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Professor Margaret Ashcroft

Research Interests

My research focuses on the role of hypoxia inducible factors (HIF) in cancer, cardiovascular disease and renal disease. Our group also studies the role of HIF in cardioprotection.

HIF-1, the prototype of the family is composed of α and β subunits. Regulation of HIF-1 activity is primarily via the HIF-1α subunit, which is rapidly turned over via ubiquitin-mediated degradation by the proteosome; however, the HIF-1β subunit is constitutively expressed. In response to low oxygen tension (hypoxia), HIF-1α protein is stabilised and localises to the nucleus where it binds to HIF-1β and recruits transcriptional coactivators.

Our main goals are to:

1) Evaluate known and novel regulators of the hypoxia/HIF signalling with particular focus on link between mitochondria and the cellular oxygen-sensing machinery.

2) Investigate the key cellular mechanisms regulating hypoxia/HIF signalling in mammalian cells and elucidate how these are mechanistically linked to disease.

3) Identify and develop strategies to exploit hypoxia/HIF signalling in disease.

Keywords

cancer ; reperfusion ; mitochondria ; hypoxia ; HIF ; angiogenesis ; cardioprotection ; ischaemia

Key Publications

Targeting tumour hypoxia to prevent cancer metastasis. From biology, biosensing and technology to drug development: the METOXIA consortium. Pettersen EO, Ebbesen P, Gieling RG, Williams KJ, Dubois L, Lambin P, Ward C, Meehan J, Kunkler IH, Langdon SP, Ree AH, Flatmark K, Lyng H, Calzada MJ, Peso LD, Landazuri MO, Görlach A, Flamm H, Kieninger J, Urban G, Weltin A, Singleton DC, Haider S, Buffa FM, Harris AL, Scozzafava A, Supuran CT, Moser I, Jobst G, Busk M, Toustrup K, Overgaard J, Alsner J, Pouyssegur J, Chiche J, Mazure N, Marchiq I, Parks S, Ahmed A, Ashcroft M, Pastorekova S, Cao Y, Rouschop KM, Wouters BG, Koritzinsky M, Mujcic H, Cojocari D. J Enzyme Inhib Med Chem. 2014 Oct 27:1-33. [Epub ahead of print]

HIF-1 reduces ischaemia-reperfusion injury in the heart by targeting the mitochondrial permeability transition pore. Ong SG, Lee WH, Theodorou L, Kodo K, Lim SY, Shukla DH, Briston T, Kiriakidis S, Ashcroft M, Davidson SM, Maxwell PH, Yellon DM, Hausenloy DJ. Cardiovasc Res. 2014 Oct 1;104(1):24-36.

The synthesis and structure revision of NSC-134754. Hickin JA, Ahmed A, Fucke K, Ashcroft M, Jones K. Chem Commun (Camb). 2014 Feb 7;50(10):1238-40.

Chemotherapy-mediated p53-dependent DNA damage response in clear cell renal cell carcinoma: role of the mTORC1/2 and hypoxia-inducible factor pathways. Selvarajah J, Nathawat K, Moumen A, Ashcroft M, Carroll VA. Cell Death Dis. 2013 Oct 17;4:e865.

Evaluation and immunohistochemical qualification of carbogen-induced ΔR₂ as a noninvasive imaging biomarker of improved tumor oxygenation. Baker LC, Boult JK, Jamin Y, Gilmour LD, Walker-Samuel S, Burrell JS, Ashcroft M, Howe FA, Griffiths JR, Raleigh JA, van der Kogel AJ, Robinson SP. Int J Radiat Oncol Biol Phys. 2013 Sep 1;87(1):160-7.

Cezanne regulates inflammatory responses to hypoxia in endothelial cells by targeting TRAF6 for deubiquitination. Luong le A, Fragiadaki M, Smith J, Boyle J, Lutz J, Dean JL, Harten S, Ashcroft M, Walmsley SR, Haskard DO, Maxwell PH, Walczak H, Pusey C, Evans PC. Circ Res. 2013 Jun 7;112(12):1583-91.

The HIF-pathway inhibitor NSC-134754 induces metabolic changes and anti-tumour activity while maintaining vascular function. Baker LC, Boult JK, Walker-Samuel S, Chung YL, Jamin Y, Ashcroft M, Robinson SP. Br J Cancer. 2012 May 8;106(10):1638-47.

Human CHCHD4 mitochondrial proteins regulate cellular oxygen consumption rate and metabolism and provide a critical role in hypoxia signaling and tumor progression. Yang J, Staples O, Thomas LW, Briston T, Robson M, Poon E, Simões ML, El-Emir E, Buffa FM, Ahmed A, Annear NP, Shukla D, Pedley BR, Maxwell PH, Harris AL, Ashcroft M. J Clin Invest. 2012 Feb 1;122(2):600-11.

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