Bradley. Thermodynamic, Structural, and Functional Characterization of MINT: A Notch Signaling Corepressor. 2013. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1377868739.

    MLA Style (8th edition)

  • VanderWielen, Bradley. "Thermodynamic, Structural, and Functional Characterization of MINT: A Notch Signaling Corepressor." Doctoral dissertation, University of Cincinnati, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1377868739

    Chicago Manual of Style (17th edition)