Enhancing Akt Imaging through Targeted Reporter Expression

The serine/threonine kinase PKB/Akt is a key mediator of survival and resistance to cancer therapy. Pharmacologic inhibition of Akt and its biologic sequelae may significantly impact the treatment of cancer. The use of molecular imaging technologies has contributed significantly to drug discovery re...

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Main Authors: Limin Zhang, Mahaveer S. Bhojani, Brian D. Ross, Alnawaz Rehemtulla
Format: Article
Language:English
Published: SAGE Publishing 2008-07-01
Series:Molecular Imaging
Online Access:https://doi.org/10.2310/7290.2008.00017A
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author Limin Zhang
Mahaveer S. Bhojani
Brian D. Ross
Alnawaz Rehemtulla
author_facet Limin Zhang
Mahaveer S. Bhojani
Brian D. Ross
Alnawaz Rehemtulla
author_sort Limin Zhang
collection DOAJ
description The serine/threonine kinase PKB/Akt is a key mediator of survival and resistance to cancer therapy. Pharmacologic inhibition of Akt and its biologic sequelae may significantly impact the treatment of cancer. The use of molecular imaging technologies has contributed significantly to drug discovery research with an emphasis on drug efficacy, the mechanism of action, and target validation studies. We constructed a genetically engineered hybrid bioluminescent Akt reporter (BAR) molecule that reports on Akt serine/threonine kinase activity. Based on the fact that Akt is recruited to the plasma membrane on activation, we here describe a modified version of this reporter molecule (myristoylated and palmitoylated bioluminescent Akt reporter [MyrPalm-BAR]), which is membrane bound and whose bioluminescence activity can be used to monitor Akt activity at the cell membrane. Using changes in Akt activation status with small molecule inhibitors of Akt, we demonstrated that the membrane-targeted Akt reporter was more sensitive and quantitative. In addition, inhibition of upstream signaling kinases such as epidermal growth factor receptor and phosphatidylinositol 3-kinase activity resulted in changes in Akt activity that were quantitatively monitored by bioluminescence imaging. Based on these results, we propose that the membrane-associated Akt reporter may be better suited for identification of novel compounds that modulate the Akt pathway by high-throughput screening.
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spelling doaj.art-8ff4eb256b074093b1895a806db5b1252025-01-03T00:11:22ZengSAGE PublishingMolecular Imaging1536-01212008-07-01710.2310/7290.2008.00017A10.2310_7290.2008.00017AEnhancing Akt Imaging through Targeted Reporter ExpressionLimin ZhangMahaveer S. BhojaniBrian D. RossAlnawaz RehemtullaThe serine/threonine kinase PKB/Akt is a key mediator of survival and resistance to cancer therapy. Pharmacologic inhibition of Akt and its biologic sequelae may significantly impact the treatment of cancer. The use of molecular imaging technologies has contributed significantly to drug discovery research with an emphasis on drug efficacy, the mechanism of action, and target validation studies. We constructed a genetically engineered hybrid bioluminescent Akt reporter (BAR) molecule that reports on Akt serine/threonine kinase activity. Based on the fact that Akt is recruited to the plasma membrane on activation, we here describe a modified version of this reporter molecule (myristoylated and palmitoylated bioluminescent Akt reporter [MyrPalm-BAR]), which is membrane bound and whose bioluminescence activity can be used to monitor Akt activity at the cell membrane. Using changes in Akt activation status with small molecule inhibitors of Akt, we demonstrated that the membrane-targeted Akt reporter was more sensitive and quantitative. In addition, inhibition of upstream signaling kinases such as epidermal growth factor receptor and phosphatidylinositol 3-kinase activity resulted in changes in Akt activity that were quantitatively monitored by bioluminescence imaging. Based on these results, we propose that the membrane-associated Akt reporter may be better suited for identification of novel compounds that modulate the Akt pathway by high-throughput screening.https://doi.org/10.2310/7290.2008.00017A
spellingShingle Limin Zhang
Mahaveer S. Bhojani
Brian D. Ross
Alnawaz Rehemtulla
Enhancing Akt Imaging through Targeted Reporter Expression
Molecular Imaging
title Enhancing Akt Imaging through Targeted Reporter Expression
title_full Enhancing Akt Imaging through Targeted Reporter Expression
title_fullStr Enhancing Akt Imaging through Targeted Reporter Expression
title_full_unstemmed Enhancing Akt Imaging through Targeted Reporter Expression
title_short Enhancing Akt Imaging through Targeted Reporter Expression
title_sort enhancing akt imaging through targeted reporter expression
url https://doi.org/10.2310/7290.2008.00017A
work_keys_str_mv AT liminzhang enhancingaktimagingthroughtargetedreporterexpression
AT mahaveersbhojani enhancingaktimagingthroughtargetedreporterexpression
AT briandross enhancingaktimagingthroughtargetedreporterexpression
AT alnawazrehemtulla enhancingaktimagingthroughtargetedreporterexpression