Mayo Clinic, United States.

Tetradecanoyl phorbol acetate-inducible sequence 11b (TIS11B) belongs to a group of RNA-binding proteins (including TIS11/TTP/tristetraprolin and TIS11D) that share characteristic tandem CCCH-type zinc-finger domains and can be rapidly induced by multiple stimuli. TIS11B has been shown to regulate vascular endothelial growth factor (VEGF) mRNA stability in ACTH-stimulated primary adrenocortical cells. TIS11B has also been documented as a negative regulator of VEGF during development, but nothing has yet been reported in the context of human cancers. Tumor suppressor protein Von Hippel Lindau (VHL) regulates VEGF gene expression at both the transcriptional and the post-transcriptional level in normoxia. However, whether it can do so in hypoxia is still unclear. Here we report a unique regulatory function of VHL on VEGF expression in hypoxia that is mediated through modulation of TIS11B protein levels in renal cancer cells (RCC). In normoxia, we detected increased expression of the microRNA (miRNA) hsa-miR-29b in the VHL-overexpressing renal cancer cell line 786-O. We also showed that this increased expression of hsa-miR-29b decreases TIS11B protein expression by post-transcriptional regulation under normoxia. In contrast, in hypoxia, increased TIS11B expression parallels an increased TIS11B mRNA stability in VHL-overexpressed 786-O cells. This VHL-mediated TIS11B up-regulation in hypoxia may be important for TIS11B-regulated gene expression: we observed a down-regulation of VEGF mRNA under hypoxia in VHL-overexpressing cells compared to parental 786-O cells, and this effect was reversible by silencing TIS11B expression.

Written by:
Sinha S, Dutta S, Datta K, Ghosh AK, Mukhopadhyay D.   Are you the author?

Reference:
J Biol Chem. 2009 Sep 28. Epub ahead of print.
doi:10.1074/jbc.M109.058065

PubMed Abstract
PMID:19801654

UroToday.com Renal Cancer Section

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