Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.3.5.1 (succinate dehydrogenase)
 8,177 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cytochrome-c-oxidase (complex IV) was histochemically studied in oncocytic adenoma (n = 10) and carcinoma of the thyroid gland (n = 3), cystadenolymphomas and oncocytic adenomas of the major salivary glands (n = 9), oncocytic neoplasia of the kidney (n = 1) and in 21 parathyroid glands with primary hyperparathyroidism and adenomatous proliferation (n = 17) and secondary hyperparathyroidism with hyperplasia (n = 4). Only in the parathyroids defects of cytochrome-c-oxidase were found being expressed in all 4 glands with hyperplasia (14 defects) and in 5 of the 17 adenomas (11 defects). All defects were confined to foci with oxyphil cell differentiation, the defect areas varying from 0.09 to 21.10 sq mm in hyperplastic glands and from 0.11 to 13.88 sq mm in adenomas, the size of the oxyphil foci varying from 0.12 sq mm-105.38 sq mm. However, not every oxyphil nodule of a gland was devoid of cytochrome-c-oxidase activity. Of 6 predominantly oxyphil adenomas, 4 showed no defects. No defects were observed either in 2 adenomas without oxyphil cells. Further enzymes of the respiratory chain, succinate dehydrogenase (complex II) and ATP synthetase, (complex V) were devoid of defects. In parathyroids with hyperplasia and oxyphil areas, defects of cytochrome-c-oxidase occurred significantly more often and tended to be larger than in adenomas, statistical analysis revealing a significant correlation between the occurrence of defects and the number of oxyphil foci but not with the total oxyphil area.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Random cytochrome-C-oxidase deficiency of oxyphil cell nodules in the parathyroid gland. A mitochondrial cytopathy related to cell ageing? 133 5

Thyroid cancer is a major component cancer of Cowden syndrome (CS), a disorder typically associated with germline mutations in PTEN. Germline variants in succinate dehydrogenase genes (SDHx) co-occurring with PTEN germline mutations confer a 2-fold increased prevalence (OR 2.7) of thyroid cancer compared to PTEN-associated CS but 50% decreased prevalence (OR 0.54) of thyroid cancer compared to SDHx-associated CS. We have previously shown that CS-associated SDHD variants G12S and H50R induce PTEN oxidation and nuclear accumulation in thyroid cancer. Our current study shows that SDHD-G12S and -H50R variants cause down-regulation of autophagy, demonstrating a role for SDHD in autophagy-associated pathogenesis of differentiated thyroid cancer. These findings could explain the increased prevalence of thyroid cancer in CS patients with SDHx germline mutations compared to those with PTEN mutations alone. Importantly, we demonstrate the dependence of this process on functional wild-type PTEN with reversal of decreased autophagy after PTEN knockdown. The latter could explain the clinically observed decrease in thyroid cancer prevalence in patients with co-existent PTEN mutations and SDHx variants. We also show that SDHD-G12S/H50R promotes mono-ubiquitination of PTEN, causing its translocation into the nucleus, upregulation of AKT and consequent phosphorylation of FOXO3a. Furthermore, SDHD-G12S/H50R-mediated increase in acetylation of FOXO3a further enhances AKT-associated phosphorylation of FOXO3a. This combination of phosphorylation and acetylation of FOXO3a results in its nuclear export for degradation and consequent down-regulation of FOXO3a-target autophagy-related gene (ATG) expression. Overall, our study reveals a novel mechanism of crosstalk amongst SDHD, PTEN and autophagy pathways and their potential roles in thyroid carcinogenesis.
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PMID:Cowden syndrome-associated germline succinate dehydrogenase complex subunit D (SDHD) variants cause PTEN-mediated down-regulation of autophagy in thyroid cancer cells. 2816 37