GNAS is a complex imprinted gene that uses multiple promoters to generate several gene products, including the G protein alpha-subunit (G(s)alpha) that couples seven-transmembrane receptors to the cAMP-generating enzyme adenylyl cyclase. Somatic activating G(s)alpha mutations, which alter key residues required for the GTPase turn-off reaction, are present in various endocrine tumors and fibrous dysplasia of bone, and in a more widespread distribution in patients with McCune- Albright syndrome. Heterozygous inactivating G(s)alpha mutations lead to Albright hereditary osteodystrophy. G(s)alpha is imprinted in a tissue-specific manner, being primarily expressed from the maternal allele in renal proximal tubules, thyroid, pituitary, and ovary. Maternally inherited mutations lead to Albright hereditary osteodystrophy (AHO) plus PTH, TSH, and gonadotropin resistance (pseudohypoparathyroidism type 1A), whereas paternally inherited mutations lead to AHO alone. Pseudohypoparathyroidism type 1B, in which patients develop PTH resistance without AHO, is almost always associated with a GNAS imprinting defect in which both alleles have a paternal-specific imprinting pattern on both parental alleles. Familial forms of the disease are associated with a mutation within a closely linked gene that deletes a region that is presumably required for establishing the maternal imprint, and therefore maternal inheritance of the mutation results in the GNAS imprinting defect. Imprinting of one differentially methylated region within GNAS is virtually always lost in pseudohypoparathyroidism type 1B, and this region is probably responsible for tissue-specific G(s)alpha imprinting. Mouse knockout models show that G(s)alpha and the alternative G(s)alpha isoform XLalphas that is expressed from the paternal GNAS allele may have opposite effects on energy metabolism in mice.
Gnas is an imprinted gene with multiple gene products resulting from alternative splicing of different first exons onto a common exon 2. These products include stimulatory G protein ␣-subunit (Gs␣), the G protein required for receptor-stimulated cAMP production; extralarge Gs␣ (XL␣s), a paternally expressed Gs␣ isoform; and neuroendocrine-specific protein (NESP55), a maternally expressed chromogranin-like protein. G s␣ undergoes tissue-specific imprinting, being expressed primarily from the maternal allele in certain tissues. Heterozygous mutation of exon 2 on the maternal (E2 m؊/؉ ) or paternal (E2 ؉/p؊ ) allele results in opposite effects on energy metabolism. E2 m؊/؉ mice are obese and hypometabolic, whereas E2 ؉/p؊ mice are lean and hypermetabolic. We now studied the effects of Gs␣ deficiency without disrupting other Gnas gene products by deleting G s␣ exon 1 (E1). E1 ؉/p؊ mice lacked the E2 ؉/p؊ phenotype and developed obesity and insulin resistance. The lean, hypermetabolic, and insulin-sensitive E2 ؉/p؊ phenotype appears to result from XL␣s deficiency, whereas loss of paternalspecific Gs␣ expression in E1 ؉/p؊ mice leads to an opposite metabolic phenotype. Thus, alternative Gnas gene products have opposing effects on glucose and lipid metabolism. Like E2 m؊/؉ mice, E1 m؊/؉ mice had s.c. edema at birth, presumably due to loss of maternal Gs␣ expression. However, E1 m؊/؉ mice differed from E2 m؊/؉ mice in other respects, raising the possibility for the presence of other maternal-specific gene products. E1 m؊/؉ mice had more severe obesity and insulin resistance and lower metabolic rate relative to E1 ؉/p؊ mice. Differences between E1 m؊/؉ and E1 ؉/p؊ mice presumably result from differential effects on Gs␣ expression in tissues where Gs␣ is normally imprinted.G protein ͉ genomic imprinting ͉ pseudohypoparathyroidism
Catechol-O-methyltransferase (COMT, EC 2.1.1.6) is a ubiquitous enzyme that is crucial to the metabolism of carcinogenic catechols and catecholamines. Regulation of human COMT gene expression may be important in the pathophysiology of various human disorders including estrogen-induced cancers, Parkinson's disease, depression, and hypertension. The gender difference in human COMT activity and variations in rat COMT activity during the estrous cycle led us to explore whether estrogen can regulate human COMT gene transcription. Our Northern analyses showed that physiological concentrations of 17--estradiol (10 Ϫ9 -10 Ϫ7 M) could decrease human 1.3-kilobase COMT mRNA levels in MCF-7 cells in a time-and dosedependent manner through an estrogen receptor-dependent mechanism. Two DNA fragments immediately 5Ј to the published human COMT gene proximal and distal promoters were cloned. Sequence analyses revealed several half-palindromic estrogen response elements and CCAAT/enhancer binding protein sites. By cotransfecting COMT promoter-chloramphenicol acetyltransferase reporter genes with human estrogen receptor cDNA and pSV--galactosidase plasmids into COS-7 cells, we showed that 17--estradiol could down-regulate chloramphenicol acetyltransferase activities, and COMT promoter activities dose-dependently. Functional deletion analyses of COMT promoters also showed that this estrogenic effect was mediated by a 280 base pair fragment with two putative half-palindromic estrogen response elements in the proximal promoter and a 323-base pair fragment with two putative CCAAT/enhancer binding protein sites in the distal promoter. Our findings provide the first evidence and molecular mechanism for estrogen to inhibit COMT gene transcription, which may shed new insight into the role of estrogen in the pathophysiology of different human disorders.Catechol-O-methyltransferase (COMT) is a ubiquitous enzyme that catalyzes the transfer of the methyl group from the coenzyme S-adenosyl-L-methionine (SAM) to one of the hydroxyl groups of catechols in the presence of Mg 2ϩ (Guldberg and Marsden, 1975). There are two isoforms of COMT of similar function: soluble and membrane-bound (MB). They are encoded by two transcripts [1.3 and 1.5 kilobase (kb) in human] regulated by the proximal and distal promoters, respectively (Tenhunen et al., 1994). The structural differences between these two human transcripts are a 5Ј extension of 150 base pairs (bp), which codes for a signal-anchor domain to direct the MB-COMT polypeptide to membranes, and the presence of a 5Ј noncoding region in the 1.5-kb transcript (Tenhunen et al., 1994).COMT may play an important role in the pathophysiology of different human disorders including estrogen-induced cancers, Parkinson's disease, depression, and hypertension, because the substrates of COMT are catechol estrogens (e.g., carcinogenic 4-hydroxyestradiol), indolic intermediates in melanin metabolism, xenobiotic catechols (e.g., carcinogenic flavonoids), catechol neurotransmitters (e.g., dopamine and noradr...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.