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Post‐transcriptional regulation of heparanase gene expression by a 3’ AU‐rich element
Author(s) -
Arvatz Gil,
Barash Uri,
Nativ Ofer,
Ilan Neta,
Vlodavsky Israel
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.10.156372
Subject(s) - heparanase , untranslated region , microbiology and biotechnology , gene expression , three prime untranslated region , gene , transcriptional regulation , regulation of gene expression , biology , messenger rna , cancer research , cancer , genetics , metastasis
ABSTRACT Heparanase up‐regulation was documented in an increasing number of human carcinomas, associated with poor prognosis. The purpose of the current study was to identify mechanisms responsible for heparanase induction. We provide evidence that heparanase expression is regulated at the post‐transcriptional level by sequences at the 3’ untranslated region (3’ UTR) of the gene. Constructing the 3’ UTR immediately following the heparanase cDNA reduces heparanase enzymatic activity and protein levels, resulting in decreased cellular invasion capacity. We further identified a 185‐bp sequence within the 3’ UTR that mediates heparanase down‐regulation, and characterized an adenine (A)/uracil (U)‐rich consensus element (ARE) within this region. Deletion of the entire 185‐bp region or the ARE eliminated the inhibitory effect of the 3’ UTR, resulting in elevated heparanase levels and formation of larger tumor xenografts indistinguishable from those produced by heparanase‐overex‐pressing cells in terms of size, vascularization, and Akt activation. These results suggest that loss of the ARE is an important regulatory mechanism contributing to hepara‐nase induction in human cancer.—Arvatz, G., Barash, U., Nativ, O., Ilan, N., Vlodavsky, I. Post‐transcriptional regulation of heparanase gene expression by a 3’ AU‐rich element. FASEB J. 24, 4969–4976 (2010). www.fasebj.org