Abstract
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.
Original language | English |
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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
Conference | 32nd Meeting of the International Society for Oncodevelopmental Biology and Medicine, ISOBM |
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Country/Territory | Finland |
City | Helsinki |
Period | 19/06/04 → 23/06/04 |