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Dr. Daniel Foxler

The LIMD1 Protein Bridges an Association between the Prolyl Hydroxylases and VHL to Repress HIF1 Activity

Abstract

The cells response to low levels of oxygen is called the hypoxic response and is critical for a normal healthy physiology. When deregulated, it can lead to many human diseases including cancer. The master regulator of the hypoxic response is the hypoxia-inducible factor (HIF), a transcriptional activator. In normal oxygen concentrations the combined action of three prolyl hydroxylases (PHD1-3) and the von Hippel-Lindau (VHL) E3-ubiquitin ligase leads to down-regulation of HIF through the ubiquitylation and degradation of the HIF1α subunit. We have discovered the Zyxin family of LIM domain containing proteins as novel key regulators of the hypoxic response. In particular, we show family member and tumour suppressor protein LIMD1 simultaneously binds the PHDs and VHL, concentrating their ezymatic activities into a single complex, enabling efficient HIF1α degradation. Depletion of endogenous LIMD1 decreases the efficiency of degradation, increasing HIF1α protein levels and transcriptional activity. Conversely, LIMD1 expression down regulates HIF1 protein and transcriptional activity. LIMD1 expression is also up-regulated in hypoxia, which facilitates HIF1α degradation under hypoxic conditions, allowing attenuation of the hypoxic response to prevent inappropriate cell proliferation. The hypoxic up-regulation of LIMD1 is driven by HIF1α, thus forming a regulatory feedback loop of HIF1 regulation.

Thus the discovery of this new family of regulator proteins represents a significant advance in our understanding of this complex process and combating many types of cancer where deregulation of the hypoxic response is known to occur.

After graduating from the University of Nottingham with my undergraduate degree in Biochemistry, I undertook my PhD studies at Nottingham under the supervision of Dr Tyson Sharp. Shortly after completing my thesis, I transferred with Tyson to Barts Cancer Institute, Queen Mary University of London, where I am currently continuing my research as a Postdoc, investigating the role of the tumour suppressor protein LIMD1 in the regulation of the hypoxic response.

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