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Submitted on March 3, 2007
Accepted on August 21, 2007
Institut de Pharmacologie Moléculaire et Cellulaire CNRS UMR 6097 and Université de Nice - Sophia Antipolis, 660 route des Lucioles - Sophia Antipolis 06560 Valbonne, France; Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas, USA; Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC, USA; Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, Tennessee, USA; Instituto de Pesquisa Pelé Pequeno Principe, Curitiba, Paraná, Brazil; Centro de Genética Molecular e Pesquisa do Câncer em Crian|fccas (CEGEMPAC), Curitiba, Paraná, Brazil
* To whom correspondence should be addressed. E-mail: ninino{at}ipmc.cnrs.fr.
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 (ACT) 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 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, 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 DHEA-S 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 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, immune response and transcription factor Stat3 are differentially expressed in Sf-1 transgenic mouse adrenals compared to 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 ACT therapy.
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