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Characterization of CSL Complexes in the Notch Pathway: the Su(H)-NICD Interaction and the RBP-J-DNA Interaction

Contreras, Ashley N.
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1416231352

Abstract Details

2014, PhD, University of Cincinnati, Medicine: Molecular Genetics, Biochemistry, and Microbiology.
In metazoans, the Notch pathway is a conserved cell-to-cell signaling mechanism that plays a key role in cellular specification. It is essential for cell fate determination in embryonic development, organogenesis, hematopoiesis, and adult tissue homeostasis. Aberrant Notch signaling has been implicated in various cancers, developmental defects, and cardiovascular disease. Despite these various roles, Notch signaling is relatively simple; extracellular ligand-receptor binding triggers proteolytic processing of the Notch receptor. The newly generated receptor fragment, the Notch intracellular domain (NICD), translocates to the nucleus and interacts with the DNA-binding protein CSL (CBF1/RBPJ in mammals; Suppressor of Hairless [Su(H)] in flies; Lag-1 in worms), to ultimately activate transcription of Notch responsive genes. In the absence of pathway activation, however, CSL also represses transcription of these genes. The ability of CSL to differentially regulate gene expression is determined by its interaction with co-regulators (co-activators or co-repressors). The research described in the following chapters characterizes the molecular details of two different interactions of CSL—the Su(H)-NICD interaction and the RBP-J-DNA interaction. Chapter 1 reviews Notch signaling. In Chapter 2, the thermodynamic details of the Su(H)-NICD interaction are explained, revealing a domain-domain interaction novel to the complex in Drosophila. The interaction between RBP-J and different sequences of DNA is quantified in Chapter 3, which demonstrates variations to the CSL binding sequence can positively or negatively affect the binding affinity of CSL. In Chapter 4, the work presented here is summarized and additional studies are proposed to further elucidate the molecular mechanisms of the complexes regulating expression of Notch target genes.
Rhett Kovall, Ph.D. (Committee Chair)
Gary Dean, Ph.D. (Committee Member)
Brian Gebelein, Ph.D. (Committee Member)
Andrew Herr, Ph.D. (Committee Member)
William Miller, Ph.D. (Committee Member)
185 p.
Biology
CSL; Notch; NICD; DNA; Ankyrin; Drosophila

Recommended Citations

Citations

  • Contreras, A. N. (2014). Characterization of CSL Complexes in the Notch Pathway: the Su(H)-NICD Interaction and the RBP-J-DNA Interaction [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1416231352

    APA Style (7th edition)

  • Contreras, Ashley. Characterization of CSL Complexes in the Notch Pathway: the Su(H)-NICD Interaction and the RBP-J-DNA Interaction. 2014. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1416231352.

    MLA Style (8th edition)

  • Contreras, Ashley. "Characterization of CSL Complexes in the Notch Pathway: the Su(H)-NICD Interaction and the RBP-J-DNA Interaction." Doctoral dissertation, University of Cincinnati, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1416231352

    Chicago Manual of Style (17th edition)

ucin1416231352
731
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This open access ETD is published by University of Cincinnati and OhioLINK.