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Inhibitors of AKT kinase increase LDL receptor mRNA expression by two different mechanisms

Protein kinase B (AKT) is a serine/threonine kinase that functions as an important downstream effector of phosphoinositide 3-kinase. We have recently shown that MK-2206 and triciribine, two highly selective AKT inhibitors increase the level of low density lipoprotein receptor (LDLR) mRNA which leads...

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Autores principales: Bjune, Katrine, Wierød, Lene, Naderi, Soheil
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6583949/
https://www.ncbi.nlm.nih.gov/pubmed/31216345
http://dx.doi.org/10.1371/journal.pone.0218537
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author Bjune, Katrine
Wierød, Lene
Naderi, Soheil
author_facet Bjune, Katrine
Wierød, Lene
Naderi, Soheil
author_sort Bjune, Katrine
collection PubMed
description Protein kinase B (AKT) is a serine/threonine kinase that functions as an important downstream effector of phosphoinositide 3-kinase. We have recently shown that MK-2206 and triciribine, two highly selective AKT inhibitors increase the level of low density lipoprotein receptor (LDLR) mRNA which leads to increased amount of cell-surface LDLRs. However, whereas MK-2206 induces transcription of the LDLR gene, triciribine stabilizes LDLR mRNA, raising the possibility that the two inhibitors may actually affect other kinases than AKT. In this study, we aimed to ascertain the role of AKT in regulation of LDLR mRNA expression by examining the effect of five additional AKT inhibitors on LDLR mRNA levels. Here we show that in cultured HepG2 cells, AKT inhibitors ARQ-092, AKT inhibitor VIII, perifosine, AT7867 and CCT128930 increase LDLR mRNA levels by inducing the activity of LDLR promoter. CCT128930 also increased the stability of LDLR mRNA. To study the role of AKT isoforms on LDLR mRNA levels, we examined the effect of siRNA-mediated knockdown of AKT1 or AKT2 on LDLR promoter activity and LDLR mRNA stability. Whereas knockdown of either AKT1 or AKT2 led to upregulation of LDLR promoter activity, only knockdown of AKT2 had a stabilizing effect on LDLR mRNA. Taken together, these results provide strong evidence for involvement of AKT in regulation of LDLR mRNA expression, and point towards the AKT isoform specificity for upregulation of LDLR mRNA expression.
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spelling pubmed-65839492019-06-28 Inhibitors of AKT kinase increase LDL receptor mRNA expression by two different mechanisms Bjune, Katrine Wierød, Lene Naderi, Soheil PLoS One Research Article Protein kinase B (AKT) is a serine/threonine kinase that functions as an important downstream effector of phosphoinositide 3-kinase. We have recently shown that MK-2206 and triciribine, two highly selective AKT inhibitors increase the level of low density lipoprotein receptor (LDLR) mRNA which leads to increased amount of cell-surface LDLRs. However, whereas MK-2206 induces transcription of the LDLR gene, triciribine stabilizes LDLR mRNA, raising the possibility that the two inhibitors may actually affect other kinases than AKT. In this study, we aimed to ascertain the role of AKT in regulation of LDLR mRNA expression by examining the effect of five additional AKT inhibitors on LDLR mRNA levels. Here we show that in cultured HepG2 cells, AKT inhibitors ARQ-092, AKT inhibitor VIII, perifosine, AT7867 and CCT128930 increase LDLR mRNA levels by inducing the activity of LDLR promoter. CCT128930 also increased the stability of LDLR mRNA. To study the role of AKT isoforms on LDLR mRNA levels, we examined the effect of siRNA-mediated knockdown of AKT1 or AKT2 on LDLR promoter activity and LDLR mRNA stability. Whereas knockdown of either AKT1 or AKT2 led to upregulation of LDLR promoter activity, only knockdown of AKT2 had a stabilizing effect on LDLR mRNA. Taken together, these results provide strong evidence for involvement of AKT in regulation of LDLR mRNA expression, and point towards the AKT isoform specificity for upregulation of LDLR mRNA expression. Public Library of Science 2019-06-19 /pmc/articles/PMC6583949/ /pubmed/31216345 http://dx.doi.org/10.1371/journal.pone.0218537 Text en © 2019 Bjune et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Bjune, Katrine
Wierød, Lene
Naderi, Soheil
Inhibitors of AKT kinase increase LDL receptor mRNA expression by two different mechanisms
title Inhibitors of AKT kinase increase LDL receptor mRNA expression by two different mechanisms
title_full Inhibitors of AKT kinase increase LDL receptor mRNA expression by two different mechanisms
title_fullStr Inhibitors of AKT kinase increase LDL receptor mRNA expression by two different mechanisms
title_full_unstemmed Inhibitors of AKT kinase increase LDL receptor mRNA expression by two different mechanisms
title_short Inhibitors of AKT kinase increase LDL receptor mRNA expression by two different mechanisms
title_sort inhibitors of akt kinase increase ldl receptor mrna expression by two different mechanisms
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6583949/
https://www.ncbi.nlm.nih.gov/pubmed/31216345
http://dx.doi.org/10.1371/journal.pone.0218537
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