China
Africa
Explore chapters and articles related to this topic
Renal Cancer
Published in Karl H. Pang, Nadir I. Osman, James W.F. Catto, Christopher R. Chapple, Basic Urological Sciences, 2021
Sabrina H. Rossi, Grant D. Stewart
Gene function:FH gene encodes the fumarate hydratase enzyme.Component of the Krebs cycle.The absence of FH staining on immunohistochemistry may confirm the diagnosis.
Renal Cell Cancer
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Type II (eosinophilic) tumors have large cells with abundant eosinophilic cytoplasm and large nuclei. Type II tumors are typically associated with a higher nuclear grade, clinical stage, and shorter survival than Type I. In patients with hereditary type II papillary RCC (hereditary leiomyomatosis RCC [HLRCC]), a mutation in the fumarate hydratase gene has been identified.5
Genetics of Uterine Leiomyomata
Published in John C. Petrozza, Uterine Fibroids, 2020
C. Scott Gallagher, Cynthia C. Morton
Loss-of-function heterozygous mutations in FH (fumarate hydratase) at 1q43 are etiologic in a rare autosomal dominant tumor predisposition syndrome known as hereditary leiomyomatosis and renal cell carcinoma (HLRCC) [58–62]. Individuals with FH mutations may develop cutaneous leiomyomas of the erector piliform muscles, earlier-onset UL, uterine leiomyosarcoma and renal cell carcinoma [58,60,63,64]. As shown in Figure 5.2b, somatic inactivation of the wild-type copy of FH either through loss of heterozygosity or mutation is frequently observed in HLRCC-associated neoplasms and is consistent with Knudson's two-hit hypothesis, suggesting FH is a bona fide tumor suppressor gene [59,65–67]. In cells deficient in FH, both fumarate and succinate accumulate and inhibit the hypoxia-inducible factor prolyl hydroxylase, which in turn results in overexpression of the transcription factor HIF-1α (hypoxia-inducible factor 1α) and a “pseudo-hypoxic” state [68–71]. Of note, a single functional copy of FH is sufficient for maintaining normal metabolic activity [72]. In HLRCC, patients heterozygous for a missense or nonsense FH mutation, MED12 mutations and somatic biallelic inactivation of FH appear to be mutually exclusive, suggesting a distinct molecular mechanism involving oxidative phosphorylation through mitochondrial complex 2, leading to UL in HLRCC [52,61,66–68,72,73]. Albeit an infrequent event, biallelic inactivation of FH has also been reported in sporadic cases of UL [74–76].
The evolution and competitive strategies of Akkermansia muciniphila in gut
Published in Gut Microbes, 2022
Ji-Sun Kim, Se Won Kang, Ju Huck Lee, Seung-Hwan Park, Jung-Sook Lee
Multiple genome alignments were performed to identify the structural differences in the genome. Genome synteny also showed no significant differences between the KGMB strains. However, it was found that there are length variations in the homopolymeric polyguanine (poly G) region in the promoter of fumarate hydratase between type strain KCTC 15667 T and KGMB strains (Figure S1). KGMB strains had a greater number of homopolymeric guanosine repeats, 22–29 mer Gs, compared to the type strain with 18-mer Gs. Fumarate hydratase, also known as fumarase, converts fumaric acid to L-malic acid in the tricarboxylic acid (TCA) cycle, and is a conserved protein in all organisms, from bacteria to humans, with respect to its sequence, structure, and enzymatic activity.37,38 Although the intergenic region (297 bp) of fumarase was identical between the type strain KCTC 15667 T and KGMB strains, differences in the number of poly G repeats in the promoter may cause physiological differences between them.
Modulations of ferroptosis in lung cancer therapy
Published in Expert Opinion on Therapeutic Targets, 2022
Robert Walters, Shaker A. Mousa
Distinct mitochondrial changes occur during ferroptosis, including mitochondrial rupture, increased mitochondrial membrane density, decrease or absence of mitochondrial cristae, and decreased mitochondrial ridges [11,32]. Important factors for glutaminolysis are mitochondrial TCA cycle and decomposition of glutamine. In the absence of glutamine, cysteine-deprived ferroptosis induction is inhibited [5]. Fumarate hydratase, involved in the mitochondrial TCA cycle, is a mitochondrial tumor suppressor and loss of its function has led to ferroptosis resistance of cancer cells [33]. Free Fe2 + is used in lipid peroxidation in the mitochondria in the forms of heme and iron-sulfur clusters. CDGSH iron sulfur domain 1 (CISD1) is a mitochondrial outer membrane protein that can inhibit the lipid peroxidation in the mitochondria [11]. Pioglitazone, an anti-diabetic medication, and RNA therapy can be used to inhibit CISD1 and further inhibit mitochondrial iron uptake to prevent mitochondrial lipid peroxidation and induction of ferroptosis [34]. Erastin has been shown to interact with voltage-dependent anion channels (VDACs), which induced mitochondrial dysfunction, release of oxides, and ferroptosis [35]. Overall, the mitochondria is one of the most important organelles in ferroptosis and plays a crucial role in its regulation.
Fumarate hydratase as a therapeutic target in renal cancer
Published in Expert Opinion on Therapeutic Targets, 2020
Priyanka Kancherla, Michael Daneshvar, Rebecca A. Sager, Mehdi Mollapour, Gennady Bratslavsky
Developing new therapeutics is predicated on understanding the molecular basis of disease. FH is an enzyme in the citric acid cycle, a series of metabolic reactions downstream of glycolysis ultimately responsible for generating cellular energy via oxidative phosphorylation (Figure 2). Specifically, fumarate hydratase catalyzes the hydration reaction that converts fumarate to malate [33]. FH is not the only citric acid cycle enzyme implicated in familial cancer syndromes. In the preceding citric acid cycle reaction, succinate dehydrogenase (SDH) catalyzes the oxidation of succinate to fumarate (Figure 2). SDH functions as a heterotetramer with each subunit individually encoded by the genes SDHA-D. Mutations in SDHB, SDHC, and SDHD have been implicated in hereditary paraganglioma-pheochromocytoma syndromes [33]. This association between disrupted cellular metabolism and tumor growth is paradoxical. Nonetheless, these two syndromes establish the role of mitochondrial and metabolic dysfunction in tumorigenesis. Understanding the mechanisms by which this occurs is important for identifying targets for treating associated malignancy.