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Fumarate hydratase as tumor suppressor
Kedrová, Kateřina ; Hansíková, Hana (advisor) ; Befekadu, Asfaw (referee)
1 Abstract Fumarate hydratase (fumarase, EC 4.2.1.2) catalyzes the reverse hydration of fumarate to S malate. In mammalian cells, it changes fumarate in the mitochondrial matrix as a part of the citric acid cycle and in the cytosol, where functions to metabolize fumarate the product of the degradation of some amino acids, of ammonia transformation to urea acid or of the purine nucleotide synthesis. . In human cells, fumarase is encoded by FH gene localized on chromosome 1 (1q42.1). The FH gene consists of 10 exons and encodes for a 510 amino acids-long protein including the N-terminal mitochondrial signal sequence. Germline heterozygous FH mutations were found in two autosomal dominant syndromes. These are multiple cutaneous and uterine leiomyomatosis (MCUL1 or MCL) and hereditary leiomyomatosis and renal cell cancer (HLRCC). In the most of tumors from these patients, loss of FH gene heterozygosity was also found. It has been suggested that fumarase acts as a tumor suppressor according to Knudson's two-hit hypothesis. The aim of the bachelor thesis was to study the activity and amounts of fumarase in a series of 22 samples of uterine leiomyomas from 22 young women patients (21-31 years) with sporadic uterine leiomyomas. As a control sample, uterine leiomyoma from a 38-year-old patient was used. Activity of...
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Impact of isolate deficiency of F1FO-ATP syntthase on other complexes of oxidative phosphorylation in skin fibroblasts depending on cullture conditions
Kedrová, Kateřina ; Stiborová, Marie (advisor) ; Poljaková, Jitka (referee)
Isolated deficiency of F1FO-ATPsynthase is a soubgroup of mitochondrial diseases caused by mutations in nuclear and mitochondrial-encoded structural subunits, or nuclear-encoded assembly factors of F1FO-ATPsynthase. The most often mutations are found in a MTATP6 gene localized in the mitochondrial DNA and a TMEM70 gene, localized in the nuclear DNA. A MTATP6 gene encodes subunit a of F1FO-ATPsynthase and its mutation usually leads to reduced phosphorylation activity of F1FO-ATPsynthase. A TMEM70 gene encodes a 21 kDa mitochondrial protein of the inner mitochondrial membrane of not completely explained function and its mutation results in the decrease in a content of fully assembled F1FO- ATPsynthase. The aim of this thesis was to investigate the impact of isolated F1FO- ATPsynthase deficiency on the oxidative phosphorylation system (complex I-IV), other selected mitochondrial proteins, and mitochondrial network in two cell lines of primary human skin fibroblasts with an isolated deficiency of F1FO-ATPsynthase (mutation m.8851T>C in MTATP6 and mutation c.317-2A>G in TMEM70) during the first days of their cultivation in media containing galactose or glucose as a carbohydrate source with a presence or absence of L-glutamine. The control cell line was found to have higher amounts of respiratory chain...
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Fumarate hydratase as tumor suppressor
Kedrová, Kateřina ; Hansíková, Hana (advisor) ; Befekadu, Asfaw (referee)
1 Abstract Fumarate hydratase (fumarase, EC 4.2.1.2) catalyzes the reverse hydration of fumarate to S malate. In mammalian cells, it changes fumarate in the mitochondrial matrix as a part of the citric acid cycle and in the cytosol, where functions to metabolize fumarate the product of the degradation of some amino acids, of ammonia transformation to urea acid or of the purine nucleotide synthesis. . In human cells, fumarase is encoded by FH gene localized on chromosome 1 (1q42.1). The FH gene consists of 10 exons and encodes for a 510 amino acids-long protein including the N-terminal mitochondrial signal sequence. Germline heterozygous FH mutations were found in two autosomal dominant syndromes. These are multiple cutaneous and uterine leiomyomatosis (MCUL1 or MCL) and hereditary leiomyomatosis and renal cell cancer (HLRCC). In the most of tumors from these patients, loss of FH gene heterozygosity was also found. It has been suggested that fumarase acts as a tumor suppressor according to Knudson's two-hit hypothesis. The aim of the bachelor thesis was to study the activity and amounts of fumarase in a series of 22 samples of uterine leiomyomas from 22 young women patients (21-31 years) with sporadic uterine leiomyomas. As a control sample, uterine leiomyoma from a 38-year-old patient was used. Activity of...
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