Increased Steroidogenic Factor-1 dosage triggers adrenocortical cell proliferation and cancer
| Autor: | Mabrouka Doghman, Leslie L. Heckert, Gerard P. Zambetti, Virginie Virolle, Malika Arhatte, Bonald C. Figueiredo, Luciane R. Cavalli, Pascal Barbry, Enzo Lalli, Tatiana S. Karpova, Juliana de Moura, Giovanna Assis Rodrigues |
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| Přispěvatelé: | Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Department of Molecular and Integrative Physiology, University of Kansas Medical Center [Lawrence], Department of Oncology, Lombardi Comprehensive Cancer Center-Georgetown University Medical Center, Department of Biochemistry, St Jude Children's Research Hospital, Instituto de Pesquisa Pelé Pequeno Principe, CEGEMPAC, Centro de Genética Molecular e Pesquisa do Câncer em Crianças |
| Jazyk: | angličtina |
| Rok vydání: | 2007 |
| Předmět: |
STAT3 Transcription Factor
Steroidogenic factor 1 Transcription Genetic Molecular Sequence Data Mice Transgenic [SDV.CAN]Life Sciences [q-bio]/Cancer Steroidogenic Factor 1 Mice 03 medical and health sciences 0302 clinical medicine Endocrinology Cell Line Tumor Neoplasms Cell Adhesion medicine Transcriptional regulation Animals Humans Histidine [SDV.BBM]Life Sciences [q-bio]/Biochemistry Molecular Biology STAT3 Molecular Biology Transcription factor Cell Proliferation 030304 developmental biology 0303 health sciences Binding Sites Base Sequence biology Cell growth Adrenal cortex General Medicine Cell cycle Lipid Metabolism Extracellular Matrix Up-Regulation Gene Expression Regulation Neoplastic Cell Transformation Neoplastic medicine.anatomical_structure 030220 oncology & carcinogenesis Mutation biology.protein Cancer research Steroids Signal transduction [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology Signal Transduction |
| Zdroj: | Molecular Endocrinology-Baltimore Molecular Endocrinology-Baltimore-, Endocrine Society, 2007, epub ahead of print. ⟨10.1210/me.2007-0120⟩ |
| ISSN: | 0888-8809 |
| DOI: | 10.1210/me.2007-0120⟩ |
| Popis: | 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 expression profiling showed that an increased SF-1 dosage regulates transcripts involved in steroid metabolism, the cell cycle, apoptosis, and cell adhesion to the extracellular matrix. Consistent with these results, increased SF-1 levels selectively modulate the steroid secretion profile of adrenocortical cells, reducing cortisol and aldosterone production and maintaining dehydroepiandrosterone sulfate secretion. As a model to understand the mechanisms of transcriptional regulation by increased SF-1 dosage, we studied FATE1, coding for a cancer-testis antigen implicated in the control of cell proliferation. Increased SF-1 levels increase its binding to a consensus site in FATE1 promoter and stimulate its activity through modulation of the recruitment of specific cofactors. On the other hand, sphingosine, which can compete with phospholipids for binding to SF-1, had no effect on the SF-1 dosage-dependent increase of adrenocortical cell proliferation and expression of the FATE1 promoter. In mice, increased Sf-1 dosage produces adrenocortical hyperplasia and formation of tumors expressing gonadal markers (Amh, Gata-4), which originate from the subcapsular region of the adrenal cortex. Gene expression profiling revealed that genes involved in cell adhesion and the immune response and transcription factor signal transducer and activator of transcription-3 (Stat3) are differentially expressed in Sf-1 transgenic mouse adrenals compared with wild-type adrenals. Our studies reveal a critical role for SF-1 dosage in adrenocortical tumorigenesis and constitute a rationale for the development of drugs targeting SF-1 transcriptional activity for adrenocortical tumor therapy. |
| Databáze: | OpenAIRE |
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