Characterization of a Novel Type of Human Microsomal 3α-Hydroxysteroid Dehydrogenase

Chetyrkin, Sergei V.; Belyaeva, Olga V.; Gough, Wendy H.; Kedishvili, Natalia Y.

doi:10.1074/jbc.m102076200

Cited by 75 publications

(79 citation statements)

References 35 publications

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“…The expression of 4 genes involved in aspects of sex hormone metabolism or regulation were increased in higher-grade cancers, including two members of the 17␤-hydroxysteroid dehydrogenase (HSD) family, HSD17␤3 and HSD17␤4. The 3-␣-hydroxysteroid dehydrogenase DHRS9 is capable of catalyzing the conversion of 3-␣-androstanediol to dihydrotestosterone (25) and also contributes to the ␤-oxidation of fatty acids. The expression of HSD17␤4, also known as D-bifunctional protein, was recently shown to be up-regulated in neoplastic prostate epithelium (26).…”

Section: Resultsmentioning

confidence: 99%

A molecular correlate to the Gleason grading system for prostate adenocarcinoma

True

Coleman²,

Hawley

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

259

225

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Adenocarcinomas of the prostate can be categorized into tumor grades based on the extent to which the cancers histologically resemble normal prostate glands. Because grades are surrogates of intrinsic tumor behavior, characterizing the molecular phenotype of grade is of potential clinical importance. To identify molecular alterations underlying prostate cancer grades, we used microdissection to obtain specific cohorts of cancer cells corresponding to the most common Gleason patterns (patterns 3, 4, and 5) from 29 radical prostatectomy samples. We paired each cancer sample with matched benign lumenal prostate epithelial cells and profiled transcript abundance levels by microarray analysis. We identified an 86-gene model capable of distinguishing low-grade (pattern 3) from high-grade (patterns 4 and 5) cancers. This model performed with 76% accuracy when applied to an independent set of 30 primary prostate carcinomas. Using tissue microarrays comprising >800 prostate samples, we confirmed a significant association between high levels of monoamine oxidase A expression and poorly differentiated cancers by immunohistochemistry. We also confirmed grade-associated levels of defender against death (DAD1) protein and HSD17␤4 transcripts by immunohistochemistry and quantitative RT-PCR, respectively. The altered expression of these genes provides functional insights into grade-associated features of therapy resistance and tissue invasion. Furthermore, in identifying a profile of 86 genes that distinguish high-from low-grade carcinomas, we have generated a set of potential targets for modulating the development and progression of the lethal prostate cancer phenotype.carcinoma ͉ monoamine oxidase A ͉ microarray ͉ expression profile

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Section: Resultsmentioning

confidence: 99%

A molecular correlate to the Gleason grading system for prostate adenocarcinoma

True

Coleman²,

Hawley

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

259

225

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“…We were unable, therefore, to determine whether zRDHA or zRDHB were direct orthologs of human RDHL. Previous studies, however, have shown that human RDHL is highly expressed in adult colon tissues, thus suggesting a specific functional role for RDHL in human gut (10,21). We, therefore, asked whether zRDHA or zRDHB showed gut-restricted expression in zebrafish.…”

Section: Phenotypes Of Apc Knockdown Zebrafish Are Rescued Bymentioning

confidence: 99%

Adenomatous Polyposis Coli Control of Retinoic Acid Biosynthesis Is Critical for Zebrafish Intestinal Development and Differentiation

Nadauld

Sandoval

Chidester

et al. 2004

Journal of Biological Chemistry

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Mutations in the APC (adenomatous polyposis coli) tumor suppressor gene cause uncontrolled proliferation and impaired differentiation of intestinal epithelial cells. Recent studies indicate that human colon adenomas and carcinomas lack retinol dehydrogenases (RDHs) and that APC regulates the expression of human RDHL. These data suggest a model wherein APC controls enterocyte differentiation by controlling retinoic acid production. However, the importance of APC and retinoic acid in mediating control of normal enterocyte development and differentiation remains unclear. To examine the relationship between APC and retinoic acid biosynthesis in normal enterocytes, we have identified two novel zebrafish retinol dehydrogenases, termed zRDHA and zRDHB, that show strong expression within the gut of developing zebrafish embryos. Morpholino knockdown of either APC or zRDHB in zebrafish embryos resulted in defects in structures known to require retinoic acid. These defects included cardiac abnormalities, pericardial edema, failed jaw and pectoral fin development, and the absence of differentiated endocrine and exocrine pancreas. In addition, APC or zRDHB morphant fish developed intestines that lacked columnar epithelial cells and failed to express the differentiation marker intestinal fatty acid-binding protein. Treatment of either APC or zRDHB morphant embryos with retinoic acid rescued the defective phenotypes. Downstream of retinoic acid production, we identified hoxc8 as a retinoic acid-induced gene that, when ectopically expressed, rescued phenotypes of APC-and zRDHB-deficient zebrafish. Our data establish a genetic link supporting a critical role for retinoic acid downstream of APC and confirm the importance of retinoic acid in enterocyte differentiation.

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“…27,28 In contrast to cytosolic 3a-HSDs, microsomal enzymes with 3a-HSD activity strongly prefer NAD þ /NADH as cofactors. [28][29][30] The predominant forms of nucleotide cofactors in the cells are NAD þ and NADPH. 28,[31][32][33] Although both cytosolic and microsomal 3a-HSDs in principle can act bidirectionally in vitro, in the living brain, cytosolic 3a-HSDs are expected to almost exclusively catalyze the reductive pathway (conversion of 5a-DHP into 3a,5a-THP; cofactor: NADPH) whereas microsomal 3a-HSDs are expected to catalyze the oxidation of 3a,5a-THP into 5a-DHP (cofactor: NAD þ ), owing to the intracellular availability of the respective cofactors.…”

Section: Introductionmentioning

confidence: 99%

Influence of mirtazapine on plasma concentrations of neuroactive steroids in major depression and on 3α-hydroxysteroid dehydrogenase activity

et al. 2005

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Concentrations of 3a-reduced neuroactive steroids are altered in depression and normalize after antidepressant pharmacotherapy with selective serotonin re-uptake inhibitors (SSRIs). We investigated the impact of mirtazapine on the activity of a key neurosteroidogenic enzyme, the 3a-hydroxysteroid dehydrogenase (3a-HSD), and on the levels of neuroactive steroids in relation to clinical response. A total of 23 drug-free in-patients suffering from a major depressive episode (DSM-IV criteria) underwent 5-week treatment with mirtazapine (45 mg/ day). Plasma samples were taken weekly at 0800 and quantified for neuroactive steroids by means of combined gas chromatography/mass spectrometry analysis. Enzyme activity was determined by assessment of steroid conversion rates. Irrespective of clinical outcome, there were significant increases in 3a,5a-tetrahydroprogesterone, 3a,5b-tetrahydroprogesterone, 5a-dihydroprogesterone, and 5b-dihydroprogesterone after mirtazapine treatment, whereas 3b,5a-tetrahydroprogesterone levels were significantly decreased. In vitro investigations demonstrated a dose-dependent inhibitory effect of mirtazapine on the activity of the microsomal 3a-HSD in the oxidative direction (conversion of 3a,5a-tetrahydroprogesterone to 5a-dihydroprogesterone). Mirtazapine affects neuroactive steroid composition similarly as do SSRIs. The inhibition of the oxidative pathway catalyzed by the microsomal 3a-HSD is compatible with an enhanced formation of 3a-reduced neuroactive steroids. However, the changes in neuroactive steroid concentrations more likely reflect direct pharmacological effects of this antidepressant rather than clinical improvement in general.

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Characterization of a Novel Type of Human Microsomal 3α-Hydroxysteroid Dehydrogenase

Cited by 75 publications

References 35 publications

A molecular correlate to the Gleason grading system for prostate adenocarcinoma

A molecular correlate to the Gleason grading system for prostate adenocarcinoma

Adenomatous Polyposis Coli Control of Retinoic Acid Biosynthesis Is Critical for Zebrafish Intestinal Development and Differentiation

Influence of mirtazapine on plasma concentrations of neuroactive steroids in major depression and on 3α-hydroxysteroid dehydrogenase activity

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