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TIAR and TIA-1 mRNA-binding proteins co-aggregate under conditions of rapid oxygen decline and extreme hypoxia and suppress the HIF-1α pathway.

Abstract：

:T-cell intracellular antigen (TIA)-1 and TIA-1-related protein (TIAR) are mRNA-binding proteins that can aggregate within granules under specific stress conditions. In this study, we analyzed TIAR/TIA-1 aggregation under different hypoxic conditions, and studied the effects on the hypoxia-inducible factor (HIF)-1α in different cancer cell lines. Under acute and pronounced hypoxic conditions TIAR/TIA-1 co-aggregated to granules and positive co-staining with eIF3η marker suggested these to represent stress granules. In parallel, HIF-1α expression was blocked in cells displaying TIAR/TIA-1 granules. Silencing of TIAR and TIA-1 caused upregulation of HIF-1α expression, as demonstrated by western blot, immunocytochemistry and HIF-1-dependent reporter gene expression. Additionally, a critical region of the 3' end of the untranslated HIF-1α mRNA with possible adenosine-uridine-rich elements (AREs) was coupled to the luciferase reporter gene, causing downregulation of expression. Employing this reporter construct, inhibition of TIAR by siRNA attenuated the inhibitory cis-effect of this ARE-sequence. Furthermore, immunohistochemical analysis of A549 cell tumor xenografts revealed a nearly complementary expression of HIF-1α and TIAR reflecting the control of HIF-1α expression by TIAR as revealed in the cell culture studies. In sum, rapid and severe hypoxia caused co-aggregation of TIAR/TIA-1 and these proteins suppressed HIF-1α expression.

journal_name

J Mol Cell Biol

journal_title

Journal of molecular cell biology

authors

Gottschald OR,Malec V,Krasteva G,Hasan D,Kamlah F,Herold S,Rose F,Seeger W,Hänze J

doi

10.1093/jmcb/mjq032

subject

Has Abstract

pub_date

2010-12-01 00:00:00

pages

345-56

issue

6

eissn

1674-2788

issn

1759-4685

pii

mjq032

journal_volume

2

pub_type

杂志文章

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