Browsing by Author "Donninger, Howard"
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- ItemOpen AccessGene mutations and expression in breast cancer(2000) Donninger, Howard; Parker, M IqbalBreast cancer is the most common cause of death amongst women, with the incidence of the disease varying between countries. Like all other cancers, breast cancer is a multigenic disorder with mutations in oncogenes and tumour suppressor genes playing an important role in cellular transformation and ultimately in tumour formation. In this study, 40 breast cancer patients from the Western Cape province in South Africa and 4 breast cancer cell lines were screened for mutations in the human Ha-ras oncogene and the p53 tumour suppressor gene.
- ItemOpen Accessp21-activated kinase 3 (PAK3) is an AP-1 regulated gene contributing to actin organisation and migration of transformed fibroblasts(Public Library of Science, 2013) Holderness-Parker, Nina; Donninger, Howard; Birrer, Michael J; Leaner, Virna DActivating Protein 1 (AP-1) plays a vital role in cell proliferation, differentiation and apoptosis. While de-regulation of AP-1 has been linked to many cancers, little is known regarding its downstream transcriptional targets that associate with cellular transformation. Previous studies identified PAK3, a serine/threonine kinase, as a potential AP-1 target gene. PAK3 has been implicated in a variety of pathological disorders and over-expression of other PAK-family members has been linked to cancer. In this study, we investigate AP-1 regulation of PAK3 expression and the role of PAK3 in cJun/AP-1-associated cellular transformation. Our results showed elevated PAK3 expression at both the mRNA and protein level in cJun-over-expressing Rat1a fibroblasts, as well as in transformed human fibroblasts. Elevated PAK3 expression in cJun/AP-1 over-expressing cells associated with a significant increase in PAK3 promoter activation. This increased promoter activity was lost when a single putative Jun binding site, which can bind AP-1 directly both in vitro and in vivo, was mutated. Further, inhibition of PAK3 using siRNA showed a regression in the cell morphology, migratory potential and actin organisation associated with AP-1 transformed cells. Our study is a first to describe a role for AP-1 in regulating PAK3 expression and suggest that PAK3 is an AP-1 target required for actin organization and migration observed in transformed cells.