PI3K-PTEN dysregulation leads to mTOR-driven upregulation of the core clock gene BMAL1 in normal and malignant epithelial cells
Autor(a) principal: | |
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Data de Publicação: | 2016 |
Outros Autores: | , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UFRGS |
Texto Completo: | http://hdl.handle.net/10183/183994 |
Resumo: | Dysfunctional clock signaling is observed in a variety of pathological conditions. Many members of the clock gene family are upregulated in tumor cells. Here, we explored the consequences of a commonly disrupted signaling pathway in head and neck cancer on the regulation of circadian clock genes. PTEN is a key molecular controller of the PI3K signaling, and loss of PTEN function is often observed in a variety of cancers. Our main goal was to determine whether PTEN regulates circadian clock signaling. We found that oxidation-driven loss of PTEN function resulted in the activation of mTOR signaling and activation of the core clock protein BMAL1 (also known as ARNTL). The PTEN-induced BMAL1 upregulation was further confirmed using small interference RNA targeting PTEN, and in vivo conditional depletion of PTEN from the epidermis. We observed that PTEN-driven accumulation of BMAL1 was mTORmediated and that administration of Rapamycin, a specific mTOR inhibitor, resulted in in vivo rescue of normal levels of BMAL1. Accumulation of BMAL1 by deletion of PER2, a Period family gene, was also rescued upon in vivo administration of mTOR inhibitor. Notably, BMAL1 regulation requires mTOR regulatory protein Raptor and Rictor. These findings indicate that mTORC1 and mTORC2 complex plays a critical role in controlling BMAL1, establishing a connection between PI3K signaling and the regulation of circadian rhythm, ultimately resulting in deregulated BMAL1 in tumor cells with disrupted PI3K signaling. |
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Matsumoto, Camila S.Almeida, Luciana OliveiraGuimarães, Douglas M.Martins, Manoela DominguesPapagerakis, PetrosPapagerakis, SilvanaLeopoldino, Andréia MachadoCastilho, Rogerio MoraesSquarize, Cristiane Helena2018-10-26T02:43:28Z20161949-2553http://hdl.handle.net/10183/183994001059511Dysfunctional clock signaling is observed in a variety of pathological conditions. Many members of the clock gene family are upregulated in tumor cells. Here, we explored the consequences of a commonly disrupted signaling pathway in head and neck cancer on the regulation of circadian clock genes. PTEN is a key molecular controller of the PI3K signaling, and loss of PTEN function is often observed in a variety of cancers. Our main goal was to determine whether PTEN regulates circadian clock signaling. We found that oxidation-driven loss of PTEN function resulted in the activation of mTOR signaling and activation of the core clock protein BMAL1 (also known as ARNTL). The PTEN-induced BMAL1 upregulation was further confirmed using small interference RNA targeting PTEN, and in vivo conditional depletion of PTEN from the epidermis. We observed that PTEN-driven accumulation of BMAL1 was mTORmediated and that administration of Rapamycin, a specific mTOR inhibitor, resulted in in vivo rescue of normal levels of BMAL1. Accumulation of BMAL1 by deletion of PER2, a Period family gene, was also rescued upon in vivo administration of mTOR inhibitor. Notably, BMAL1 regulation requires mTOR regulatory protein Raptor and Rictor. These findings indicate that mTORC1 and mTORC2 complex plays a critical role in controlling BMAL1, establishing a connection between PI3K signaling and the regulation of circadian rhythm, ultimately resulting in deregulated BMAL1 in tumor cells with disrupted PI3K signaling.application/pdfengOncotarget. Albany. Vol. 7, no. 27 (July 2016), p. 42393-42406Patologia bucalNeoplasias bucaisCélulas epiteliaisPI3K-PTEN dysregulation leads to mTOR-driven upregulation of the core clock gene BMAL1 in normal and malignant epithelial cellsEstrangeiroinfo:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da UFRGSinstname:Universidade Federal do Rio Grande do Sul (UFRGS)instacron:UFRGSORIGINAL001059511.pdfTexto completo (inglês)application/pdf6941025http://www.lume.ufrgs.br/bitstream/10183/183994/1/001059511.pdf16339d4cffa945d1fdcdcba62c91a644MD51TEXT001059511.pdf.txt001059511.pdf.txtExtracted Texttext/plain47506http://www.lume.ufrgs.br/bitstream/10183/183994/2/001059511.pdf.txt636c132aa7764f21ac67daf5fe9e54caMD52THUMBNAIL001059511.pdf.jpg001059511.pdf.jpgGenerated Thumbnailimage/jpeg2237http://www.lume.ufrgs.br/bitstream/10183/183994/3/001059511.pdf.jpgd395d7e558d07ed7929e6dc84ae85095MD5310183/1839942018-10-27 03:12:37.381927oai:www.lume.ufrgs.br:10183/183994Repositório de PublicaçõesPUBhttps://lume.ufrgs.br/oai/requestopendoar:2018-10-27T06:12:37Repositório Institucional da UFRGS - Universidade Federal do Rio Grande do Sul (UFRGS)false |
dc.title.pt_BR.fl_str_mv |
PI3K-PTEN dysregulation leads to mTOR-driven upregulation of the core clock gene BMAL1 in normal and malignant epithelial cells |
title |
PI3K-PTEN dysregulation leads to mTOR-driven upregulation of the core clock gene BMAL1 in normal and malignant epithelial cells |
spellingShingle |
PI3K-PTEN dysregulation leads to mTOR-driven upregulation of the core clock gene BMAL1 in normal and malignant epithelial cells Matsumoto, Camila S. Patologia bucal Neoplasias bucais Células epiteliais |
title_short |
PI3K-PTEN dysregulation leads to mTOR-driven upregulation of the core clock gene BMAL1 in normal and malignant epithelial cells |
title_full |
PI3K-PTEN dysregulation leads to mTOR-driven upregulation of the core clock gene BMAL1 in normal and malignant epithelial cells |
title_fullStr |
PI3K-PTEN dysregulation leads to mTOR-driven upregulation of the core clock gene BMAL1 in normal and malignant epithelial cells |
title_full_unstemmed |
PI3K-PTEN dysregulation leads to mTOR-driven upregulation of the core clock gene BMAL1 in normal and malignant epithelial cells |
title_sort |
PI3K-PTEN dysregulation leads to mTOR-driven upregulation of the core clock gene BMAL1 in normal and malignant epithelial cells |
author |
Matsumoto, Camila S. |
author_facet |
Matsumoto, Camila S. Almeida, Luciana Oliveira Guimarães, Douglas M. Martins, Manoela Domingues Papagerakis, Petros Papagerakis, Silvana Leopoldino, Andréia Machado Castilho, Rogerio Moraes Squarize, Cristiane Helena |
author_role |
author |
author2 |
Almeida, Luciana Oliveira Guimarães, Douglas M. Martins, Manoela Domingues Papagerakis, Petros Papagerakis, Silvana Leopoldino, Andréia Machado Castilho, Rogerio Moraes Squarize, Cristiane Helena |
author2_role |
author author author author author author author author |
dc.contributor.author.fl_str_mv |
Matsumoto, Camila S. Almeida, Luciana Oliveira Guimarães, Douglas M. Martins, Manoela Domingues Papagerakis, Petros Papagerakis, Silvana Leopoldino, Andréia Machado Castilho, Rogerio Moraes Squarize, Cristiane Helena |
dc.subject.por.fl_str_mv |
Patologia bucal Neoplasias bucais Células epiteliais |
topic |
Patologia bucal Neoplasias bucais Células epiteliais |
description |
Dysfunctional clock signaling is observed in a variety of pathological conditions. Many members of the clock gene family are upregulated in tumor cells. Here, we explored the consequences of a commonly disrupted signaling pathway in head and neck cancer on the regulation of circadian clock genes. PTEN is a key molecular controller of the PI3K signaling, and loss of PTEN function is often observed in a variety of cancers. Our main goal was to determine whether PTEN regulates circadian clock signaling. We found that oxidation-driven loss of PTEN function resulted in the activation of mTOR signaling and activation of the core clock protein BMAL1 (also known as ARNTL). The PTEN-induced BMAL1 upregulation was further confirmed using small interference RNA targeting PTEN, and in vivo conditional depletion of PTEN from the epidermis. We observed that PTEN-driven accumulation of BMAL1 was mTORmediated and that administration of Rapamycin, a specific mTOR inhibitor, resulted in in vivo rescue of normal levels of BMAL1. Accumulation of BMAL1 by deletion of PER2, a Period family gene, was also rescued upon in vivo administration of mTOR inhibitor. Notably, BMAL1 regulation requires mTOR regulatory protein Raptor and Rictor. These findings indicate that mTORC1 and mTORC2 complex plays a critical role in controlling BMAL1, establishing a connection between PI3K signaling and the regulation of circadian rhythm, ultimately resulting in deregulated BMAL1 in tumor cells with disrupted PI3K signaling. |
publishDate |
2016 |
dc.date.issued.fl_str_mv |
2016 |
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2018-10-26T02:43:28Z |
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1949-2553 |
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001059511 |
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dc.language.iso.fl_str_mv |
eng |
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dc.relation.ispartof.pt_BR.fl_str_mv |
Oncotarget. Albany. Vol. 7, no. 27 (July 2016), p. 42393-42406 |
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