TITLE

Inhibition of Hypoxia-Inducible Factor-1a (HIF-1a) Protein Synthesis by DNA Damage Inducing Agents

AUTHOR(S)

Lou, Jessica Jie Wei; Yee Liu Chua; Eng Hui Chew; Jie Gao; Bushell, Martin; Hagen, Thilo

PUB. DATE

May 2010

SOURCE

PLoS ONE;2010, Vol. 5 Issue 5, p1

SOURCE TYPE

Academic Journal

DOC. TYPE

Article

ABSTRACT

Hypoxia-inducible factor (HIF) is a heterodimeric transcription factor that is composed of a hypoxia-inducible a subunit (HIF-1a and HIF-2a) and a constitutively expressed � subunit (HIF-1�). 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-1a translation, while mitomycin C has been reported to induce p53-dependent HIF-1a degradation. In this study we demonstrate that the inhibitory effect of mitomycin C on HIF-1a protein expression is not dependent on p53 and protein degradation, but also involves HIF-1a translational regulation. Initiation of a DNA damage response with the small molecule p53 activator NSC-652287 (RITA) has been reported to inhibit HIF-1a protein synthesis by increasing the phosphorylation of eIF2a. However, we show here that even when eIF2a phosphorylation is prevented, the DNA damage inducing drugs mitomycin C, camptothecin and NSC-652287 still inhibit HIF-1a protein synthesis to the same extent. The inhibitory effects of camptothecin on HIF-1a 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-1a protein synthesis. Further characterization of the involved mechanisms may reveal important novel therapeutic targets.

ACCESSION #

52682110

Tags: ANOXEMIA;  CYCLIN-dependent kinases;  GENES;  PROTEINS -- Synthesis;  DNA damage;  BIOCHEMICAL genetics;  CAMPTOTHECIN;  MITOMYCIN C;  PROTEINS;  PHOSPHORYLATION;  TUMORS -- Treatment

 

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