Transcriptional regulation of human CYP11A1 in gonads and adrenals

Guo, Ing-Cherng; Shih, Meng Chun; Lan, Hsin Chieh; Hsu, Nai Chi; Hu, Meng Chun; Chung, Bon Chu

doi:10.1007/s11373-007-9177-z

Cited by 46 publications

(34 citation statements)

References 37 publications

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“…Promoter regions of the genes IFT172 and SLC4A8 contain multiple binding sites for various nuclear factor proteins (see Fig. S3 in the supplemental material), most of which were reported to participate in a tissue-specific regulation of gene transcription (6,19,34,40). Therefore, the concentration of mRNA for these genes is most likely regulated by the antisense RNAs and by the content of specific protein transcriptional factors, which may differ greatly among the tissues.…”

Section: Discussionmentioning

confidence: 99%

Human-Specific Modulation of Transcriptional Activity Provided by Endogenous Retroviral Insertions

Gogvadze

Stukacheva

Buzdin

et al. 2009

J Virol

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Many phenotypic differences exist between Homo sapiens and its closest relatives, chimpanzees, and these differences can arise as a result of variations in the regulation of certain genes common to these closely related species. Human-specific endogenous retroviruses (HERVs) and their solitary long terminal repeats (LTRs) are probable candidates for such a role due to the presence of regulatory elements, such as enhancers, promoters, splice sites, and polyadenylation signals. In this study we show for the first time that HERVs can participate in the specific antisense regulation of human gene expression owing to their LTR promoter activity. We found that two HERV LTRs situated in the introns of genes SLC4A8 (for sodium bicarbonate cotransporter) and IFT172 (for intraflagellar transport protein 172) in the antisense orientation serve in vivo as promoters for generating RNAs complementary to the exons of enclosing genes. The antisense transcripts formed from LTR promoter were shown to decrease the mRNA level of the corresponding genes. The human-specific regulation of these genes suggests their involvement in the evolutionary process.Retroelements (REs) are mobile genetic elements that replicate and transpose through RNA intermediates (11, 13, 22, 39). They constitute more than 42% of human DNA and are the only known class of mobile elements that transpose in mammals in vivo. Four RE families (L1, Alu, SVA, and HERV-K [HML-2]) were transpositionally active after the divergence of human and chimpanzee ancestries, forming a relatively modest fraction of human specific inserts (approximately thousands of copies [33] compared to a total of ϳ3 million of human REs [25,44]). REs are known to be recombination hot spots and provide promoters, polyadenylation signals, and additional splice sites, thus modifying the activity of preexisting human genes (7,22,27,37,38,42,43). At least one-third of all human-specific REs have been mapped within or close to genes (33). Therefore, REs are thought to be one of the causative agents responsible for phenotypic differences between Homo sapiens and its closest relatives, the Pan paniscus and P. troglodytes chimpanzees.

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Section: Discussionmentioning

confidence: 99%

Human-Specific Modulation of Transcriptional Activity Provided by Endogenous Retroviral Insertions

Gogvadze

Stukacheva

Buzdin

et al. 2009

J Virol

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“…1). These factors have been previously implicated in the transcriptional regulation of CYP11A1 promoter (Guo et al 2007). Besides, several bindings sites for known co-regulators of SF1 including Sox proteins, GATA factors, and WT1 have also been identified in these promoters (data not shown).…”

Section: Resultsmentioning

confidence: 94%

“…Among them, the cholesterol side-chain cleavage enzyme (P450scc, also known as CYP11A1) catalyzes the first and rate-limiting step in the steroidogenesis pathway by converting cholesterol to prenegnolone. Thus, the gene product of CYP11A1 occupies a key regulatory point in the biosynthesis of steroids (reviewed in Chung et al (1997) and Guo et al (2003Guo et al ( , 2007). …”

Section: Introductionmentioning

confidence: 99%

“…The transcriptional regulation of mammalian CYP11A1, including human (Morohashi et al 1987), mouse (Rice et al 1990), rat (Oonk et al 1990), sheep (Pestell et al 1993), and bovine (Ahlgren et al 1999), has been intensively studied. Key cis-acting elements and their corresponding trans-acting factors, like steroidogenic factor 1 (SF1), AP-2, Sp1, TreP-132, and c-jun/AP-1, have been implicated in their transcriptional activation, particularly in relation to cAMP stimulation (Guo et al 2007). The synthesis of steroid hormones is restricted to steroidogenic tissues and this is due to the developmentally important SF1, which is the central regulator responsible for tissue-specific expression of steroid hydroxylases, including CYP11A1 (Bakke et al 2001, Kelly et al 2004, Li et al 2004.…”

Section: Introductionmentioning

confidence: 99%

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Transcriptional activation of zebrafish cyp11a1 promoter is dependent on the nuclear receptor Ff1b

Quek

Chan

2009

Journal of Molecular Endocrinology

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The cytochrome P450scc (cholesterol side-chain cleavage enzyme) encoded by CYP11A1 catalyzes the first step in steroidogenesis by converting cholesterol to pregnenolone, and thus, controls the synthesis rate of steroid hormones. In mammals, steroidogenic factor 1 (SF1) has been implicated in the cAMP-mediated transcriptional activation of CYP11A1 promoter. In zebrafish, Ff1b has been established as the homolog of SF1. To assess the dependency of cyp11a1 expression on Ff1b, the putative promoter of zebrafish cyp11a1, spanning 1 . 7 kb, was isolated and bioinformatic analysis revealed two conserved FF1 response elements (FREs) that potentially bind Ff1b. Transfection studies in cell lines of different lineages confirmed that this promoter fragment contained the necessary regulatory elements required for its basal transcription. Truncation and mutagenesis studies performed in Y1 adrenocortical cells revealed that only the proximal FRE was essential for transcriptional activation. Electrophoretic mobility shift assay, however, indicated that Ff1b bound to both FREs, while their in vivo occupancy was confirmed using a chromatin immunoprecipitation assay. Lastly, the cyp11a1 promoter was able to direct EGFP expression specifically to the interrenal gland and genital ridge when transiently expressed in microinjected zebrafish embryos, and the promoter activity is potentiated by ff1b overexpression as measured from luciferase reporter activity in zebrafish embryos.

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“…The CYP11A1 promoter is composed of multiple cis-acting response elements that control transcriptional activity by binding with trans-acting factors (37). Thus, polymorphisms located within or near these regulatory regions, such as D15S520, may especially influence CYP11A1 expression or cytochrome P450scc enzyme activity, although which, if any, do so are unknown.…”

Section: Discussionmentioning

confidence: 99%

Polymorphisms in Steroid Hormone Biosynthesis Genes and Risk of Breast Cancer and Fibrocystic Breast Conditions in Chinese Women

Sakoda

Blackston

Doherty³

et al. 2008

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Common variants in genes encoding for key enzymes involved in steroidogenesis may alter sex steroid hormone levels, thereby influencing susceptibility to breast carcinoma and related conditions. In a casecontrol study of Chinese women, we examined genotypes of the CYP11A1 pentanucleotide [(TAAAA) n ] repeat (D15S520), CYP17A1 rs743572, and HSD17B1 rs605059 polymorphisms in relation to the risk of breast cancer and fibrocystic breast conditions, comparing 615 women with breast cancer and 467 women with fibrocystic breast conditions separately with 879 women without clinical breast disease. We also evaluated whether these relationships differed by the presence of proliferation in the extratumoral epithelium or fibrocystic lesions, menopausal status, or body mass index. Only CYP11A1 genotype was related to breast cancer risk, with women homozygous for the 4-repeat allele, relative to those homozygous for the 6-repeat allele, at reduced risk (age-adjusted odds ratio, 0.58; 95% confidence interval, 0.37-0.91). There was some suggestion of a stronger inverse association for breast cancer with evidence of proliferation in the extratumoral epithelium than for breast cancer without extratumoral proliferation. Breast cancer risk associated with CYP11A1 genotype did not differ by menopausal status or body mass index level. No associations between CYP11A1, CYP17A1, and HSD17B1 genotypes and risk of fibrocystic breast conditions were observed. Our findings support the possibility that common allelic variation at the CYP11A1 D15S520 locus alters breast cancer risk in Chinese women. (Cancer Epidemiol Biomarkers Prev 2008;17(5):1066 -73)

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Transcriptional regulation of human CYP11A1 in gonads and adrenals

Cited by 46 publications

References 37 publications

Human-Specific Modulation of Transcriptional Activity Provided by Endogenous Retroviral Insertions

Human-Specific Modulation of Transcriptional Activity Provided by Endogenous Retroviral Insertions

Transcriptional activation of zebrafish cyp11a1 promoter is dependent on the nuclear receptor Ff1b

Polymorphisms in Steroid Hormone Biosynthesis Genes and Risk of Breast Cancer and Fibrocystic Breast Conditions in Chinese Women

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