Binding Sites for Transcription Factor SF-1 in Promoter Regions of Genes Encoding Mouse Steroidogenesis Enzymes 3βHSDI and P450c17

Busygina, T. V.; Vasiliev, Gennady V.; Климова, Н. В.; Ignatieva, E. V.; Осадчук, А. В.

doi:10.1007/s10541-005-0239-4

Cited by 5 publications

(2 citation statements)

References 27 publications

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“…Thus, establishing the presence of SF1 and its pro-steroidogenic and growth promoting activities within cancerous prostate cells uncovers a critical molecular mechanism to explain local steroid production that drives aggressive prostate cancer. It has long been established that SF1 is a potent regulator of steroidogenesis (15,17,18,61). Our data suggest that this role is conserved within prostate epithelial cell lines.…”

Section: Discussionsupporting

confidence: 59%

Steroidogenic Factor 1 Promotes Aggressive Growth of Castration-Resistant Prostate Cancer Cells by Stimulating Steroid Synthesis and Cell Proliferation

et al. 2014

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The dependence of prostate cancer on androgens provides a targeted means of treating advanced disease. Unfortunately, androgen deprivation therapies eventually become ineffective, leading to deadly castration-resistant prostate cancer (CRPC). One of many factors implicated in the transition to CRPC is the onset of de novo steroidogenesis. Although reactivation of steroid receptors likely plays a pivotal role in aggressive CRPC, little is understood regarding the mechanisms whereby prostate cancer cells initiate and maintain steroidogenesis. We hypothesize that steroidogenic factor 1 (SF1, NR5A1, AD4BP), a key regulator of steroidogenesis in normal endocrine tissues, is expressed in CRPC where it stimulates aberrant steroidogenesis and fuels aggressive growth. Notably, SF1 is not expressed in normal prostate tissue. Our results indicated that SF1 was absent in benign cells but present in aggressive prostate cancer cell lines. Introduction of ectopic SF1 expression in benign human prostate epithelial cells (BPH-1) stimulated increased steroidogenic enzyme expression, steroid synthesis, and cell proliferation. In contrast, data from an aggressive human prostate cancer cell line (BCaPT10) demonstrated that SF1 was required for steroid-mediated cell growth because BCaPT10 cell growth was diminished by abiraterone treatment and short hairpin RNA-mediated knockdown of SF1 (shSF1). SF1-depleted cells also exhibited defective centrosome homeostasis. Finally, whereas xenograft experiments in castrated hosts with BCaPT10 control transplants grew large, invasive tumors, BCaPT10-shSF1 knockdown transplants failed to grow. Therefore, we conclude that SF1 stimulates steroid accumulation and controls centrosome homeostasis to mediate aggressive prostate cancer cell growth within a castrate environment. These findings present a new molecular mechanism and therapeutic target for deadly CRPC.

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Section: Discussionsupporting

confidence: 59%

Steroidogenic Factor 1 Promotes Aggressive Growth of Castration-Resistant Prostate Cancer Cells by Stimulating Steroid Synthesis and Cell Proliferation

et al. 2014

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“…It appears that Cyp17 is therefore upregulated in Mrp1-/- mouse testes to compensate for the low levels of androstenedione and testosterone. Although there are several transcription factors that regulate Cyp17 expression, the predominant one appears to be SF-1 (Nr5a1) (Busygina et al, 2005; Mellon et al, 1998; Ozbay et al, 2006; Patel et al, 2009; Shi et al, 2009; Zhang et al, 2001). SF-1 mRNA levels were increased by 1.7-fold in the testes of mice lacking Mrp1, although this was not statistically different.…”

Section: Discussionmentioning

confidence: 99%

Mice lacking Mrp1 have reduced testicular steroid hormone levels and alterations in steroid biosynthetic enzymes

Sivils

González

Bain

2010

General and Comparative Endocrinology

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The multidrug resistance-associated protein 1 (MRP1/ABCC1) is a member of the ABC active transporter family that can transport several steroid hormone conjugates, including 17β-estradiol glucuronide, dehydroepiandrosterone sulfate (DHEAS), and estrone 3-sulfate. The present study investigated the role that MRP1 plays in maintaining proper hormone levels in the serum and testes. Serum and testicular steroid hormone levels were examined in both wild-type mice and Mrp1 null mice. Serum testosterone levels were reduced 5-fold in mice lacking Mrp1, while testicular androstenedione, testosterone, estradiol, and dehydroepiandrosterone (DHEA) were significantly reduced by 1.7-to 4.5-fold in Mrp1 knockout mice. Investigating the mechanisms responsible for the reduction in steroid hormones in Mrp1-/-mice revealed no differences in the expression or activity of enzymes that inactivate steroids, the sulfotransferases or glucuronosyltransferases. However, steroid biosynthetic enzyme levels in the testes were altered. Cyp17 protein levels were increased by 1.6-fold, while Cyp17 activity using progesterone as a substrate was also increased by 1.4-2.0-fold in mice lacking Mrp1. Additionally, the ratio of 17β-hydroxysteroid dehydrogenase to 3β-hydroxysteroid dehydrogenase, and steroidogenic factor 1 to 3βhydroxysteroid dehydrogenase were significantly increased in the testes of Mrp1-/-mice. These results indicate that Mrp1-/-mice have lowered steroid hormones levels, and suggests that upregulation of steroid biosynthetic enzymes may be an attempt to maintain proper steroid hormone homeostasis.

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CCAAT/Enhancer Binding Protein β, But Not Steroidogenic Factor-1, Modulates the Phthalate-Induced Dysregulation of Rat Fetal Testicular Steroidogenesis

2007

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Prolonged in utero exposure of fetal male rats to dibutyl phthalate (DBP) can result in a feminized phenotype characterized by malformed epididymides, hypospadias, cryptorchidism, and retained thoracic nipples, among others. These symptoms likely result, in part, from decreased expression of steroidogenic enzymes and, therefore, reduced testosterone biosynthesis. However, the molecular mechanisms involved in these changes in gene expression profiles are unknown. To understand these mechanisms in rats, in vivo DNase footprinting was adapted to provide a semiquantitative map of changes in DNA-protein interactions in the promoter region of steroidogenic genes, including steroidogenic acute regulatory, scavenger receptor B-1, cytochrome P450 side chain cleavage, and cytochrome P450 17A1, that are down-regulated after an in utero DBP exposure. Regions with altered DNase protection were coordinated with a specific DNA binding protein event by EMSA, and binding activity confirmed with chromatin immunoprecipitation. Results demonstrated altered DNase protection at regions mapping to CCAAT/enhancer binding protein β (c/ebp β) and steroidogenic factor-1 (SF-1). Chromatin immunoprecipitation confirmed declines in DNA-protein interactions of c/ebp β in DBP treated animals, whereas SF-1 was reduced in both diethyl phthalate (nontoxic) and DBP (toxic) treatments. These results suggest that inhibition of c/ebp β, and not SF-1, is critical in DBP induced inhibition of steroidogenic genes. In addition, these observations suggest a pathway redundancy in the regulation of steroidogenesis in fetal testis. In conclusion, this study presents a snapshot of changes in the structure of transcriptional machinery and proposes a mechanism of action resulting from DBP exposure.

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Binding Sites for Transcription Factor SF-1 in Promoter Regions of Genes Encoding Mouse Steroidogenesis Enzymes 3βHSDI and P450c17

Abstract: Using gel retardation of DNA samples and specific antibodies, binding sites for the transcription factor SF-1 were found in positions -53/-44 and -285/-270 in the promoter region of the mouse Cyp17 gene and in position -117/-108 of the promoter region of the mouse 3betaHSDI gene.

Cited by 5 publications

References 27 publications

Steroidogenic Factor 1 Promotes Aggressive Growth of Castration-Resistant Prostate Cancer Cells by Stimulating Steroid Synthesis and Cell Proliferation

Steroidogenic Factor 1 Promotes Aggressive Growth of Castration-Resistant Prostate Cancer Cells by Stimulating Steroid Synthesis and Cell Proliferation

Mice lacking Mrp1 have reduced testicular steroid hormone levels and alterations in steroid biosynthetic enzymes

CCAAT/Enhancer Binding Protein β, But Not Steroidogenic Factor-1, Modulates the Phthalate-Induced Dysregulation of Rat Fetal Testicular Steroidogenesis

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