Abstract/Details

Mechanisms of Ret/PTC 3-induced pro-inflammatory signaling


2011 2011

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Abstract (summary)

The close association between cancer and chronic inflammation has been noted clinically for many years. To address the mechanism underlying this association we investigated the role of Ret/PTC 3 (RP3) in promoting inflammation. In fact, RET/PTC’s, have been found in both Hashimoto’s thyroiditis and in the differentiated thyroid malignancy, papillary thyroid carcinoma (PTC’s). While, earlier studies have shown that RP3 can activate classical NF-κB, there are several lines of evidence that suggest the RET/PTC’s could activate the non-canonical NF-κB pathway as well. Despite the accumulated evidence, the precise mechanism of NF-κB activation by RP3 remains unknown. Therefore, we hypothesized that RP3 induces inflammation by activating both the classical and non-canonical NF-κB pathways. To address this mechanism, we took two different approaches. The first approach was to make an inducible mouse model, while the second approach was to examine the molecular signaling events that lead to NF-κB activation by expressing RP3 in mouse embryonic fibroblasts lacking key components of the classical and noncanonical NF-κB pathways. What we have shown is that RP3 activates a novel signaling pathway that involved the stabilization of NIK protein levels that signal downstream through IKKα and NEMO to activate classical NF-κB. This new signaling paradigm for RP3 can then be looked at in the physiologically relevant disease models. This information is critical in understanding the pathogenesis of these diseases and future therapeutic developments.

Indexing (details)


Subject
Immunology;
Oncology
Classification
0982: Immunology
0992: Oncology
Identifier / keyword
Health and environmental sciences; Hashimoto's thyroiditis; Nfkb; Nik; Papillary thyroid carcinoma; Pro-inflammatory signaling; Ret/ptc
Title
Mechanisms of Ret/PTC 3-induced pro-inflammatory signaling
Author
Neely, Robert John
Number of pages
137
Publication year
2011
Degree date
2011
School code
0272
Source
DAI-B 72/09, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
ISBN
9781124728810
Advisor
May, Michael; Rothstein, Jay
Committee member
Eisenlohr, Laurence; Manser, Timothy; Zhang, Jianke
University/institution
Thomas Jefferson University
Department
Immunology and Microbial Pathogenesis
University location
United States -- Pennsylvania
Degree
Ph.D.
Source type
Dissertations & Theses
Language
English
Document type
Dissertation/Thesis
Dissertation/thesis number
3460698
ProQuest document ID
879043030
Copyright
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
http://search.proquest.com/docview/879043030
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