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The Role of Hypoxia Inducible Factor-1 Alpha in Bypassing Oncogene-Induced Senescence

Oncogene induced senescence (OIS) is a sustained anti-proliferative response acutely induced in primary cells via activation of mitogenic oncogenes such as Ras/BRAF. This mechanism acts as an initial barrier preventing normal cells transformation into malignant cell. Besides oncogenic activation and...

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Autores principales: Kilic Eren, Mehtap, Tabor, Vedrana
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4077769/
https://www.ncbi.nlm.nih.gov/pubmed/24984035
http://dx.doi.org/10.1371/journal.pone.0101064
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author Kilic Eren, Mehtap
Tabor, Vedrana
author_facet Kilic Eren, Mehtap
Tabor, Vedrana
author_sort Kilic Eren, Mehtap
collection PubMed
description Oncogene induced senescence (OIS) is a sustained anti-proliferative response acutely induced in primary cells via activation of mitogenic oncogenes such as Ras/BRAF. This mechanism acts as an initial barrier preventing normal cells transformation into malignant cell. Besides oncogenic activation and DNA damage response (DDR), senescence is modulated by a plethora of other factors, and one of the most important one is oxygen tension of the tissue. The aim of this study was to determine the impact of hypoxia on Ras(V12)-induced senescence in human diploid fibroblasts (HDFs). We showed here that hypoxia prevents execution of oncogene induced senescence (OIS), through a strong down-regulation of senescence hallmarks, such as SA- β-galactosidase, H3K9me3, HP1γ, p53, p21(CIP1) and p16(INK4a) in association with induction of hypoxia inducible factor-1α (HIF-1α). In addition, hypoxia also decreased marks of H-Ras(V12)-induced DDR in both cell lines through down-regulation of ATM/ATR, Chk1 and Chk2 phosphorylation as well as decreased γ-H2AX positivity. Utilizing shRNA system targeting HIF-1α we show that HIF-1α is directly involved in down regulation of p53 and its target p21(CIP1) but not p16(INK4a). In line with this finding we found that knock down of HIF-1α leads to a strong induction of apoptotic response, but not restoration of senescence in Ras expressing HDFs in hypoxia. This indicates that HIF-1α is an important player in early steps of tumorigenesis, leading to suppression of senescence through its negative regulation of p53 and p21(CIP1). In our work we describe a mechanism through which hypoxia and specifically HIF-1α preclude cells from maintaining senescence-driven anti proliferative response. These findings indicate the possible mechanism through which hypoxic environment helps premalignant cells to evade impingement of cellular failsafe pathways.
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spelling pubmed-40777692014-07-03 The Role of Hypoxia Inducible Factor-1 Alpha in Bypassing Oncogene-Induced Senescence Kilic Eren, Mehtap Tabor, Vedrana PLoS One Research Article Oncogene induced senescence (OIS) is a sustained anti-proliferative response acutely induced in primary cells via activation of mitogenic oncogenes such as Ras/BRAF. This mechanism acts as an initial barrier preventing normal cells transformation into malignant cell. Besides oncogenic activation and DNA damage response (DDR), senescence is modulated by a plethora of other factors, and one of the most important one is oxygen tension of the tissue. The aim of this study was to determine the impact of hypoxia on Ras(V12)-induced senescence in human diploid fibroblasts (HDFs). We showed here that hypoxia prevents execution of oncogene induced senescence (OIS), through a strong down-regulation of senescence hallmarks, such as SA- β-galactosidase, H3K9me3, HP1γ, p53, p21(CIP1) and p16(INK4a) in association with induction of hypoxia inducible factor-1α (HIF-1α). In addition, hypoxia also decreased marks of H-Ras(V12)-induced DDR in both cell lines through down-regulation of ATM/ATR, Chk1 and Chk2 phosphorylation as well as decreased γ-H2AX positivity. Utilizing shRNA system targeting HIF-1α we show that HIF-1α is directly involved in down regulation of p53 and its target p21(CIP1) but not p16(INK4a). In line with this finding we found that knock down of HIF-1α leads to a strong induction of apoptotic response, but not restoration of senescence in Ras expressing HDFs in hypoxia. This indicates that HIF-1α is an important player in early steps of tumorigenesis, leading to suppression of senescence through its negative regulation of p53 and p21(CIP1). In our work we describe a mechanism through which hypoxia and specifically HIF-1α preclude cells from maintaining senescence-driven anti proliferative response. These findings indicate the possible mechanism through which hypoxic environment helps premalignant cells to evade impingement of cellular failsafe pathways. Public Library of Science 2014-07-01 /pmc/articles/PMC4077769/ /pubmed/24984035 http://dx.doi.org/10.1371/journal.pone.0101064 Text en © 2014 Kilic Eren, Tabor 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
Kilic Eren, Mehtap
Tabor, Vedrana
The Role of Hypoxia Inducible Factor-1 Alpha in Bypassing Oncogene-Induced Senescence
title The Role of Hypoxia Inducible Factor-1 Alpha in Bypassing Oncogene-Induced Senescence
title_full The Role of Hypoxia Inducible Factor-1 Alpha in Bypassing Oncogene-Induced Senescence
title_fullStr The Role of Hypoxia Inducible Factor-1 Alpha in Bypassing Oncogene-Induced Senescence
title_full_unstemmed The Role of Hypoxia Inducible Factor-1 Alpha in Bypassing Oncogene-Induced Senescence
title_short The Role of Hypoxia Inducible Factor-1 Alpha in Bypassing Oncogene-Induced Senescence
title_sort role of hypoxia inducible factor-1 alpha in bypassing oncogene-induced senescence
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4077769/
https://www.ncbi.nlm.nih.gov/pubmed/24984035
http://dx.doi.org/10.1371/journal.pone.0101064
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