Date of Award
5-2010
Document type
dissertation
Access Type
Open Access Dissertation
Degree Name
Doctor of Philosophy (PhD)
Degree Program
Molecular and Cellular Biology
First Advisor
Barbara A. Osborne
Second Advisor
Juan Anguita
Third Advisor
Lisa Minter
Subject Categories
Cell Biology
Abstract
It is widely accepted that activating mutations of genes encoding the Notch family of transmembrane receptors, specifically Notch1, are associated with oncogenic transformation. Previous data from our lab has shown that an active form of Notch1 (NICD) provides protection against apoptosis in D011.10 T cells; and that this effect may be attributed to NICD binding the pro-apoptotic protein Nur77. Nur77 is an immediate early gene that is upregulated during both negative selection of thymocytes and activation-induced apoptosis in D011.10 T cells. Nur77 upregulation is tightly regulated and requires MEF2D, NFAT, and the transcriptional co-activator, p300, to effectively respond to apoptotic stimuli. Here, we show that NICD has the ability to interfere with the transcription of Nur77, and that this interference is directly related to the inability of p300 to bind the Nur77 promoter in the presence of NICD. We also show that blocking Notch activation, through inhibition of gamma secretase or shRNA directed against Notch1, in T cell acute lymphoblastic leukemia (T-ALL) cell lines restores Nur77 expression in response to apoptotic stimuli. These observations support a mechanism by which NICD over-expression can suppress the activation of a known pro-apoptotic molecule, and further suggests this mechanism may operate in T-ALL.
DOI
https://doi.org/10.7275/1557265
Recommended Citation
Rud, Jonathan George, "Notch 1 Mediated Inhibition of Nur77-induced apoptosis: Implications for T-cell Leukemia" (2010). Open Access Dissertations. 253.
https://doi.org/10.7275/1557265
https://scholarworks.umass.edu/open_access_dissertations/253