Iron Metabolism and Chelation Program

Lab head: Des Richardson
Location: Blackburn Building (D06), Department of Pathology

Iron is essential for life and growth. While it is well known that iron deficiency can lead to anaemia it is generally not appreciated that iron is critical for the growth of all cells, particularly cancer cells. The Iron Metabolism and Chelation Program is concerned with understanding the basic processes of how tumour cells utilise and transport iron. This knowledge will lead to the development of therapies that can selectively starve tumour cells of iron and inhibit their growth. In addition, we are studying the mechanisms involved in iron loading in the inherited diseases I2-thalassaemia and Friedreich's ataxia.

Lab members: D Richardson (head), C Austin (pfellow), K Dixon (pfellow), P Jansson (pfellow), D Kalinowski (pfellow), D Lane (pfellow), K Loh (pfellow), D Lovejoy (pfellow), P Quach (pfellow), Y Suryo Rahmanto (pfellow), D Zhang (pfellow)

The role of ascorbate in modulating hypoxic signalling in iron metabolism

Primary supervisor: Darius Lane

Knowledge of the biochemistry of the cell is important for understanding normal metabolism and disease processes. Iron (Fe) is essential for life and it has long been recognised that vitamin C (ascorbate)-deficiency contributes to Fe-deficiency anaemia and other symptoms of ascorbate deficiency. Revealingly, this anaemia can only be rectified by both ascorbate and Fe supplementation.

Under physiological conditions, circulating Fe is bound to the Fe-binding protein, transferrin (Tf), with Tf-Fe uptake being the major route of Fe uptake by mammalian cells. Tf-Fe uptake is also the sole contributor of Fe for the daily production 200 billion new erythrocytes. We have recently identified that ascorbate, which is abundant in vivo but typically absent in standard cell culture, dramatically stimulates Fe uptake from Tf-Fe in certain cell types, although the molecular mechanism involved is still unclear.

It is known that cellular hypoxia (low oxygen tension) stimulates Tf-Fe uptake by up-regulating the expression of proteins involved in the classical Tf-to-cell cycle for Fe delivery (e.g., the Tf receptor; TfR1). Hypoxia signals for an increase in the transcription of specific genes containing so-called hypoxia response elements (HREs) by promoting stabilisation of the hypoxia-inducible factor (HIF)1α sub-unit of the HIF1 transcription factor. Crucially, as ascorbate is known to modulate HIF1 expression and HIF1-dependent signalling, it is important to determine if the effect of ascorbate on Tf-Fe uptake relates to the effect of ascorbate on HIF1 signalling.

A variety of fundamental biochemical and molecular biological techniques will be employed, including mammalian cell culture, Western blotting, quantitative reverse-transcriptional PCR, gene ‘knockdown’ via RNA interference, transfection, 59Fe uptake assays, ascorbate determination assays etc.

The aim of this project is to determine the contribution of ascorbate to the modulation of HIF1-dependent signalling in cellular Fe metabolism. This will have important ramifications for the treatment of diseases ranging from anaemia to cancer (in which HIF1 signalling is activated and Fe uptake is increased).

Discipline: Pathology
Co-supervisors: Des Richardson
Keywords: Cell & Molecular Biology, Iron Metabolism, Biochemistry