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Professor Margaret Ashcroft

Research themes

Vascular Medicine:

Research Interests

The main goal of the Ashcroft laboratory is to understand the key cellular mechanisms involved in oxygen sensing and hypoxia signalling in mammalian cells. In particular, we have a strong interest in the hypoxia inducible factor (HIF) family of transcription factors and their role in cancer, renal disease and cardiovascular disease.

Background

We are interested in how the oxygen sensing machinery controls cell function and adaptive processes that are associated with a variety of diseases including cancer, renal disease and cardiovascular disease. Our work primarily focuses on the heterodimeric transcription factor family, hypoxia inducible factor (HIF). 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.

Research Aims

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

Collaborators outside this directory

Key Publications

CHCHD4 confers metabolic vulnerabilities to tumour cells through its control of the mitochondrial respiratory chain.   Thomas LW, Stephen JM, Esposito C, Hoer S, Antrobus R, Ahmed A, Al-Habib H, Ashcroft M.

Cancer Metab. 2019 Mar 6;7:2. doi: 10.1186/s40170-019-0194-y. eCollection 2019.

Exploring the molecular interface between hypoxia-inducible factor signalling and mitochondria.   Thomas LW, Ashcroft M.  

Cell Mol Life Sci. 2019 Feb 14. doi: 10.1007/s00018-019-03039-y. [Epub ahead of print] Review.

VHL-mediated regulation of CHCHD4 and mitochondrial function. Briston T., Stephen J., Thomas L.W., Esposito C., Chung Y.L., Syafruddin S., Turmaine M., Maddalena L., Greef B., Szabadkai G., Maxwell P.H., Vanharanta S. and Ashcroft M. Front Oncology (2018) 8: 388.

The mitochondrial oxidoreductase CHCHD4 is present in a semi-oxidized state in vivo. Erdogan A.J., Ali M., Habich M., Salscheider S.L., Schu L., Petrungaro C., Thomas L.W., Ashcroft M., Leichert L.I., Roma L.P. and Riemer J. Redox Biol (2018) 17: 200-206.

CHCHD4 regulates intracellular oxygenation and perinuclear distribution of mitochondria. Thomas L.W., Staples O., Turmaine M., Ashcroft M. Frontiers in Oncology (2017) 7: 71.

Mutations in mitochondrial DNA causing tubulointerstitial kidney disease. Connor T.M., Hoer S., Mallett A., Gale D.P., Gomez-Duran A., Posse V., Antrobus R., Moreno P., Sciacovelli M., Frezza C., Duff J., Sheerin N.S., Sayer J.A., Ashcroft M., Wiesener M.S., Hudson G., Gustafsson C.M., Chinnery P.F., Maxwell P.H. PLoS Genet (2017) 13: e1006620.

The synthesis and structure revision of NSC-134754. Hickin J.A., Ahmed A., Fucke K., Ashcroft M., Jones K. Chem Commun (Camb) (2014) 50: 1238-1240.

The HIF-pathway inhibitor NSC-134754 induces metabolic changes and anti-tumour activity while maintaining vascular function. Baker L.C., Boult J.K., Walker-Samuel S., Chung, Y.L. Jamin Y., Ashcroft M., Robinson, S.P. Br J Cancer (2012) 106: 1638-1647.

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 L.W., Briston T., Robson M., Poon E., Simões M.L., El-Emir E., Buffa F.M., Ahmed A., Annear N.P., Shukla D., Pedley B.R., Maxwell P.H., Harris A.L., Ashcroft M. J Clin Invest (2012) 122: 600-611.

HIF-1alpha localization with mitochondria: A new role for an old favorite? Briston, T., Yang J., Ashcroft M. Cell Cycle (2011) 10: 4170-4171.

Pharmacological activation of a novel p53-dependent S-phase checkpoint involving CHK-1. Ahmed A., Yang J., Maya-Mendoza A., Jackson D.A., Ashcroft M. Cell death & disease (2011) 2: e160.

Small-molecule activation of p53 blocks hypoxia-inducible factor 1alpha and vascular endothelial growth factor expression in vivo and leads to tumor cell apoptosis in normoxia and hypoxia. Yang J., Ahmed A., Poon E., Perusinghe N., de Haven Brandon A., Box G., Valenti M., Eccles S., Rouschop K., Wouters B., Ashcroft M. Mol Cell Biol (2009) 29: 2243-2253.

Targeting the hypoxia-inducible factor (HIF) pathway in cancer. Poon E., Harris A.L., Ashcroft M. Expert Rev Mol Med (2009) 11: e26.

Selective inhibition of MEK1/2 reveals a differential requirement for ERK1/2 signalling in the regulation of HIF-1 in response to hypoxia and IGF-1. Sutton K.M., Hayat S., Chau N.M., Cook S., Pouyssegur N., Ahmed A., Perusinghe N., Le Floch R., Yang J.,  Ashcroft M.   Oncogene (2007) 26(27):3920-9.

Role of hypoxia-inducible factor (HIF)-1alpha versus HIF-2alpha in the regulation of HIF target genes in response to hypoxi, insulin-like growth factor-I, or loss of von Hippel-Lindau function: implications for targeting the HIF pathway. Carroll V.A.,  Ashcroft M. Cancer Res (2006) 66(12):6264-70.

Identification of novel small molecule inhibitors of hypoxia-inducible factor-1 that differentially block hypoxia-inducible factor-1 activity and hypoxia-inducible factor-1alpha induction in response to hypoxic stress and growth factors. Chau N.M., Rogers P., Aherne W., Carroll V., Collins I., McDonald E., Workman P., Ashcroft M.   Cancer Res  (2005) 65(11):4918-28.

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