Dissertation/Thesis Abstract

Molecular regulation of inflammation by the proteasome
by Cullen, Sarah, Ph.D., University of Arkansas for Medical Sciences, 2009, 230; 3392182
Abstract (Summary)

Proteasome inhibition has become synonymous with inhibition of NF-κB activity. However, hyperactive NF-κB responses accompany physiological conditions in which proteasomal function is compromised, i.e. advancing age, geriatric diseases, and bortezomib resistance. These paradoxical NF-κB responses are likely to be impervious to proteasomal defects because they stem from atypical NF-κB signaling induced by proteasome-independent mechanisms. Associated with redox stimuli and various growth factors, this atypical pathway does not require proteasome for NF-κB nuclear translocation; however, a potential role for proteasome in nuclear signaling remains unexplored. We now demonstrate that proteasome stringently controls transcription of inflammatory mediators regulated by this atypical NF-κB pathway. Proteolytic activity of the proteasome mediates the removal of the NF-κB subunit, p65/RelA, from inflammatory genes, thereby terminating atypical NF-κB-dependent transcriptional responses. Since proteasome inhibition results in sustained transcription of particular inflammatory genes, this implies that such exaggerated transcription results from prolonged nuclear NF-κB activity and persistently remodeled chromatin. In accordance with our hypothesis, proteasome inhibits persistent nucleosome remodeling activity by the SWI/SNF class of ATP-dependent remodeling complex. In summary, proteasome targets promoter-associated subunits of both NF-κB and the SWI/SNF complexes to terminate their activities. Thus, an inability to down-regulate NF-κB activity induced by proteasome-independent mechanisms may contribute to the hyperactive NF-κB responses accompanying physiological conditions characterized by proteasomal defects, i.e. advancing age, geriatric diseases, and bortezomib resistance.

Indexing (document details)
Advisor: Ponnappan, Usha
Commitee:
School: University of Arkansas for Medical Sciences
School Location: United States -- Arkansas
Source: DAI-B 71/01, Dissertation Abstracts International
Source Type: DISSERTATION
Subjects: Immunology
Keywords: Inflammation, Molecular regulation, NF-kappaB, Proteasome
Publication Number: 3392182
ISBN: 9781109579796
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