Research interests

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.

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.

 

 Group Members

Pauline van der Watt	PhD student
Beverley Rose	PhD student (co-supervised with Prof. M.I. Parker)
Kevin Dzobo	PhD student (co-supervised with Prof. M.I. Parker)
Michelle Ward	MSc student
Maurice Itoe	Research Assistant
Hajira Guzgay	Technical Officer / Laboratory Manager (Cancer Group)
Robert Samuels	Departmental Assistant (Cancer Group)

 

Publications 2003-2010

Leaner VD, Chick JF, Donninger H, Linniola I, Mendoza A, Khanna C, Birrer MJ. 
Inhibition of AP-1 Transcriptional Activity Blocks the Migration, Invasion, and Experimental Metastasis Murine Osteosarcoma.
American Journal of Pathology, 2009, 174(01): 265-275

Calvisi DF, Donninger H, Vos MD, Birrer MJ, Gordon L, Leaner VD, Clark GJ.
NORE1A Tumor Suppressor Candidate Modulates p21CIP1 via p53.
Cancer Research, 2009, 69(11): 4629-4637.

Leaner VD, Chick JF, Donninger H, Linniola I, Mendoza A, Khanna C, Birrer MJ.
Inhibition of AP-1 transcriptional activity blocks the migration, invasion, and experimental metastasis of murine osteosarcoma.
Am J Pathol. 2009 Jan;174(1):265-75. Epub 2008 Dec 12.

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. Epub 2007 Aug 1

Catherine E. Whibley, Kerry L. McPhail, Robert A. Keyzers, Michelle F. Maritz, Virna D. Leaner, Michael J. Birrer, Michael T. Davies-Coleman and Denver T. Hendricks, Reactive oxygen species mediated apoptosis of oesophageal cancer cells induced by marine triprenyl toluquinones and toluhydroquinones. Mol Cancer Ther. Sep;6 (9):2535-43 (2007).

Virna D. Leaner, Howard Donninger and Michael J. Birrer., Transcription factors as targets for cancer therapy: AP-1 as a potential target. Current Cancer Therapy Reviews, 3: 1-6 (2007).

Virna D. Leaner and M. Iqbal Parker, Phosphorylation of the α2(1) procollagen promoter binding proteins is required for DNA binding and proximal promoter activity. IUBMB Life. 58(2):97-102 (2006).

Nummela P, Yin M, Kielosto M, Leaner V, Birrer MJ, Holtta E. Thymosin beta4 is a determinant of the transformed phenotype and invasiveness of S-adenosylmethionine decarboxylase-transfected fibroblasts. Cancer Res. 66 (2):701-12 (2006).

Virna D. Leaner, Howard Donninger, Chad A. Ellis, Geoffrey J. Clark and Michael J. Birrer, p75-Ras-GRF1 is a cJun/AP-1 target gene: its up regulation results in increased Ras activity and is necessary for cJun induced non adherent growth of Rat1a cells,Mol. Cell. Biol. 8: 3324-3337 (2005).

Virna D. Leaner, Agatha Masemola, and M. Iqbal Parker., Species-specific regulation of the α2(I) procollagen gene by proximal promoter elements., IUBMB Life 5: 363-369 (2005).

Katabami M, Donninger H, Hommura F, Leaner VD, Kinoshita I, Chick JF, Birrer MJ. Cyclin A is a cJun target gene and is necessary for cJun-induced anchorage independent growth in Rat1a cells. J. Biol. Chem. 280: 16728-16738 (2005).

Matladi 'Ndlovo, Virna D. Leaner and M.Iqbal Parker, Methylation of the α2(I) procollagen proximal promoter inhibits gene expression in SV40-transformed fibroblasts., SAJS., 101: 187-191 (2005).

Hommura F, Katabami M, Leaner VD, Donninger H, Sumter TF, Resar LM, Birrer MJ. HMG-I/Y is a c-Jun/activator protein-1 target gene and is necessary for c-Jun-induced anchorage-independent growth in Rat1a cells. Mol. Cancer Res.; 2(5): 305-14 (2004).

Kielosto M, Nummela P, Katainen R, Leaner V, Birrer MJ, Holtta E. Reversible regulation of the transformed phenotype of ornithine decarboxylase- and ras-overexpressing cells by dominant-negative mutants of c-Jun. Cancer Research. 64 (11):3772-9 (2004).

Virna D. Leaner, Ichiro Kinoshita and Michael J. Birrer. AP-1 complexes containing cJun and JunB cause cellular transformation of Rat1a cells and share transcriptional targets. Oncogene, 22: 5619-5629, (2003).

Shen YH, Godlewski J, Zhu J, Sathyanarayana P, Leaner V, Birrer MJ, Rana A, Tzivion G. Cross talk between JNK/SAPK and ERK/MAPK pathways: Sustained activation of JNK blocks ERK activation by mitogenic factors. J. Biol. Chem., 278 (29): 26715-21 (2003).

Kinoshita I, Leaner V, Katabami M, Manzano RG, Dent P, Sabichi A, Birrer MJ. Identification of cJun-responsive genes in Rat-1a cells using multiple techniques: increased expression of stathmin is necessary for cJun-mediated anchorage-independent growth. Oncogene, 22 (18):2710-22 (2003)

 

List of Collaborators

Dr. D. Hendricks	Medical Biochemistry, UCT
Prof. M.I. Parker	ICGEB (SA) & Medical Biochemistry, UCT
Prof. L. Denny	Obstetrics and Gynaecology, UCT & Groote Schuur Hospital
Prof. D. Govender	Anatomical Pathology, UCT
Dr. C. Maske	Anatomical Pathology, UCT
Dr. M. Birrer	National Institutes of Health, USA
Dr. H. Donninger	University of Louisville, Kentucky, USA