SDHAF2
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Mitochondrial complex II or succinate dehydrogenase (SDH) is at the crossroads of oxidative phosphorylation and the tricarboxylic acid cycle. It has been shown that Sdh5 (SDHAF2/SDH5 in mammals) is required for flavination of the subunit Sdh1 (SDHA in human cells) in yeast. Here we demonstrate that in human breast cancer cells, SDHAF2/SDH5 is dispensable for SDHA flavination. In contrast to yeast, CRISPR-Cas9 nickase-mediated SDHAF2 KO breast cancer cells feature flavinated SDHA and retain fully assembled and functional complex II, as well as normal mitochondrial respiration. Our data show that SDHA flavination is independent of SDHAF2 in breast cancer cells, employing an alternative mechanism.
- Klíčová slova
- SDH assembly factor, SDHA, SDHAF2, assembly factor, cancer biology, cancer cells, cell biology, complex II assembly, flavin adenine dinucleotide, flavination, flavinylation, mammal, mitochondria, mitochondrial complex II, mitochondrial respiratory chain complex, succinate dehydrogenase,
- MeSH
- flaviny MeSH
- genový knockdown MeSH
- lidé MeSH
- mitochondriální proteiny genetika metabolismus MeSH
- mitochondrie genetika metabolismus MeSH
- nádorové buněčné linie MeSH
- nádorové proteiny genetika metabolismus MeSH
- nádory prsu genetika metabolismus MeSH
- posttranslační úpravy proteinů * MeSH
- respirační komplex II genetika metabolismus MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- flaviny MeSH
- mitochondriální proteiny MeSH
- nádorové proteiny MeSH
- respirační komplex II MeSH
- SDHA protein, human MeSH Prohlížeč
- SDHAF2 protein, human MeSH Prohlížeč
Pheochromocytomas and paragangliomas are tumors arising from chromaffin cells. These tumors produce catecholamines and are typically found with symptoms and signs that may include hypertension (persistent or episodic), palpitations, headache and sweating. So far, 10 different genes have been associated with both tumors and other genes are expected to be detected. Pheochromocytoma and paraganglioma can occur as a part of genetic syndromes - familial paragangliomas (SDH genes, SDHAF2 gene), von Hippel-Lindau syndrome (VHL gene), multiple endocrine neoplasia type 2 (RET gene), and neurofibromatosis type 1 (NF1 gene). These tumors may be the first and only manifestation of these genetic syndromes. Patients with SDHB mutations are at high risk to develop malignant disease and unfortunately current therapeutic options for malignant form of disease are poor. Genetic testing plays a key role in the management of these tumors and therefore not only index patients with pheochromocytoma but also relatives should be tested. Management of this disease requires multidisciplinary cooperation and should be performed in the specialized medical centres.
Succinate dehydrogenase (SDH), formed by four subunits SDHA, SDHB, SDHC, SDHD, and an assembly factor SDHAF2, functions as a key respiratory enzyme. Biallelic inactivation of genes encoding any of the components, almost always in the presence of a germline mutation, causes loss of function of the entire enzyme complex (so-called SDH deficiency) and subsequent development of SDH-deficient neoplasms which include pheochromocytoma/paraganglioma, gastrointestinal stromal tumor, and renal cell carcinoma (RCC). These tumors may occur in the same patient or kindred. SDH-deficient RCC shows distinctive morphological features with vacuolated eosinophilic cytoplasm due to distinctive cytoplasmatic inclusions containing flocculent material. The diagnosis is confirmed by loss of SDHB on immunohistochemistry with positive internal control. The majority of tumors occur in the setting of germline mutations in one of the SDH genes, most commonly SDHB. The prognosis is excellent for low-grade tumors but worse for high-grade tumors with high-grade nuclei, sarcomatoid change, or coagulative necrosis. Awareness of the morphological features and low-threshold for applying SDHB immunohistochemistry help identify patients with SDH-deficient RCC and hereditary SDH-deficient tumor syndromes. In this review we summarize recent development on the clinical and genetic features, diagnostic approach, and pitfalls of SDH-deficient syndrome, focusing on SDH-deficient renal cell carcinomas.
- Klíčová slova
- Deficiency, Mutation, Renal cell carcinoma, Succinate dehydrogenase,
- MeSH
- dědičné nádorové syndromy * genetika MeSH
- karcinom z renálních buněk * genetika MeSH
- lidé MeSH
- nádory ledvin * genetika patologie MeSH
- sarkom * MeSH
- sukcinátdehydrogenasa genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- sukcinátdehydrogenasa MeSH
PURPOSE OF REVIEW: To summarize the recent advances in the genetics of pheochromocytoma and paraganglioma (PHEO/PGL), focusing on the new susceptibility genes and dividing PHEOs/PGLs into two groups based on their transcription profile. RECENT FINDINGS: Recently, TMEM127, MYC-associated factor X, and hypoxia-inducible factor (HIF) 2α have been described in the pathogenesis of PHEOs/PGLs. Thus, now about 30-40% of these tumors are linked to the germline mutations, which also include mutations in the VHL, RET, NF1, SDHx, and SDHAF2 genes. Furthermore, PHEOs/PGLs have been divided into two groups, cluster 1 (SDHx/VHL) and cluster 2 (RET/NF1), based on the transcription profile revealed by genome-wide expression microarray analysis. SUMMARY: PHEOs/PGLs are the most inherited tumors among (neuro)endocrine tumors. Future approaches in genetics, including whole-genome sequencing, will allow the discovery of additional PHEO/PGL susceptibility genes. The current division of PHEOs/PGLs into cluster 1 and 2 provides us with additional knowledge related to the pathogenesis of these tumors, including the introduction of new treatment options for patients with metastatic PHEOs/PGLs. New discoveries related to the role of the HIF-1/HIF-2α genes in the pathogenesis of almost all inherited PHEOs/PGLs may call for a new regrouping of these tumors and discoveries of new treatment targets.
- MeSH
- feochromocytom genetika metabolismus terapie MeSH
- genetická predispozice k nemoci MeSH
- izoenzymy genetika metabolismus MeSH
- lidé MeSH
- mutace * MeSH
- nádorový supresorový protein VHL genetika metabolismus MeSH
- nádory nadledvin genetika metabolismus terapie MeSH
- neurofibromin 1 genetika metabolismus MeSH
- paragangliom genetika metabolismus terapie MeSH
- protoonkogenní proteiny c-ret genetika metabolismus MeSH
- sukcinátdehydrogenasa genetika metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, N.I.H., Intramural MeSH
- Názvy látek
- izoenzymy MeSH
- nádorový supresorový protein VHL MeSH
- neurofibromin 1 MeSH
- protoonkogenní proteiny c-ret MeSH
- RET protein, human MeSH Prohlížeč
- sukcinátdehydrogenasa MeSH
- VHL protein, human MeSH Prohlížeč
