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Research

Pauline van der Watt group

Research interests

Investigating disruptions in the circadian clock in cancer and transformed cells

The circadian clock is man’s internal time-keeping mechanism; it synchronises physiological processes with the external 24 hour cycle of day and night. It is becoming increasingly apparent that disruptions in the circadian clock can promote cancer development, as highlighted by the increasing cancer incidence amongst night shift workers. Furthermore, alternations in expression of circadian clock genes have been identified in multiple tumour types. At the molecular level, circadian clock proteins are shuttled from the cytoplasm into the nucleus at particular times of the day to perform their functions, and the nuclear transport machinery is thus critical in maintaining the correct pace of the circadian clock. Yet, we have previously shown that components of the nuclear transport machinery are significantly deregulated in cancer cells. We are interested in investigating the molecular circadian clock in cancer cells, focusing on how altered nuclear transport in cancer cells could contribute to a disrupted circadian clock. An improved understanding of how the circadian clock is altered in cancer cells is highly relevant as it has been shown that the time of day of administration of chemotherapy greatly influences the tumour response. In addition, it has been shown that targeting the circadian clock can improve the efficacy of certain chemotherapies, as well as having an anti-tumourigenic effect itself.   

Investigating the nuclear importer protein, Karyopherin β1, as a cancer diagnostic and therapeutic target

Karyopherin β1 (Kpnβ1) is the principle nuclear importer protein in the cell; it recognises proteins carrying a nuclear localisation signal (NLS) and transports them from the cytoplasm into the nucleus. We have found that Kpnβ1 expression is significantly increased in cancer cells compared to normal cells, implicating it as potential cancer diagnostic marker. In addition, we have found that its inhibition results in cancer cell death while only having a minor effect on normal cell viability, suggesting that its targeting with small molecules could have therapeutic potential. We are currently investigating its potential in these regards by analysing Kpnβ1 levels in normal and cancer patients, and identifying novel small molecule inhibitors to target Kpnβ1. This work is done in collaboration with Prof. Virna Leaner.


Group members

Pauline van der Watt

NRF Early Career Award Fellow

Prof. Virna Leaner

Mentor

Sarah Carden

MSc student (co-supervised with Prof. V.Leaner)

Andrew Wishart

MSc student (co-supervised with Prof. V.Leaner)

Michael Okpara

MSc student (co-supervised with Prof. V.Leaner)

Kate Davis

Honours student

Machaba Sathekge

Honours student (co-supervised with Prof. V.Leaner)

Hajira Guzgay

Technical officer/laboratory manager (Cancer Group)

Robert Samuels

Departmental Assistant (Cancer Group)

 

Publications 2008-2017

Stelma T, Chi A, van der Watt PJ, Verrico A, Lavia P, Leaner VD. Targeting nuclear transporters in cancer: Diagnostic, prognostic and therapeutic potential. IUBMB Life. 2016 Apr;68(4):268-80.

van der Watt PJ, Chi A, Stelma T, Stowell C, Strydom E, Carden S, Angus L, Hadley K, Lang D, Wei W, Birrer MJ, Trent JO, Leaner VD. Targeting the Nuclear Import Receptor Kpnβ1 as an Anticancer Therapeutic. Mol Cancer Ther. 2016 Apr;15(4):560-73.

van der Watt PJ, Zemanay W, Govender D, Hendricks DT, Parker MI, Leaner VD. Elevated expression of the nuclear export protein, Crm1 (exportin 1), associates with human oesophageal squamous cell carcinoma. Oncol Rep. 2014 Aug;32(2):730-8.

Angus L, van der Watt PJ, Leaner VD. Inhibition of the nuclear transporter, Kpnβ1, results in prolonged mitotic arrest and activation of the intrinsic apoptotic pathway in cervical cancer cells. Carcinogenesis. 2014 May;35(5):1121-31.

van der Watt PJ, Stowell CL, Leaner VD. The nuclear import receptor Kpnβ1 and its potential as an anticancer therapeutic target. Crit Rev Eukaryot Gene Expr. 2013;23(1):1-10.

van der Watt PJ, Ngarande E, Leaner VD. Overexpression of Kpnβ1 and Kpnα2 importin proteins in cancer derives from deregulated E2F activity. PLoS One. 2011;6(11):e27723.

Ward MC, van der Watt PJ, Tzoneva G, Leaner VD. Deregulated LAP2α expression in cervical cancer associates with aberrant E2F and p53 activities. IUBMB Life. 2011 Nov;63(11):1018-26.

van der Watt PJ, Leaner VD. The nuclear exporter, Crm1, is regulated by NFY and Sp1 in cancer cells and repressed by p53 in response to DNA damage. Biochim Biophys Acta. 2011 Jul;1809(7):316-26.

Maritz MF, van der Watt PJ, Holderness N, Birrer MJ, Leaner VD. Inhibition of AP-1 suppresses cervical cancer cell proliferation and is associated with p21 expression. Biol Chem. 2011 May;392(5):439-48.

van der Watt PJ, Maske CP, Hendricks DT, Parker MI, Denny L, Govender D, Birrer MJ, Leaner VD. The Karyopherin proteins, Crm1 and Karyopherin beta1, are overexpressed in cervical cancer and are critical for cancer cell survival and proliferation. Int J Cancer. 2009 Apr 15;124(8):1829-40.

Fromme BJ, Coetsee M, van der Watt P, Chan MC, Sperling KM, Katz AA, Flanagan CA. High-affinity binding of southern African HIV type 1 subtype C envelope protein, gp120, to the CCR5 coreceptor. AIDS Res Hum Retroviruses. 2008 Dec;24(12):1527-36.

Copley L, van der Watt P, Wirtz KW, Parker MI, Leaner VD. Photolon, a chlorin e6 derivative, triggers ROS production and light-dependent cell death via necrosis. Int J Biochem Cell Biol. 2008;40(2):227-35.