Human 3β-hydroxysteroid dehydrogenase types 1 and 2: Gene sequence variation and functional genomics

Wang, Liewei; Salavaggione, Ezequiel; Pelleymounter, Linda L.; Eckloff, Bruce W.; Wieben, Eric D.; Weinshilboum, Richard M.

doi:10.1016/j.jsbmb.2007.03.037

Cited by 20 publications

(25 citation statements)

References 52 publications

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“…A quantitative trait locus for BP was identified in the HSD3b2 chromosomal region in the genome-wide linkage analysis [22]. In agreement with our findings regarding rs12410453, mutation analysis of the 5 0 flanking region of HSD3b2 (À194) demonstrated that SNP significantly increased reporter activity in prostate cancer cell line [23]. Furthermore, the missense mutations for severe saltwasting syndrome resulted from HSD3b2 deficiency [6].…”

Section: Discussionsupporting

confidence: 87%

Association of the variations in the HSD3β gene with primary aldosteronism

Wu²,

Chang³

et al. 2013

Journal of Hypertension

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Section: Discussionsupporting

confidence: 87%

Association of the variations in the HSD3β gene with primary aldosteronism

Wu²,

Chang³

et al. 2013

Journal of Hypertension

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“…PCR primer sequences and amplification conditions are listed in Supplementary Table S1. Resequencing was done using dye termination sequencing chemistry as described previously (18)(19)(20). Amplicons were sequenced on both strands in the Mayo Molecular Biology Core Facility with an ABI 377 DNA sequencer.…”

Section: Dna Samplesmentioning

confidence: 99%

“…These DNA samples have been widely used for human gene resequencing studies (15)(16)(17)(18)(19)(20). Immortalized lymphoblastoid cell lines from these same subjects are available from the Coriell Institute, and those cell lines were also used in the experiments described subsequently.…”

Section: Dna Samplesmentioning

confidence: 99%

Proteasome β Subunit Pharmacogenomics: Gene Resequencing and Functional Genomics

Wang

Kumar²,

Fridley³

et al. 2008

Clinical Cancer Research

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Purpose-The proteasome is a multisubunit cellular organelle that functions as a nonlysosomal threonine protease. Proteasomes play a critical role in the degradation of proteins, regulating a variety of cellular processes, and they are also the target for antineoplastic proteasome inhibitors. Genetic variation in proteasome subunits could influence both proteasome function and response to drug therapy.Experimental Design-We resequenced genes encoding the three active proteasome β subunits using 240 DNA samples from four ethnic groups and the β5 subunit gene in 79 DNA samples from multiple myeloma patients who had been treated with the proteasome inhibitor bortezomib. Resequencing was followed by functional studies of polymorphisms identified in the coding region and 3′-flanking region (3′-FR) of PSMB5, the gene encoding the target for clinically useful proteasome inhibitors.Results-Resequencing of 240 DNA samples identified a series of novel ethnic-specific polymorphisms that are not represented in public databases.The PSMB5 3′-FR1042 G allele significantly increased transcription during reporter gene studies, observations confirmed by genotype-phenotype correlations between single nucleotide polymorphisms (SNP) in PSMB5 and mRNA expression in the 240 lymphoblastoid cell lines from which the resequenced DNA was obtained. Studies with patient DNA samples identified additional novel PSMB5 polymorphisms, including a SNP and an insertion in the 3′-FR. Reporter-gene studies indicated that these two novel polymorphisms might decrease transcription. Protein degradation regulates a variety of critical cellular processes, including cell division, signal transduction, and apoptosis (1-4). The proteasome is a multisubunit cellular organelle that functions as a nonlysosomal threonine protease. It plays a critical role in protein degradation and is the target for antineoplastic proteasome inhibitors (1-5). The 26S proteasome consists of a 20S barrel-shaped core particle and two 19S regulatory complexes that cap the 20S core particle. The 20S core particle is a multisubunit enzyme complex that consists of four heptameric rings arranged in α 7 β 7 β 7 α 7 fashion, surrounding a central cavity where the catalytic sites are found (6-8). Three of the seven β subunits, β1, β2, and β5, are proteolytically active with different substrate specificities. The β1 subunit catalyzes a postglutamyl peptidyl hydrolytic-like activity; the β2 subunit catalyzes a trypic-like activity; and the β5 subunit catalyzes a chymotryptic-like activity (9).Proteasome inhibitors have been tested for the treatment of a variety of types of cancers. One of those drugs, bortezomib, with activity directed mainly against the β5 subunit, has been approved for the treatment of refractory multiple myeloma (10,11). However, clinical response to bortezomib therapy varies widely (12)(13)(14). Because the proteasome has critical importance for cellular processes and because it is also a drug target, it would be important to identify common sequence variation in...

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“…They also found decreased enzyme activity with common polymorphisms of the HSD3B1 in an in vitro luciferase (LUC) reporter gene assay (16). Thus, genetic variation in the peripheral metabolism of steroid hormones may be one factor explaining the phenotypic variability in children with PA from different ethnic backgrounds.…”

mentioning

confidence: 97%

“…Variations in genes encoding steroid sulfatase, HSD3B1, and 5α-reductase have not been studied in PA. However, Wang et al (16) found significant differences in the gene encoding HSD3B1 in four different ethnic groups of Articles Liimatta et al…”

mentioning

confidence: 98%

Serum androgen bioactivity is low in children with premature adrenarche

et al. 2014

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Background: Clinical findings in children with premature adrenarche (PA) correlate only partly with circulating levels of adrenal androgens. It is not known whether the prepubertal low circulating concentrations of testosterone (T) and dihydrotestosterone, together with those of adrenal androgens, are capable of activating the androgen receptor. Methods: This cross-sectional study was performed at a university hospital. Circulating androgen bioactivity was measured in 67 prepubertal children with clinical signs of PA and 94 control children using a novel androgen bioassay. results: Circulating androgen bioactivity was low in the PA and control children. In the subgroup of children (n = 28) with serum T concentration over the assay sensitivity (0.35 nmol/l) and a signal in the androgen bioassay, we found a positive correlation between androgen bioactivity and serum T (r = 0.50; P < 0.01) and the free androgen index (r = 0.61; P < 0.01) and a negative correlation with serum sex hormone-binding globulin concentration (r = −0.41; P < 0.05). conclusion: Peripheral metabolism of adrenal androgen precursors may be required for any androgenic effects in PA. However, the limitations in the sensitivity of the bioassay developed herein may hide some differences between the PA and control children. t he reticular zone (zona reticularis (ZR)) of the adrenal cortex starts to develop from small focal islets in early childhood (1). Later on, continuous ZR begins to produce weak androgen precursors, mostly dehydroepiandrosterone (DHEA) and its sulfate (DHEAS), and this phenomenon is referred to as adrenarche. During adrenarche, increasing androgenic activity leads to greasiness of the skin and hair, comedones/acne, adult-type body odor, and finally to the development of axillary and pubic hair. Though not uniformly used, adrenarche may be defined as premature (premature adrenarche (PA)) if these clinical signs are evident together with elevated serum levels of adrenal androgens before the age of 8 y in girls or 9 y in boys (2).In both normal-timed and PA, the clinical signs of androgen activity do not correlate well with the circulating levels of DHEA, DHEAS, or androstenedione (A4) (2,3). In peripheral tissues such as the skin, DHEA and DHEAS interconvert via hydroxysteroid sulfotransferase and steroid sulfatase (4), but DHEAS desulfonation in the liver is controversial (5). DHEAS is biologically inactive, and DHEA is only a weak androgen receptor (AR) agonist (6), but they are present in the serum of PA subjects in excess concentrations.The effects of androgens are mediated via the AR, resulting in the activation of target gene transcription (7). Whereas testosterone (T) and dihydrotestosterone (DHT) are potent AR agonists, the affinity of adrenal androgen precursors to AR is weak (6,8), and prereceptor level conversion to more potent androgens is needed for the full activation of AR. In peripheral tissues, DHEA is converted to the most potent androgen, DHT, through A4 and T. The main enzymes responsible for this intracrine co...

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Human 3β-hydroxysteroid dehydrogenase types 1 and 2: Gene sequence variation and functional genomics

Cited by 20 publications

References 52 publications

Association of the variations in the HSD3β gene with primary aldosteronism

Association of the variations in the HSD3β gene with primary aldosteronism

Proteasome β Subunit Pharmacogenomics: Gene Resequencing and Functional Genomics

Serum androgen bioactivity is low in children with premature adrenarche

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