Unknown,Transcriptomics,Genomics,Proteomics

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Identification of genes regulated by overexpressed SF-1 in human adrenocortical cells

ABSTRACT: SF-1, a transcription factor belonging to the nuclear receptor superfamily, has a pivotal role for adrenogonadal development in humans and mice. A constant feature of childhood adrenocortical tumors (ACT) is SF-1 amplification and overexpression. Using an inducible cellular system, here we show that SF-1 overexpression increases human adrenocortical cell proliferation through opposing effects on cell cycle and apoptosis. SF-1 overexpression also selectively modulates steroidogenesis, reducing cortisol and aldosterone secretion. We identified a novel pro-apoptotic factor for adrenocortical cells, NOV/CCN3, whose levels are significantly reduced by SF-1 overexpression in human adrenocortical cells and are also reduced in primary adrenal tumors. Moreover, Sf-1 overexpression triggers adrenocortical hyperplasia and tumor formation in mice. These tumors express gonadal markers and activated Stat3. Our studies reveal the critical role of SF-1 gene dosage for adrenocortical tumorigenesis and constitute a rationale for the development of drugs targeting SF-1 transcriptional activity for ACT therapy. Keywords: differential expression, transcription factor Gene expression profiles were analyzed in two different H295R TR/SF-1 WT clones overexpressing SF-1 in a tetracycline-regulated fashion cultured in basal conditions or after three days of doxycycline treatment. For each condition, two biological replicates were examined. Array #22354 Clone #1 replicate 1 basal Cy3/Dox Cy5 Array #22416 Clone #1 replicate 2 basal Cy5/Dox Cy3 Array #22446 Clone #2 replicate 1 basal Cy3/Dox Cy5 Array #22447 Clone #2 replicate 2 basal Cy5/Dox Cy3

ORGANISM(S): Homo sapiens

SUBMITTER: Juliana De Moura

PROVIDER: E-GEOD-5911 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Increased steroidogenic factor-1 dosage triggers adrenocortical cell proliferation and cancer.

Doghman Mabrouka M Karpova Tatiana T Rodrigues Giovanna Assis GA Arhatte Malika M De Moura Juliana J Cavalli Luciane R LR Virolle Virginie V Barbry Pascal P Zambetti Gerard P GP Figueiredo Bonald C BC Heckert Leslie L LL Lalli Enzo E

Molecular endocrinology (Baltimore, Md.) 20070830 12

Steroidogenic factor-1 (SF-1/Ad4BP; NR5A1), a nuclear receptor transcription factor, has a pivotal role in adrenal and gonadal development in humans and mice. A frequent feature of childhood adrenocortical tumors is SF-1 amplification and overexpression. Here we show that an increased SF-1 dosage can by itself augment human adrenocortical cell proliferation through concerted actions on the cell cycle and apoptosis. This effect is dependent on an intact SF-1 transcriptional activity. Gene express ...[more]

PMID: 17761949

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Project description:SF-1, a transcription factor belonging to the nuclear receptor superfamily, has a pivotal role for adrenogonadal development in humans and mice. A constant feature of childhood adrenocortical tumors (ACT) is SF-1 amplification and overexpression. Using an inducible cellular system, here we show that SF-1 overexpression increases human adrenocortical cell proliferation through opposing effects on cell cycle and apoptosis. SF-1 overexpression also selectively modulates steroidogenesis, reducing cortisol and aldosterone secretion. We identified a novel pro-apoptotic factor for adrenocortical cells, NOV/CCN3, whose levels are significantly reduced by SF-1 overexpression in human adrenocortical cells and are also reduced in primary adrenal tumors. Moreover, Sf-1 overexpression triggers adrenocortical hyperplasia and tumor formation in mice. These tumors express gonadal markers and activated Stat3. Our studies reveal the critical role of SF-1 gene dosage for adrenocortical tumorigenesis and constitute a rationale for the development of drugs targeting SF-1 transcriptional activity for ACT therapy. Keywords: comparative gene expression Gene expression profiles were analyzed by two-color microarrays in transgenic mice from line #56 heterozygous or homozygous for the transgene, male or female and of different ages. Profiles from each transgenic mouse were directly compared to a sex- and age-matched wild-type littermate. For each experimental point, two technical replicates (dye-swaps) were examined. Array # Age Sex Transgene copy # Cy3 Cy5 16682 10 days M 1 WT transgenic 16479 10 days M 1 transgenic WT 16683 10 days M 1 WT transgenic 16625 10 days M 1 transgenic WT 16685 10 days F 1 WT transgenic 16680 10 days F 1 transgenic WT 16516 4 months M 2 WT transgenic 16452 4 months M 2 transgenic WT 16517 4 months M 2 WT transgenic 16453 4 months M 2 transgenic WT 16518 4 months F 2 WT transgenic 16475 4 months F 2 transgenic WT

Project description:Cows were selected from two groups of 12 cows enrolled in a large experiment to assess the effects of ad libitum or restricted intake of moderate-energy diets during the entire dry period on pre-partum metabolism and post-partum metabolism and performance. A corn silage-based diet (26% of diet dry matter) providing 1.59 Mcal/kg during the far-off dry period (first 5 wk of an 8-wk dry period) or providing 1.61 Mcal/kg during the close-up dry period (last 3 wk of the dry period) was fed for ad libitum or restricted intake. Four multiparous Holstein cows were randomly selected from the ad libitum and restricted intake groups. A 7,872-element cDNA microarray spotted in duplicate on amino silane-coated glass slides (Everts et al. 2005, Vet. Immunol. Immunopathol. 105:235-245) was used for transcript profiling. Annotation was based on similarity searches (January, 2005) using sequential BLASTN and TBLASTX against human and mouse UniGene databases and the human genome. The 7,872-element array represents more than 6,300 unique genes. Gene Ontology (GO) terms were parsed from LocusLink to functionally annotate cDNA sequences. RNA (20 ug) from liver tissue and a reference standard derived from a mixture of tissues not including liver were used to make aminoallyl-labeled cDNA followed by incorporation of Cy3-ester and Cy5-ester (Amersham, Piscataway, NJ). Each experimental sample was co-hybridized with the reference standard, which allowed the treatment of fluorescence ratios as measurements of relative expression across all samples and time points. Probes were hybridized to the array for 2 days at 42 C. All samples were hybridized to duplicate slides for a total of 4 spots per cDNA element. A total of 106 microarrays were run to complete the experiment. Slides were scanned for both dye channels with a Scanarray 4000 (GSI-Lumonics, Billerica, MA) dual-laser confocal scanner and images were processed using GenePix 4.0 (Axon Instruments, Inc., CA).

Dataset Information

Identification of genes regulated by overexpressed SF-1 in human adrenocortical cells

Publications

Increased steroidogenic factor-1 dosage triggers adrenocortical cell proliferation and cancer.

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