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C-rel deficiency and its effect on proliferation and survival in immunodeficient lymphoblastic B cells
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Valentin Acevedo, Anibal J.. C-rel deficiency and its effect on proliferation and survival in immunodeficient lymphoblastic B cells. Retrieved from https://doi.org/doi:10.7282/T3348JP1

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TitleC-rel deficiency and its effect on proliferation and survival in immunodeficient lymphoblastic B cells
NameValentin Acevedo, Anibal J. (author); Covey, Lori (chair); Werlen, Guy (internal member); Jacinto, Estela (internal member); Gelinas, Celine (outside member); Rutgers University; Graduate School - New Brunswick
Date Created2011
Other Date2011-05 (degree)
SubjectCell and Developmental Biology, Lymphocytes—Research, Immunodeficiency, Immunological deficiency syndromes, B cells--Research
Extentxi, 144 p. : ill.
DescriptionThe analysis of lymphocytes from immunodeficient patients has provided valuable insights into understanding the development and function of the immune system. In particular, studies of patients with Hyper IgM syndrome, a rare immunodeficiency resulting from defects in both CD40L in activated CD4+ T cells and components of the CD40 signaling pathway in B cells have been crucial for the elucidation of molecular pathways involved in the activation, proliferation and differentiation of B lymphocytes. Previously our lab generated EBV transformed lymphoblastic cells with inducible LMP1 from a female patient diagnosed with non-X-linked HIGM (Pt1-LCLtet cells, Pt1). Analysis of these cells revealed a CD40-specific activation defect associated with low c-Rel levels. To broaden our understanding of the Pt1 phenotype we analyzed c-Rel expression and found that low c-Rel levels were the outcome of depressed transcriptional activation of the c-rel promoter. In-vivo analysis revealed that low transcription was coincident with increased p65 activity at the c-rel promoter although this was insufficient to induce normal c-Rel expression. Further investigations of the Pt1-LCLtet cells uncovered a proliferation and survival defect characterized by reduced c-Myc transcription and increased levels of caspase-4. This defect was complemented after c-Rel overexpression, supporting a causative role for c-Rel deficiency in the observed phenotype of the Pt1-LCLtet cells. The LCLtet cells were further utilized as a model system for the independent analysis of LMP1 and CD40 signaling. These studies revealed several outcomes of LMP1 signaling in the biology and function of CD40. Specifically, LMP1 signaling induced a unique pattern of CD40 phosphorylation as well as the expression of several novel CD40 isoforms. Moreover, when CD40 and LMP1 were activated simultaneously a synergistic effect was observed towards p65 and p38 phosphorylation suggesting a functional interaction that might occur during early stages of EBV infection or malignant transformation where both LMP1 and CD40 are co-expressed in the infected cell. Collectively, our results demonstrate that a majority of the defects displayed in the Pt1-LCLtet cells are a result of reduced c-Rel expression. Importantly, these results ascribe c-Rel a novel function as a negative regulator of caspase-4 expression and a putative key player in the control of cell survival in EBV-immortalized B cells.
NotePh.D.
NoteIncludes bibliographical references
Noteby Anibal J. Valentin Acevedo
Genretheses, ETD doctoral
Persistent URLhttps://doi.org/doi:10.7282/T3348JP1
Languageeng
CollectionGraduate School - New Brunswick Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.
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