Head of Division, Medical Biochemistry, Department of Integrative Biomedical Sciences, Associate Member, Institute of Infectious Disease and Molecular Medicine (IDM), Faculty of Health Sciences, UCT.
KEY EXPERTISE: Cancer biology, molecular biology, gene expression patterns, transcriptional regulation, nuclear transport proteins
Identify genes associated with the development and progression of cancer, as markers and potential therapeutic targets. The role of the transcription factor AP-1 in oncogenesis.
AP-1 is a dimeric transcription factor that often shows increased expression in a variety of cancers and is reported to be necessary for the transformed status of cancer cells. This project is aimed at (i) determining whether AP-1 is essential for cervical cancer biology and (ii) the characterisation of genes that are regulated by AP-1. Our results show that cJun/AP-1 and JunB/AP-1 expression levels are elevated in cervical cancers. Inhibition of AP-1 activity with a dominant-negative mutant, Tam67 and siRNA's has a significant inhibitory effect on the growth of cervical cancer cells, which is associated with changes in cell cycle progression. These findings suggest that AP-1 activity is critical for the biology of cervical cancer cells. This observation is being explored further to determine the mechanisms through which inhibition of AP-1 activity affects the growth and oncogenic potential of cervical cancer cells.
Investigate the role of transcription factors such e.g. AP-1 and associated signaling events that are altered in cancer cells. Identification of transcriptional changes and genes associated with the development of cervical cancer.
Cervical cancer is one of the most common cancers affecting women in developing countries and is associated with risk factors such as the human papiloma virus (HPV). The disease is characterised through a series of stages including low-grade squamous intraepithelial lesion, high-grade intraepithelial lesions before becoming a carcinoma. The major objective of this project is to identify genes associated with the development of cervical cancer. We have used normal and cervical cancer specimens in expression array analysis and determined gene profiles and markers that associate with the disease. Our results show that normal cervical samples and cervical cancer tissue can be separated on the basis of their gene expression patterns and we identified a subset of genes involved in nuclear transport, including Crm1, Karyopherin β1, Karyopherin α1 and Ran as highly expressed in cancer cells. The relevance of these proteins and others as potential markers of cancer progression and therapeutic targets are currently under investigation.
Stelma, T., Chi, A., Van Der Watt, P.J., Verrico, A., Lavia, P., Leaner, V.D. Targeting nuclear transporters in cancer: Diagnostic, prognostic and therapeutic potential. IUBMB Life (2016) 68(4):268-280
Van Der Watt, P.J., Chi, A., Stelma, T., Stowell, C., Strydom, E., Carden, S., Angus, L., Hadley, K., Lang, D., Wei, W., Birrer, M.J., Trent, J.O., Leaner, V.D. Targeting the nuclear import receptor Kpnβ1 as an anticancer therapeutic. Molecular Cancer Therapeutics (2016) 15(4):560-573
Dzobo, K., Leaner, V.D., Parker, M.I. Absence of feedback regulation in the synthesis of COL1A1. Life Sciences (2014) 103(1):25-33
Angus, L., Van der Watt, P.J., Leaner, V.D. Inhibition of the nuclear transporter, Kpnß1, results in prolonged mitotic arrest and activation of the intrinsic apoptotic pathway in cervical cancer cells. Carcinogenesis (2014) 35(5):1121-1131
Van Der Watt, P.J., Zemanay, W., Govender, D., Hendricks, D.T., Parker, M.I., Leaner, V.D. Elevated expression of the nuclear export protein, Crm1 (exportin 1), associates with human oesophageal squamous cell carcinoma. Oncology Reports (2014) 32(2):730-738
Division of Medical Biochemistry
Rm 6.04, Falmouth Building
Faculty of Health Sciences
University of Cape Town