Role of Siah proteins in inflammation and cancer

Funded Activity Summary

In this project we aim to define the role of the Siah proteins in tumour angiogenesis and inflammatory responses. Hypoxia, a decrease in oxygen tension, places constrains on tumour growth where access to oxygen is yet to be established via new blood vessel formation. In addition hypoxia is common in areas of inflammation and wound healing, where blood vessels have been shut down to help in recovery. With the use of our Siah knockout mice we have a unique model that allows us, for the first time, to investigate the role of Siah in the hypoxia signalling cascade. How cells sense and react to low oxygen levels is complex and involves several proteins. A key protein is called Hypoxia induced factor, Hif-1. It accumulates under hypoxia and is responsible for the expression of genes enabling the cell to tolerate and function under hypoxic conditions. tolerate and function under hypoxic conditions, which is involved in new blood vessel formation. PHD protein directs the degradation of Hif1, while Siah directs the degradation of PHD, when oxygen is limiting. Loss of Siah proteins (eg in our knockout models) leads to an increase in PHD proteins under hypoxia thus no stabilisation of Hif-1 and impaired response to hypoxia. Thus, sitting on the top of a cascade, which controls the trashing of proteins in the cell (focus of this year's Nobel price for medicine), Siah has primary control on the response to oxygen deprivation. The relative immunity of multicellular organisms to acquired defects is through redundancy. Oxygen is a unique case, for which organisms can not bypass the defect via redundancy, making it an attractive target for future therapy. Therefore, understanding the molecular and cellular response to hypoxia may allow us to identify key molecules which could be targeted for the development of novel anti inflammatory and cancer drugs. The scope of this study is to understand the key role of Siah utilising our knockout mice in models of inflammation and cancer.

Funded Activity Details

Start Date: 2006

End Date: 2008

Funding Scheme: NHMRC Project Grants

Funding Amount: $507,270.00

Funder: National Health and Medical Research Council

Research Topics

ANZSRC Field of Research (FoR)

Oncology and Carcinogenesis

ANZSRC Socio-Economic Objective (SEO)

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