Inhibition of hypoxia-inducible factor-1alpha (HIF-1alpha) protein synthesis by DNA damage inducing agents.
Hypoxia-inducible factor (HIF) is a heterodimeric transcription factor that is composed of a hypoxia-inducible alpha subunit (HIF-1alpha and HIF-2alpha) and a constitutively expressed beta subunit (HIF-1beta). HIF mediates the adaptation of cells and tissues to low oxygen concentrations. It also pla...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2010-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC2866540?pdf=render |
| _version_ | 1818193614073757696 |
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| author | Jessica Jie Wei Lou Yee Liu Chua Eng Hui Chew Jie Gao Martin Bushell Thilo Hagen |
| author_facet | Jessica Jie Wei Lou Yee Liu Chua Eng Hui Chew Jie Gao Martin Bushell Thilo Hagen |
| author_sort | Jessica Jie Wei Lou |
| collection | DOAJ |
| description | Hypoxia-inducible factor (HIF) is a heterodimeric transcription factor that is composed of a hypoxia-inducible alpha subunit (HIF-1alpha and HIF-2alpha) and a constitutively expressed beta subunit (HIF-1beta). HIF mediates the adaptation of cells and tissues to low oxygen concentrations. It also plays an important role in tumorigenesis and constitutes an important therapeutic target in anti-tumor therapy. We have screened a number of reported HIF inhibitors for their effects on HIF-transcriptional activity and found that the DNA damage inducing agents camptothecin and mitomycin C produced the most robust effects. Camptothecin is a reported inhibitor of HIF-1alpha translation, while mitomycin C has been reported to induce p53-dependent HIF-1alpha degradation. In this study we demonstrate that the inhibitory effect of mitomycin C on HIF-1alpha protein expression is not dependent on p53 and protein degradation, but also involves HIF-1alpha translational regulation. Initiation of a DNA damage response with the small molecule p53 activator NSC-652287 (RITA) has been reported to inhibit HIF-1alpha protein synthesis by increasing the phosphorylation of eIF2alpha. However, we show here that even when eIF2alpha phosphorylation is prevented, the DNA damage inducing drugs mitomycin C, camptothecin and NSC-652287 still inhibit HIF-1alpha protein synthesis to the same extent. The inhibitory effects of camptothecin on HIF-1alpha expression but not that of mitomycin C and NSC-652287 were dependent on cyclin-dependent kinase activity. In conclusion, specific types of DNA damage can bring about selective inhibition of HIF-1alpha protein synthesis. Further characterization of the involved mechanisms may reveal important novel therapeutic targets. |
| first_indexed | 2024-12-12T00:49:11Z |
| format | Article |
| id | doaj.art-6e2c7a7131b546e3a04f65033f1b1c0c |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-12T00:49:11Z |
| publishDate | 2010-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-6e2c7a7131b546e3a04f65033f1b1c0c2022-12-22T00:44:04ZengPublic Library of Science (PLoS)PLoS ONE1932-62032010-01-0155e1052210.1371/journal.pone.0010522Inhibition of hypoxia-inducible factor-1alpha (HIF-1alpha) protein synthesis by DNA damage inducing agents.Jessica Jie Wei LouYee Liu ChuaEng Hui ChewJie GaoMartin BushellThilo HagenHypoxia-inducible factor (HIF) is a heterodimeric transcription factor that is composed of a hypoxia-inducible alpha subunit (HIF-1alpha and HIF-2alpha) and a constitutively expressed beta subunit (HIF-1beta). HIF mediates the adaptation of cells and tissues to low oxygen concentrations. It also plays an important role in tumorigenesis and constitutes an important therapeutic target in anti-tumor therapy. We have screened a number of reported HIF inhibitors for their effects on HIF-transcriptional activity and found that the DNA damage inducing agents camptothecin and mitomycin C produced the most robust effects. Camptothecin is a reported inhibitor of HIF-1alpha translation, while mitomycin C has been reported to induce p53-dependent HIF-1alpha degradation. In this study we demonstrate that the inhibitory effect of mitomycin C on HIF-1alpha protein expression is not dependent on p53 and protein degradation, but also involves HIF-1alpha translational regulation. Initiation of a DNA damage response with the small molecule p53 activator NSC-652287 (RITA) has been reported to inhibit HIF-1alpha protein synthesis by increasing the phosphorylation of eIF2alpha. However, we show here that even when eIF2alpha phosphorylation is prevented, the DNA damage inducing drugs mitomycin C, camptothecin and NSC-652287 still inhibit HIF-1alpha protein synthesis to the same extent. The inhibitory effects of camptothecin on HIF-1alpha expression but not that of mitomycin C and NSC-652287 were dependent on cyclin-dependent kinase activity. In conclusion, specific types of DNA damage can bring about selective inhibition of HIF-1alpha protein synthesis. Further characterization of the involved mechanisms may reveal important novel therapeutic targets.http://europepmc.org/articles/PMC2866540?pdf=render |
| spellingShingle | Jessica Jie Wei Lou Yee Liu Chua Eng Hui Chew Jie Gao Martin Bushell Thilo Hagen Inhibition of hypoxia-inducible factor-1alpha (HIF-1alpha) protein synthesis by DNA damage inducing agents. PLoS ONE |
| title | Inhibition of hypoxia-inducible factor-1alpha (HIF-1alpha) protein synthesis by DNA damage inducing agents. |
| title_full | Inhibition of hypoxia-inducible factor-1alpha (HIF-1alpha) protein synthesis by DNA damage inducing agents. |
| title_fullStr | Inhibition of hypoxia-inducible factor-1alpha (HIF-1alpha) protein synthesis by DNA damage inducing agents. |
| title_full_unstemmed | Inhibition of hypoxia-inducible factor-1alpha (HIF-1alpha) protein synthesis by DNA damage inducing agents. |
| title_short | Inhibition of hypoxia-inducible factor-1alpha (HIF-1alpha) protein synthesis by DNA damage inducing agents. |
| title_sort | inhibition of hypoxia inducible factor 1alpha hif 1alpha protein synthesis by dna damage inducing agents |
| url | http://europepmc.org/articles/PMC2866540?pdf=render |
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