Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.6.3.1 (NADPH oxidase)
 11,281 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The thyroid gland is a unique endocrine organ that requires hydrogen peroxide (H(2)O(2)) for thyroid hormone formation. The molecule for H(2)O(2) production in the thyroid gland has been known as dual oxidase 2 (DUOX2). Recently, NADPH oxidase 4 (NOX4), a homolog of the NOX family, was added as a new intracellular source of reactive oxygen species (ROS) in the human thyroid gland. This review focuses on the recent progress of the DUOX system and its possible contribution to human thyroid diseases. Also, we discuss human thyroid diseases related to abnormal H(2)O(2) generation. The DUOX molecule contains peroxidase-like and NADPH oxidase-like domains. Human thyroid gland also contains DUOX1 that shares 83% similarity with the DUOX2 gene. However, thyroid DUOX1 protein appears to play a minor role in H(2)O(2) production. DUOX proteins require DUOX maturation or activation factors (DUOXA1 or 2) for proper translocation of DUOX from the endoplasmic reticulum to the apical plasma membrane, where H(2)O(2) production takes place. Thyroid cells contain antioxidants to protect cells from the H(2)O(2)-mediated oxidative damage. Loss of this balance may result in thyroid cell dysfunction and thyroid diseases. Mutation of either DUOX2 or DUOXA2 gene is a newly recognized cause of hypothyroidism due to insufficient H(2)O(2) production. Papillary thyroid carcinoma, the most common thyroid cancer, is closely linked to the increased ROS production by NOX4. Hashimoto's thyroiditis, a common autoimmune thyroid disease in women, becomes conspicuous when iodide intake increases. This phenomenon may be explained by the abnormality of iodide-induced H(2)O(2) or other ROS in susceptible individuals. Discovery of DUOX proteins and NOX4 provides us with valuable tools for a better understanding of pathophysiology of prevalent thyroid diseases.
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PMID:Dual oxidase, hydrogen peroxide and thyroid diseases. 2040 74

Dual oxidase 2 (Duox2), one of the seven members of the NADPH oxidase gene family, plays a critical role in generating H2O2 for thyroid hormone biosynthesis and as an integral part of the host defense system of the respiratory epithelium and the gastrointestinal tract. Recent evidence suggests that the regulation of Duox2 expression is under the control of pro-inflammatory cytokines and that Duox2-induced reactive oxygen species (ROS) contribute to the inflammation-related tissue injury that occurs in two pre-malignant, inflammatory conditions: chronic pancreatitis and inflammatory bowel disease. Because no reliable Duox antibodies are commercially available, we report the development of a murine monoclonal antibody (MAb) to Duox2 (clone Duox S-12) and its use for the characterization of Duox2 expression in human tumors, tumor cell lines and normal tissues. Duox S-12 specifically detected both endogenously- and ectopically-expressed Duox2 protein by immunoblotting, immunofluorescence microscopy and immunohistochemistry (where both membranous and cytoplasmic staining were present). Duox2 expression detected by Duox S-12 was functionally coupled to the generation of H(2)O(2) in pancreatic cancer cells that expressed Duox2 and its cognate maturation factor DuoxA2. Although Duox S-12 recognizes ectopically expressed Duox1 protein because of the extensive amino acid homology between Duox1 and Duox2, the lack of substantial Duox1 mRNA expression in human tumors (except thyroid cancer) allowed us to evaluate Duox2 expression across a wide range of normal and malignant tissues by immuno-histochemistry. Duox2 was expressed at elevated levels in many human cancers, most notably tumors of the prostate, lung, colon and breast while brain tumors and lymphomas demonstrated the lowest frequency of expression. The Duox-specific monoclonal antibody described here provides a promising tool for the further examination of the role of Duox-dependent reactive oxygen production in inflammation-related carcinogenesis, where alterations in oxidant tone play a critical role in cell growth and proliferation.
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PMID:Functional activity and tumor-specific expression of dual oxidase 2 in pancreatic cancer cells and human malignancies characterized with a novel monoclonal antibody. 2340 10

Hydrogen peroxide (H2O2) is a crucial substrate for thyroid peroxidase, a key enzyme involved in thyroid hormone synthesis. However, as a potent oxidant, H2O2 might also be responsible for the high level of oxidative DNA damage observed in thyroid tissues, such as DNA base lesions and strand breakages, which promote chromosomal instability and contribute to the development of tumours. Although the role of H2O2 in thyroid hormone synthesis is well established, its precise mechanisms of action in pathological processes are still under investigation. The NADPH oxidase/dual oxidase family are the only oxidoreductases whose primary function is to produce reactive oxygen species. As such, the function and expression of these enzymes are tightly regulated. Thyrocytes express dual oxidase 2, which produces most of the H2O2 for thyroid hormone synthesis. Thyrocytes also express dual oxidase 1 and NADPH oxidase 4, but the roles of these enzymes are still unknown. Here, we review the structure, expression, localization and function of these enzymes. We focus on their potential role in thyroid cancer, which is characterized by increased expression of these enzymes.
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PMID:NADPH oxidases: new actors in thyroid cancer? 2717 22

Reactive oxygen species (ROS) are the most critical class of free radicals or reactive metabolites produced by all living organisms. ROS regulate several cellular functions through redox-dependent mechanisms, including proliferation, differentiation, hormone synthesis, and stress defense response. However, ROS overproduction or lack of appropriate detoxification is harmful to cells and can be linked to the development of several diseases, such as cancer. Oxidative damage in cellular components, especially in DNA, can promote the malignant transformation that has already been described in thyroid tissue. In thyrocyte physiology, NADPH oxidase enzymes produce large amounts of ROS that are necessary for hormone biosynthesis and might contribute to the high spontaneous mutation rate found in this tissue. Thyroid cancer is the most common endocrine malignancy, and its incidence is significantly higher in women than in men. Several lines of evidence suggest the sex hormone estrogen as a risk factor for thyroid cancer development. Estrogen in turn, besides being a potent growth factor for both normal and tumor thyroid cells, regulates different mechanisms of ROS generation. Our group demonstrated that the thyroid gland of adult female rats exhibits higher hydrogen peroxide (H2O2) production and lower enzymatic antioxidant defense in comparison with male glands. In this review, we discuss the possible involvement of thyroid redox homeostasis and estrogen in the development of thyroid carcinogenesis.
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PMID:The Emerging Role of Estrogens in Thyroid Redox Homeostasis and Carcinogenesis. 3072 83

Highly penetrant hereditary thyroid cancer manifests as familial nonmedullary thyroid cancer (FNMTC), whereas low-penetrance hereditary thyroid cancer manifests as sporadic disease and is associated with common polymorphisms, including rs965513[A]. Whole-exome sequencing of an FNMTC kindred identified a novel Y1203H germline dual oxidase-2 (DUOX2) mutation. DUOX2Y1203H is enzymatically active, with increased production of reactive oxygen species. Furthermore, patients with sporadic thyroid cancer homozygous for rs965513[A] demonstrated higher DUOX2 expression than heterozygous rs965513[A/G] or homozygous rs965513[A]-negative patients. These data suggest that dysregulated hydrogen peroxide metabolism is a common mechanism by which high- and low-penetrance genetic factors increase thyroid cancer risk. SIGNIFICANCE: This study provides novel insights into the genetic and molecular mechanisms underlying familial and sporadic thyroid cancers.
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PMID:Genetic Variants Implicate Dual Oxidase-2 in Familial and Sporadic Nonmedullary Thyroid Cancer. 3150 Nov 91