Regulation of hypoxia inducible factors by Sprouty2 (842.9)

Abstract

Sprouty2 (Spry2) is an inhibitor of receptor tyrosine kinase signaling. Spry2 levels are decreased in cancers of the breast, lung, prostate and liver, thereby permitting excessive receptor tyrosine kinase signaling in these pathologies. Furthermore, a decrease in Spry2 levels has been correlated with poor patient prognosis. In development and tumor growth, cells experience a hypoxic environment to which they adapt to by up regulating the transcription factors, Hypoxia Inducible Factors (HIFs). The HIFs are composed of a beta subunit (HIF1β or aryl hydrocarbon nuclear translocator (ARNT)) and an oxygen sensitive alpha subunit (HIF1α or HIF2α). Using a hepatocellular carcinoma cell line (HuH7), we have shown that Spry2 decreases the protein levels of HIF1α, HIF2α, and ARNT without altering the mRNA levels. Additionally, Spry2 reduces the ability of the HIFs to induce transcription as measured by luciferase assays and mRNA levels of their target genes. We also show that Spry2 interacts with HIF1α and ARNT and that Spry2 decreases the stability of ARNT and HIF1α. To begin to deduce the mechanism, we have shown that Spry2 enhances the ubiquitination of HIF1α. Collectively, our data reveal a novel regulation of the HIFs by Spry2.Grant Funding Source: Supported in part by NIH grant GM 073181