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Dissecting the Roles of the Non-canonical NF-kB signaling in the Pathogenesis of Lymphoma and Autoimmunity

Wang, Zhe
http://rave.ohiolink.edu/etdc/view?acc_num=mco1207681135

Abstract Details

2008, Doctor of Philosophy in Medical Sciences (Ph.D.), University of Toledo, College of Graduate Studies.
NF-κB2 (p52 and its precursor p100) is a member of the Rel/NF-κB family of transcription factors. The NF-κB2 gene is recurrently mutated in human lymphoid malignancies including both B cell and T cell lymphomas. The mechanism by which how these mutations lead to lymphomagenesis has not been unveiled. Using NF-κB2 deficient mice, we revealed that the loss of NF-κB2 p100 is not lymphomagenic, instead itpredisposes mice to autoimmunity. Furthermore, we demonstrated that the NF-κB2 defecient mice have a defect in the development/maintenance of UEA-1+ mTECs, the main cell population expressing a wide variety of peripheral tissue-restricted antigens essential for induction of self-tolerance in thymus. The impaired development of UEA-1+ mTECs and the resulting breakdown in self-tolerance are probably the cause for the autoimmunity in these mice. We generated transgenic mice expressing an NF-κB2 mutant p80HT. We demonstrated that these mice develop malignant lymphomas mainly of B cell origin, we also found that p80HT promote lymphoma development primarily through a TRAF1-dependent antiapoptotic pathway. These findings provide direct evidence that the NF-κB2 mutation is oncogenic in vivo. It is well known that NF-κB2 mutants manifest constitutive processing to p52, and the constitutive production of p52 has been suggested as a major mechanism for lymphomagenesis induced by mutations of the NF-κB2 gene. To test this hypothesis, we generated transgenic mice expressing p52 using the same strategy as for p80HT mice. p52 transgenic mice do not develop lymphoma, instead they display autoimmunity characterized by multi-organ infiltration of activated lymphocytes, high levels of autoantibodies in the serum, and immune-complex glomerulonephritis. Mechanistically, p52 represses Bim expression, leading to defects in apoptotic processes critical for elimination of autoreactive lymphocytes and control of immune response. In summary, these studies provide in vivo evidence for a gain of oncogenic activity for NF-κB2 mutants and indicate that fine-tuning the alternative NF-κB signaling is required for control of autoimmunity.
Han-Fei Ding, MD, PhD (Committee Chair)
William Maltese, PhD (Committee Member)
Z. Kevin Pan, MD, PhD (Committee Member)
James Trempe, PhD (Committee Member)
Sonia Najjar, PhD (Committee Member)
183 p.
Cellular Biology; Molecular Biology
NF-kB; Apoptosis; Lymphoma; Autoimmunity

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Citations

  • Wang, Z. (2008). Dissecting the Roles of the Non-canonical NF-kB signaling in the Pathogenesis of Lymphoma and Autoimmunity [Doctoral dissertation, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=mco1207681135

    APA Style (7th edition)

  • Wang, Zhe. Dissecting the Roles of the Non-canonical NF-kB signaling in the Pathogenesis of Lymphoma and Autoimmunity. 2008. University of Toledo, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=mco1207681135.

    MLA Style (8th edition)

  • Wang, Zhe. "Dissecting the Roles of the Non-canonical NF-kB signaling in the Pathogenesis of Lymphoma and Autoimmunity." Doctoral dissertation, University of Toledo, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=mco1207681135

    Chicago Manual of Style (17th edition)

mco1207681135
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© 2008, all rights reserved.
This open access ETD is published by University of Toledo Health Science Campus and OhioLINK.