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Doctor of Philosophy (PhD)
Molecular and Cellular Biology
Year Degree Awarded
Dr. Barbara A. Osborne
Cleavage of the Notch receptor via a γ-secretase, results in the release of the active intra-cellular domain of Notch that migrates to the nucleus and interacts with RBP-JΚ, resulting in the activation of downstream target genes. This canonical Notch signaling pathway has been documented to influence T-cell development and function. However, the mechanistic details underlying this process remain obscure. In addition to RBP-JΚ, the intra-cellular domain of Notch also interacts with other proteins in the cytoplasm and nucleus, giving rise to the possibility of an alternate, RBP-JΚ independent Notch pathway. However, the contribution of such RBP-JΚ independent, “non-canonical” Notch signaling in regulating peripheral T-cell responses is unknown. We specifically demonstrate the requirement of Notch1 for regulating signal strength and signaling events distal to the T-cell receptor in peripheral CD4+ T cells. By using mice with a conditional deletion in Notch1 or RBP-JΚ, we show that Notch1 regulates activation and proliferation of CD4+ T cells independently of RBP-JΚ. Furthermore, differentiation towards TH1 and iTreg lineages is also Notch dependent but RBP-JΚ independent. Our data provide evidence that non-canonical regulation of these processes likely occurs through NF-ΚB. Additionally, we also provide evidence suggestive of cross-talk between Notch and the mTOR pathway. Notch1, but not RBP-JΚ, is required for phosphorylation of several substrates directly downstream of mTORC2. Collectively, these striking observations demonstrate that many of the cell intrinsic functions of Notch occur independently of RBP-JΚ. This reveals a previously unknown, novel role of non-canonical Notch signaling in regulating peripheral T-cell responses.
Dongre, Anushka, "NON-CANONICAL NOTCH SIGNALING REGULATES ACTIVATION AND DIFFERENTIATION OF PERIPHERAL CD4+ T CELLS" (2014). Doctoral Dissertations. 74.