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The Max b-HLH-LZ Can Transduce into Cells and Inhibit c-Myc Transcriptional Activities

The inhibition of the functions of c-Myc (endogenous and oncogenic) was recently shown to provide a spectacular therapeutic index in cancer mouse models, with complete tumor regression and minimal side-effects in normal tissues. This was achieved by the systemic and conditional expression of omomyc,...

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Autores principales: Montagne, Martin, Beaudoin, Nicolas, Fortin, David, Lavoie, Christine L., Klinck, Roscoe, Lavigne, Pierre
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3284561/
https://www.ncbi.nlm.nih.gov/pubmed/22384171
http://dx.doi.org/10.1371/journal.pone.0032172
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author Montagne, Martin
Beaudoin, Nicolas
Fortin, David
Lavoie, Christine L.
Klinck, Roscoe
Lavigne, Pierre
author_facet Montagne, Martin
Beaudoin, Nicolas
Fortin, David
Lavoie, Christine L.
Klinck, Roscoe
Lavigne, Pierre
author_sort Montagne, Martin
collection PubMed
description The inhibition of the functions of c-Myc (endogenous and oncogenic) was recently shown to provide a spectacular therapeutic index in cancer mouse models, with complete tumor regression and minimal side-effects in normal tissues. This was achieved by the systemic and conditional expression of omomyc, the cDNA of a designed mutant of the b-HLH-LZ of c-Myc named Omomyc. The overall mode of action of Omomyc consists in the sequestration of Max and the concomitant competition of the Omomyc/Max complex with the endogenous c-Myc/Max heterodimer. This leads to the inhibition of the transactivation of Myc target genes involved in proliferation and metabolism. While this body of work has provided extraordinary insights to guide the future development of new cancer therapies that target c-Myc, Omomyc itself is not a therapeutic agent. In this context, we sought to exploit the use of a b-HLH-LZ to inhibit c-Myc in a cancer cell line in a more direct fashion. We demonstrate that the b-HLH-LZ domain of Max (Max*) behaves as a bona fide protein transduction domain (PTD) that can efficiently transduce across cellular membrane via through endocytosis and translocate to the nucleus. In addition, we show that the treatment of HeLa cells with Max* leads to a reduction of metabolism and proliferation rate. Accordingly, we observe a decrease of the population of HeLa cells in S phase, an accumulation in G1/G0 and the induction of apoptosis. In agreement with these phenotypic changes, we show by q-RT-PCR that the treatment of HeLa cells with Max* leads to the activation of the transcription c-Myc repressed genes as well as the repression of the expression of c-Myc activated genes. In addition to the novel discovery that the Max b-HLH-LZ is a PTD, our findings open up new avenues and strategies for the direct inhibition of c-Myc with b-HLH-LZ analogs.
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spelling pubmed-32845612012-03-01 The Max b-HLH-LZ Can Transduce into Cells and Inhibit c-Myc Transcriptional Activities Montagne, Martin Beaudoin, Nicolas Fortin, David Lavoie, Christine L. Klinck, Roscoe Lavigne, Pierre PLoS One Research Article The inhibition of the functions of c-Myc (endogenous and oncogenic) was recently shown to provide a spectacular therapeutic index in cancer mouse models, with complete tumor regression and minimal side-effects in normal tissues. This was achieved by the systemic and conditional expression of omomyc, the cDNA of a designed mutant of the b-HLH-LZ of c-Myc named Omomyc. The overall mode of action of Omomyc consists in the sequestration of Max and the concomitant competition of the Omomyc/Max complex with the endogenous c-Myc/Max heterodimer. This leads to the inhibition of the transactivation of Myc target genes involved in proliferation and metabolism. While this body of work has provided extraordinary insights to guide the future development of new cancer therapies that target c-Myc, Omomyc itself is not a therapeutic agent. In this context, we sought to exploit the use of a b-HLH-LZ to inhibit c-Myc in a cancer cell line in a more direct fashion. We demonstrate that the b-HLH-LZ domain of Max (Max*) behaves as a bona fide protein transduction domain (PTD) that can efficiently transduce across cellular membrane via through endocytosis and translocate to the nucleus. In addition, we show that the treatment of HeLa cells with Max* leads to a reduction of metabolism and proliferation rate. Accordingly, we observe a decrease of the population of HeLa cells in S phase, an accumulation in G1/G0 and the induction of apoptosis. In agreement with these phenotypic changes, we show by q-RT-PCR that the treatment of HeLa cells with Max* leads to the activation of the transcription c-Myc repressed genes as well as the repression of the expression of c-Myc activated genes. In addition to the novel discovery that the Max b-HLH-LZ is a PTD, our findings open up new avenues and strategies for the direct inhibition of c-Myc with b-HLH-LZ analogs. Public Library of Science 2012-02-22 /pmc/articles/PMC3284561/ /pubmed/22384171 http://dx.doi.org/10.1371/journal.pone.0032172 Text en Montagne 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, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Montagne, Martin
Beaudoin, Nicolas
Fortin, David
Lavoie, Christine L.
Klinck, Roscoe
Lavigne, Pierre
The Max b-HLH-LZ Can Transduce into Cells and Inhibit c-Myc Transcriptional Activities
title The Max b-HLH-LZ Can Transduce into Cells and Inhibit c-Myc Transcriptional Activities
title_full The Max b-HLH-LZ Can Transduce into Cells and Inhibit c-Myc Transcriptional Activities
title_fullStr The Max b-HLH-LZ Can Transduce into Cells and Inhibit c-Myc Transcriptional Activities
title_full_unstemmed The Max b-HLH-LZ Can Transduce into Cells and Inhibit c-Myc Transcriptional Activities
title_short The Max b-HLH-LZ Can Transduce into Cells and Inhibit c-Myc Transcriptional Activities
title_sort max b-hlh-lz can transduce into cells and inhibit c-myc transcriptional activities
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3284561/
https://www.ncbi.nlm.nih.gov/pubmed/22384171
http://dx.doi.org/10.1371/journal.pone.0032172
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