17 beta-Hydroxysteroid dehydrogenase (17HSD) isoenzymes catalyse the interconversion between highly active 17 beta-hydroxy- and low-activity 17-keto-steroids and thereby regulate the biological activity of sex steroids. The present study was carried out to characterize 17HSD activity and the expression of 17HSD type 1 and 2 isoenzymes in several human cell types and tissues. The data indicate that in cultured cells the direction of 17HSD activity is exclusively determined by the expression of these distinct isoenzymes. The intracellular environment could not modulate the direction of the enzyme activities in any of the cell types analysed. 17HSD type 1 acts as a reductase converting oestrone into oestradiol, whereas 17HSD type 2 possesses oxidative activity inactivating oestradiol by converting it into oestrone. The data, furthermore, suggest that of the two 17HSD type 1 mRNAs (1.3 and 2.3 kb), expression of the 1.3 kb mRNA is related to enzyme concentration in all the cell types studied. This mRNA is principally expressed in cells of placental and ovarian origin, but is also present in malignant breast epithelial cells. In contrast, 17HSD type 2 is more widely expressed. It is present in several oestradiol-metabolizing tissues as well as in some target cells of sex steroid action. The opposite reaction directions observed in the cultured cells, together with differences in the distribution of the isoenzymes, suggest that type 1 is involved in oestradiol production in females while type 2 plays a role in the inactivation of this sex steroid in peripheral tissues, both in females and in males. However, some examples exist of simultaneous expression of both enzymes in the same cell type or tissue.
The results show that there is an inverse relationship between the extent of apoptosis and bcl-2 expression in breast lesions suggesting that its expression affects the regulation of apoptosis in them.
17beta-Hydroxysteroid dehydrogenases (17HSDs) are responsible for the conversion of low-activity sex steroids to more potent forms, and vice versa. 17HSD activity is essential for the biosynthesis of sex steroids in the gonads, and it is also one of the key factors regulating the availability of active ligands for sex-steroid receptors in various extragonadal tissues. In this study, we have characterized mouse 17HSD type 2 cDNA, and analysed the relative expression of 17HSD types 1, 2, 3, 4 and 5 mRNAs in mouse embryos and adult male and female tissues. The cDNA characterized has a open reading frame of 1146 bp, and encodes a protein of 381 amino acids with a predicted molecular mass of 41837 kDa. Northern-blot analysis of adult mouse tissues revealed that, of the different 17HSDs, the type 2 enzyme is most abundantly expressed. High expression of the enzyme, which oxidizes both testosterone and oestradiol, in several large organs of both sexes indicates that it is the isoform having the most substantial role in the metabolism of sex steroids. Interestingly, four of the five 17HSD enzymes were also detected by Northern blots of whole mouse embryos, and each of the enzymes showed a unique pattern of expression. The oestradiol-synthesizing type 1 enzyme predominates in early days of development embryonic day 7, but after that the oxidative type 2 enzyme becomes the predominant form of all 17HSDs. The data therefore suggest that there is transient oestradiol production in the early days of embryonic development, after which inactivation of sex steroids predominates in the fetus and placenta.
A cDNA library specific for mRNA over-expressed in prostate cancer was generated by subtractive hybridization of transcripts originating from prostatic hyperplasia and cancer tissues. cDNA encoding ribosomal proteins L4, L5, L7a, L23a, L30, L37, S14 and S18 was found to be present among 100 analyzed clones. Levels of ribosomal mRNA were significantly higher at least in one of the prostate-cancer cell lines, LNCaP, DU-145 and PC-3, than in hyperplastic tissue, as determined by slot-blot hybridization. Furthermore, L23a-and S14-transcript levels were significantly elevated in PC-3 cells as compared with those in the normal prostate epithelial cell line PrEC. Generally, dramatic changes in the mRNA content of the ribosomal proteins were not detected, the most evident over-expression being that of L37 mRNA, which was 3.4 times more abundant in LNCaP cells than in hyperplastic prostate tissue. The over-expression of L7a and L37 mRNA was confirmed in prostate-cancer tissue samples by in situ hybridization. Elevated cancer-related expression of L4 and L30 has not been reported, but levels of the other ribosomal proteins are known to be increased in several types of cancers. These results therefore suggest that prostate cancer is comparable with other types of cancers, in that a larger pool of some ribosomal proteins is gained during the transformation process, by an unknown mechanism. Int.
17Beta-hydroxysteroid dehydrogenase activity represents a group of several isoenzymes (17HSDs) that catalyze the interconversion between highly active 17beta-hydroxy- and low activity 17-ketosteroids and thereby regulate the biological activity of sex steroids. The present study was carried out to characterize the expression of 17HSD isoenzymes in human mammary epithelial cells and breast tissue. In normal breast tissues 17HSD types 1 and 2 mRNAs were both evenly expressed in glandular epithelium. In two human mammary epithelial cell lines, mRNAs for 17HSD types 1, 2 and 4 were detected. In enzyme activity measurements only oxidative 17HSD activity, corresponding to either type 2 or type 4 enzyme, was present. The role of 17HSD type 4 in estrogen metabolism was further investigated, using several cell lines originating from various tissues. No correlation between the presence of 17HSD type 4 mRNA and 17HSD activity in different cultured cell lines was detected. Instead, oxidative 17HSD activity appeared in cell lines where 17HSD type 2 was expressed and reductive 17HSD activity was present in cells expressing 17HSD type 1. These data strongly suggest that in mammary epithelial cell lines the oxidative activity is due to type 2 17HSD and that oxidation of 17beta-hydroxysteroids is not the primary activity of the 17HSD type 4 enzyme.
We have generated two transgenic mouse lines (GPX5-Tag1 and GPX5-Tag2) by expressing the Simian virus 40 large and small T-antigens under a 5-kb promoter of the murine glutathione peroxidase 5 (GPX5) gene. In GPX5-Tag1 mice, with a high level of T-antigen expression, severe dysplasia was found in the epididymis and seminal vesicles. These mice also developed adrenal and prostate tumors, and spermatogenesis was disrupted. In GPX5-Tag2 mice, with a lower level of T-antigen expression, the only histological change was the slightly hyperplastic epithelium in the initial segment of the epididymidis and in the seminal vesicles. Despite normal mating behavior, these mice were infertile. The most conspicuous feature of the sperm was angulation of the flagellum, which appeared during epididymal transit, probably due to the observed reduction in the osmotic pressure of cauda epididymidal fluid. The angulation did not affect the motility or kinematic parameters of the sperm, but the sperm were also incapable of fertilization in vitro. The lack of expression of several genes specific for the initial segment suggests that in the GPX5-Tag2 mice the transgene expression brings about a differentiation arrest in this part of epididymis. This novel mouse line provides a model for epididymal dysfunction leading to defects in posttesticular sperm maturation and infertility.
According to the current hypothesis, 17beta-hydroxysteroid dehydrogenases (17HSDs) regulate the extent of estrogen influence in the endometrium by converting estradiol (E2) locally into a biologically less active sex steroid, estrone (E1), and vice versa. Recently, we have shown that both 17HSD type 1 and type 2 are expressed in the human endometrium, and in the present work, using in situ hybridization, we show that 17HSD type 2 is localized in the glandular epithelial cells as previously shown for the type 1 enzyme, but in contrast to type 1, the expression of type 2 is highest at the end of the cycle. Hence, we hypothesize that the differential expression of the two 17HSD enzymes, with opposite activities in same cell types, could modulate intracellular E2 concentrations during the end of the luteal phase of the menstrual cycle. We further analyzed the expression of 17HSD type 1 and type 2 mRNAs in term human placenta. Expression of 17HSD type 1 mRNA was detected in the syncytiotrophoblasts, and signals for type 2 mRNA were found inside the villi, corresponding to cytotrophoblasts. The expression of 17HSD type 2 in the placenta may serve to maintain the presence of inactive sex steroids and attenuate the formation of biologically potent androgens and estrogens.
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