The Role of Hypoxia Inducible Factor-1 Alpha in Bypassing Oncogene-Induced Senescence
| Autor: | Mehtap Kılıç Eren, Vedrana Tabor |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Cyclin-Dependent Kinase Inhibitor p21
Senescence Aging lcsh:Medicine Down-Regulation Ras Signaling Biology medicine.disease_cause Hypoxia-Inducible Factor 1-Alpha Cell Signaling Downregulation and upregulation Molecular Cell Biology medicine Humans lcsh:Science Hypoxia Cells Cultured Cellular Senescence Cell Proliferation Cellular Stress Responses Oncogenic Signaling Multidisciplinary Cell Death lcsh:R Biology and Life Sciences Oncogenes Cell Biology Fibroblasts Hypoxia (medical) Hypoxia-Inducible Factor 1 alpha Subunit Diploidy Cell biology Oxygen tension Cell Processes Cell culture Immunology lcsh:Q Tumor Suppressor Protein p53 medicine.symptom Carcinogenesis Organism Development Cell aging Research Article Developmental Biology Signal Transduction |
| Zdroj: | PLoS ONE PLoS ONE, Vol 9, Iss 7, p e101064 (2014) |
| ISSN: | 1932-6203 |
| Popis: | 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-beta-galactosidase, H3K9me3, HP1 gamma, p53, p21(CIP1) and p16(INK4a) in association with induction of hypoxia inducible factor-1 alpha (HIF-1 alpha). 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 gamma-H2AX positivity. Utilizing shRNA system targeting HIF-1a we show that HIF-1a 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-1a leads to a strong induction of apoptotic response, but not restoration of senescence in Ras expressing HDFs in hypoxia. This indicates that HIF-1a 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-1 alpha 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. |
| Databáze: | OpenAIRE |
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