Aims: Hereditary Leiomyomata and Renal Cell Cancer (HLRCC) is a genetic disorder predisposing to dominantly inherited uterine fibroids, skin leiomyomata and renal cell cancer and has been linked to mutations in fumarase, one of the mitochondrial Kreb's cycle genes, which has been proposed to act as a tumor suppressor gene. In this study S. cerevisiae was used as a model organism to study the mechanisms of HLRCC by creating yeast strains with disease-linked mutations H153R, K187R or knockout deletion in the yeast fumarase gene. Methods: The phenotypes and functionalities of the constructed mutant strains were studied using growth tests on fermentative and respiratory carbon sources, protein expression tests and enzyme activity assays. Transcriptional profiling of the strains was done using DNA microarray technology. Results: In growth tests reduced growth was observed in mutated yeast strains on fermentative medium. Both H153R and K187R mutant strains were shown to express fumarase with considerable decrease in enzyme activities while in the deletion strain no fumarase activity was detected. This was in agreement with the microarray results, where the fumarase gene expression levels in the mutant and knockout strains had decreased. In general, over 300 genes were found to have over 3 fold change in expression levels in response to fumarase mutation or deletion when compared to the strain containing the wild type fumarase. Conclusions: The deletion of fumarase in yeast blocked the mitochondrial respiratory function of the cell, which was restored, at least partially, by the introduction of fumarase with mutation H153R or K187R to the cell. The experimental results indicated yeast S. cerevisiae to be a useful model for studies of the mechanisms behind the HLRCC.
|Publication status||Published - 2004|
|MoE publication type||Not Eligible|
|Event||32nd Meeting of the International Society for Oncodevelopmental Biology and Medicine, ISOBM - Helsinki, Finland|
Duration: 19 Jun 2004 → 23 Jun 2004
|Conference||32nd Meeting of the International Society for Oncodevelopmental Biology and Medicine, ISOBM|
|Period||19/06/04 → 23/06/04|