Accumulation of Krebs cycle intermediates and over-expression of HIF1α in tumours which result from germline FH and SDH mutations

We have shown that fumarate hydratase -deficient cells and tumours accumulate fumarate and, to a lesser extent, succinate

P.J. Pollard; J.J. Brière; N.A. Alam; J. Barwell; E. Barclay; N.C. Wortham; T. Hunt; M. Mitchell; S. Olpin; S.J. Moat; I.P. Hargreaves; S.J. Heales; Y.L. Chung; J.R. Griffiths; A. Dalgleish; J.A. McGrath; M.J. Gleeson; S.V. Hodgson; R. Poulsom; P. Rustin; I.P.M. Tomlinson

2005

Scholarcy highlights

  • Succinate dehydrogenase and fumarate hydratase are housekeeping genes which encode the Krebs cycle proteins involved in the fundamental processes of energy production
  • We initially used metabolomic profiling to study the effects of FH mutations on succinate and fumarate accumulation by analysing skin fibroblasts from four patients suffering from the recessive disorder fumarase deficiency
  • Our results have demonstrated that bi-allelic FH mutations, whether in hereditary leiomyomatosis and renal cell cancer tumours or in cells from fumarase deficiency patients, result in raised levels of both fumarate and succinate
  • We have shown that benign and malignant tumours in the HLRCC syndrome exhibit accumulation of the hypoxia-inducible factor 1a protein, the central signalling molecule in the hypoxia pathway
  • HIF1a accumulates in hereditary paragangliomatosis with phaeochromocytomas tumours, which result from germline SDHB mutations, adding to the existing data showing HIF1a expression in SDHD-mutant tumours
  • HIF1a levels are higher in HLRCC fibroids than in surrounding myometrium, and we have previously found that the expression levels of HIF1a targets, such as vascular endothelial growth factor, TSP1 and BNIP1, are higher in HLRCC fibroids than in sporadic leiomyomas
  • Activities of mitochondrial respiratory chain enzymes were measured in fumarate hydratase-deficient and control cells as previously described

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