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Insights from yeast into whether the rapamycin inhibition of heat shock transcription factor (Hsf1) can prevent the Hsf1 activation that results from treatment with an Hsp90 inhibitor
In human cells TORC1 mTOR (target of rapamycin) protein kinase complex renders heat shock transcription factor 1 (Hsf1) competent for stress activation. In such cells, as well as in yeast, the selective TORC1 inhibitor rapamycin blocks this activation in contrast to Hsp90 inhibitors which potently a...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4148121/ https://www.ncbi.nlm.nih.gov/pubmed/24970820 |
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author | Millson, Stefan H. Piper, Peter W. |
author_facet | Millson, Stefan H. Piper, Peter W. |
author_sort | Millson, Stefan H. |
collection | PubMed |
description | In human cells TORC1 mTOR (target of rapamycin) protein kinase complex renders heat shock transcription factor 1 (Hsf1) competent for stress activation. In such cells, as well as in yeast, the selective TORC1 inhibitor rapamycin blocks this activation in contrast to Hsp90 inhibitors which potently activate Hsf1. Potentially therefore rapamycin could prevent the Hsf1 activation that frequently compromises the efficiency of Hsp90 inhibitor cancer drugs. Little synergy was found between the effects of rapamycin and the Hsp90 inhibitor radicicol on yeast growth. However certain rapamycin resistance mutations sensitised yeast to Hsp90 inhibitor treatment and an Hsp90 mutation that overactivates Hsf1 sensitised cells to rapamycin. Rapamycin inhibition of the yeast Hsf1 was abolished by this Hsp90 mutation, as well as with the loss of Ppt1, the Hsp90-interacting protein phosphatase that is the ortholog of mammalian PP5. Unexpectedly Hsf1 activation was found to have a requirement for the rapamycin binding immunophilin FKBP12 even in the absence of rapamycin, while TORC1 “bypass” strains revealed that the rapamycin inhibition of yeast Hsf1 is not exerted through two of the major downstream targets of TORC1, the protein phosphatase regulator Tap42 and the protein kinase Sch9 – the latter the ortholog of human S6 protein kinase 1. Significance: A problem with most of the Hsp90 inhibitor drugs now in cancer clinic trials is that they potently activate Hsf1. This leads to an induction of heat shock proteins, many of which have a “pro-survival” role in that they help to protect cells from apopotosis. As the activation of Hsf1 requires TORC1, inhibitors of mTOR kinase could potentially block this activation of Hsf1 and be of value when used in combination drug therapies with Hsp90 inhibitors. However many of the mechanistic details of the TORC1 regulation of Hsf1, as well as the interplay between cellular resistances to rapamycin and to Hsp90 inhibitors, still remain to be resolved. |
format | Online Article Text |
id | pubmed-4148121 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-41481212014-08-29 Insights from yeast into whether the rapamycin inhibition of heat shock transcription factor (Hsf1) can prevent the Hsf1 activation that results from treatment with an Hsp90 inhibitor Millson, Stefan H. Piper, Peter W. Oncotarget Research Paper In human cells TORC1 mTOR (target of rapamycin) protein kinase complex renders heat shock transcription factor 1 (Hsf1) competent for stress activation. In such cells, as well as in yeast, the selective TORC1 inhibitor rapamycin blocks this activation in contrast to Hsp90 inhibitors which potently activate Hsf1. Potentially therefore rapamycin could prevent the Hsf1 activation that frequently compromises the efficiency of Hsp90 inhibitor cancer drugs. Little synergy was found between the effects of rapamycin and the Hsp90 inhibitor radicicol on yeast growth. However certain rapamycin resistance mutations sensitised yeast to Hsp90 inhibitor treatment and an Hsp90 mutation that overactivates Hsf1 sensitised cells to rapamycin. Rapamycin inhibition of the yeast Hsf1 was abolished by this Hsp90 mutation, as well as with the loss of Ppt1, the Hsp90-interacting protein phosphatase that is the ortholog of mammalian PP5. Unexpectedly Hsf1 activation was found to have a requirement for the rapamycin binding immunophilin FKBP12 even in the absence of rapamycin, while TORC1 “bypass” strains revealed that the rapamycin inhibition of yeast Hsf1 is not exerted through two of the major downstream targets of TORC1, the protein phosphatase regulator Tap42 and the protein kinase Sch9 – the latter the ortholog of human S6 protein kinase 1. Significance: A problem with most of the Hsp90 inhibitor drugs now in cancer clinic trials is that they potently activate Hsf1. This leads to an induction of heat shock proteins, many of which have a “pro-survival” role in that they help to protect cells from apopotosis. As the activation of Hsf1 requires TORC1, inhibitors of mTOR kinase could potentially block this activation of Hsf1 and be of value when used in combination drug therapies with Hsp90 inhibitors. However many of the mechanistic details of the TORC1 regulation of Hsf1, as well as the interplay between cellular resistances to rapamycin and to Hsp90 inhibitors, still remain to be resolved. Impact Journals LLC 2014-06-07 /pmc/articles/PMC4148121/ /pubmed/24970820 Text en Copyright: © 2014 Millson and Piper http://creativecommons.org/licenses/by/2.5/ 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 credited. |
spellingShingle | Research Paper Millson, Stefan H. Piper, Peter W. Insights from yeast into whether the rapamycin inhibition of heat shock transcription factor (Hsf1) can prevent the Hsf1 activation that results from treatment with an Hsp90 inhibitor |
title | Insights from yeast into whether the rapamycin inhibition of heat shock transcription factor (Hsf1) can prevent the Hsf1 activation that results from treatment with an Hsp90 inhibitor |
title_full | Insights from yeast into whether the rapamycin inhibition of heat shock transcription factor (Hsf1) can prevent the Hsf1 activation that results from treatment with an Hsp90 inhibitor |
title_fullStr | Insights from yeast into whether the rapamycin inhibition of heat shock transcription factor (Hsf1) can prevent the Hsf1 activation that results from treatment with an Hsp90 inhibitor |
title_full_unstemmed | Insights from yeast into whether the rapamycin inhibition of heat shock transcription factor (Hsf1) can prevent the Hsf1 activation that results from treatment with an Hsp90 inhibitor |
title_short | Insights from yeast into whether the rapamycin inhibition of heat shock transcription factor (Hsf1) can prevent the Hsf1 activation that results from treatment with an Hsp90 inhibitor |
title_sort | insights from yeast into whether the rapamycin inhibition of heat shock transcription factor (hsf1) can prevent the hsf1 activation that results from treatment with an hsp90 inhibitor |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4148121/ https://www.ncbi.nlm.nih.gov/pubmed/24970820 |
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