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Identification of a Nuclear Localization Sequence in Beta-Arrestin1:Implications in NF- kB Activation

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Title: Identification of a Nuclear Localization Sequence in Beta-Arrestin1:Implications in NF- kB Activation
Author(s): Hoeppner, Crystal Z.
Advisor(s): Ye, Richard D.
Contributor(s): Skidgel, Randal A.; Christman, John W.; O'Bryan, John P.; Colamonici, Oscar
Department / Program: Pharmacology
Graduate Major: Pharmacology
Degree Granting Institution: University of Illinois at Chicago
Degree: PhD, Doctor of Philosophy
Genre: Doctoral
Subject(s): G Protein-Coupled Receptors Transcription Beta-Arrestin Nuclear Localization
Abstract: A mounting body of evidence suggests that beta-arrestin1 plays important roles in the nucleus, but how beta-arrestin1 enters the nucleus remains unclear since no nuclear import signal has been identified in the -arrestins. We sought to characterize the cellular localization of wild type beta-arrestin1 and a series of N domain mutants to determine the structural basis and functional implications of beta-arrestin1 nuclear localization. A seven-residue candidate nuclear localization sequence (NLS) was identified based on sequence analysis. Mutation of the NLS led to a loss of beta-arrestin1 nuclear localization in transfected cells. Exogenous expression of wild type beta-arrestin1 enhanced the transcriptional activity of nuclear factor kappaB (NF-kappaB) induced by bradykinin, while mutation of the NLS reduced this effect by two thirds relative to wild type controls. Loss of beta-arrestin1 nuclear localization was accompanied by reduced recruitment of the CREB binding protein and altered post-translational modification profile of p65/RelA. Further mutational analysis identified Lys157 within the putative NLS as being critical to nuclear localization of beta-arrestin1. Substitution of Lys157 to Ala led to reduced nuclear localization, decreased promoter binding by p65/RelA and decreased IL-1beta gene transcription. These results demonstrate a critical role for beta-arrestin1 nuclear localization in scaffolding and transcriptional regulation.
Issue Date: 2012-12-10
Genre: thesis
Rights Information: Copyright 2012 Crystal Z. Hoeppner
Date Available in INDIGO: 2014-04-15
Date Deposited: 2012-05

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