https://search.dev.ndltd.org/etd/ku/oai:kuscholarworks.ku.edu:1808/6175
type: CreativeWork
name: Using High-Resolution NMR to Examine the Components that Contribute to the Activity and Stability of Phosphatase of Regenerating Liver (PRL-1) and Their Dependence on the Redox State of Cysteine Residues
description: Phosphatase of regenerating liver (PRL-1) has gained attention as an important therapeutic target because of its involvement in cancer and metastasis, where it promotes proliferation and cell motility. The protein is found at high concentration in numerous cancer tissues and when over-expressed induces cellular transformation. Elevated levels of PRL-1 have been shown to trigger metastasis and to promote cellular transformation and tumorigenesis. Because its enzyme activity contributes to both tumorigenesis and metastasis, this protein is an attractive target for therapeutic intervention. The problem with ubiquitously inhibiting PRL-1 is that this enzyme is also essential to cell survival and tissue regeneration under normal physiological conditions. Inhibition may result in nonspecific and unwanted cell death of healthy tissues. Targeting only the overactive form of an enzyme would provide a reasonable resolution to this problem, but it is currently unknown how PRL-1 prompts proliferation in some cells and differentiation in others. The long-term goal of this project is to identify the crucial structural and dynamic features that support the enzymatic activity of PRL-1 and characterize the different forms to identify ones appropriate to target for therapeutic intervention. In this work, we have shown that the full-length unmodified form of PRL-1 is primarily inactive based on its determined reduction potential (-364.3 ± 1.5 mV) and that in vivo, activation is likely conferred through a posttranslational modification at the C-terminus. Using an assortment of biophysical techniques, we have also shown that a mutant form of PRL-1 (PRL-1-C170S/C171S) is reduced and active and can serve as a model for posttranslationally modified PRL-1 at this site. A second goal of this dissertation project is to use PRL-1 as a model system for studying protein stability. An understanding of the forces that contribute to protein stability is crucial to the development of new biotechnolo…
abstract: Phosphatase of regenerating liver (PRL-1) has gained attention as an important therapeutic target because of its involvement in cancer and metastasis, where it promotes proliferation and cell motility. The protein is found at high concentration in numerous cancer tissues and when over-expressed induces cellular transformation. Elevated levels of PRL-1 have been shown to trigger metastasis and to promote cellular transformation and tumorigenesis. Because its enzyme activity contributes to both tumorigenesis and metastasis, this protein is an attractive target for therapeutic intervention. The problem with ubiquitously inhibiting PRL-1 is that this enzyme is also essential to cell survival and tissue regeneration under normal physiological conditions. Inhibition may result in nonspecific and unwanted cell death of healthy tissues. Targeting only the overactive form of an enzyme would provide a reasonable resolution to this problem, but it is currently unknown how PRL-1 prompts proliferation in some cells and differentiation in others. The long-term goal of this project is to identify the crucial structural and dynamic features that support the enzymatic activity of PRL-1 and characterize the different forms to identify ones appropriate to target for therapeutic intervention. In this work, we have shown that the full-length unmodified form of PRL-1 is primarily inactive based on its determined reduction potential (-364.3 ± 1.5 mV) and that in vivo, activation is likely conferred through a posttranslational modification at the C-terminus. Using an assortment of biophysical techniques, we have also shown that a mutant form of PRL-1 (PRL-1-C170S/C171S) is reduced and active and can serve as a model for posttranslationally modified PRL-1 at this site. A second goal of this dissertation project is to use PRL-1 as a model system for studying protein stability. An understanding of the forces that contribute to protein stability is crucial to the development of new biotechnolo…
author: Skinner, Andria L.
language: EN
keywords: Pharmaceutical chemistry, Physical chemistry, Chemistry, Biochemistry, Drug screening, Nmr, Prl-1, Redox regulation, Stability, Structure activity relationship
date published: 2009-12-15
date modified: 2026-07-24T02:47:27Z
provider: University of Kansas
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Kansas

PropertyValue
property ID: Handle
value: http://hdl.handle.net/1808/6175