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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Mizrahi, Aya Degroot, Nathan Ohana, Patricia Fellig, Yakov Galun, Eithan Hochberg, Abraham Mezan, Shaul Matouk, Imad J. Abu-lail, Rasha |
| Description | Author Affiliation: Matouk IJ ( The Department of Biological Chemistry, Alexander Silberman Institute of life Science, The Hebrew University of Jerusalem, Israel. imad.matouq@mail.huji.ac.il) |
| Abstract | Expression of the imprinted H19 gene is remarkably elevated in a large number of human cancers. Recently, we reported that H19 RNA is up-regulated in hypoxic stress and furthermore, it possesses oncogenic properties. However, the underlying mechanism(s) of these phenomena remain(s) unknown. Here we demonstrate a tight correlation between H19 RNA elevation by hypoxia and the status of the p53 tumor suppressor. Wild type p53 (p53 $^{wt}$ ) prevents the induction of H19 upon hypoxia, and upon its reconstitution in p53 $^{null}$ cells. The last case is accompanied by a decrease in cell viability. The p53 effect is nuclear and seems independent of its tetramerization. Furthermore, using knockdown and over-expression approaches we identified HIF1-α as a critical factor that is responsible for H19 induction upon hypoxia. Knocking down HIF1-α abolishes H19 RNA induction, while its over-expression significantly enhances the H19 elevation in p53 $^{null}$ hypoxic cells. In p53 $^{wt}$ hypoxic cells simultaneous suppression of p53 and over-expression of HIF1-α are needed to induce H19 significantly, while each treatment separately resulting in a mild induction, indicating that the molecular mechanism of p53 suppression effect on H19 may at least in part involve interfering with HIF1-α activity . In vivo a significant increase in H19 expression occurred in tumors derived from p53 $^{null}$ cells but not in p53 $^{wt}$ cells. Taken together, our results indicate that a functional link exists between p53, HIF1-α and H19 that determines H19 elevation in hypoxic cancer cells. We suggest that this linkage plays a role in tumor development. |
| ISSN | 00063002 |
| Journal | Biochimica et Biophysica Acta (BBA) - Reviews on Cancer |
| Issue Number | 4 |
| Volume Number | 1803 |
| Language | English |
| Publisher | Elsevier |
| Publisher Date | 2010-04-01 |
| Publisher Place | Netherlands |
| Access Restriction | Open |
| Subject Keyword | Hypoxia-Inducible Factor 1, Alpha Subunit Metabolism Anoxia Neoplasms RNA, Untranslated Genetics Tumor Suppressor Protein P53 Physiology Animals Blotting, Western Cell Line, Tumor Cell Proliferation Gene Expression Regulation, Neoplastic Antagonists & Inhibitors Mice Mice, Nude Pathology RNA, Long Noncoding RNA, Messenger RNA, Small Interfering Pharmacology Reverse Transcriptase Polymerase Chain Reaction Research Support, Non-U.S. Gov't Biochemistry |
| Content Type | Text |
| Resource Type | Article |
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