Expression Profiles of COUP–TF, DAX-1, and SF-1 in the Human Adrenal Gland and Adrenocortical Tumors: Possible Implications in Steroidogenesis

Shibata, Hirotaka; Ikeda, Yayoi; Mukai, Tokuo; Morohashi, Ken Ichirou; Kurihara, Isao; Ando, Takashi; Suzuki, Toshihiko; Kobayashi, Sakiko; Murai, Masaru; Saito, Ikuo; Saruta, Takao

doi:10.1006/mgme.2001.3231

Cited by 63 publications

(49 citation statements)

References 42 publications

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“…27 According with these functions, DAX1 is mainly expressed in the hypothalamic-pituitary-adrenal-gonadal steroidogenic axis. DAX1 expression studies in cancer are sparse, and they have been exclusively focused to tumors derived from DAX1-expressing tissues such as pituitary adenomas 39 or adrenocortical tumors, 40,41 in which an inverse correlation between DAX1 expression and steroid hormone production has been observed. To our knowledge, this is the first time that DAX1 is reported to be specifically up-regulated by an oncogene, and to be highly expressed in tumors unrelated with steroidogenic tissues such as Ewing tumors and alveolar rhabdomyosarcoma.…”

Section: Discussionmentioning

confidence: 99%

The orphan nuclear receptor DAX1 is up-regulated by the EWS/FLI1 oncoprotein and is highly expressed in Ewing tumors

Mendiola¹,

Carrillo²,

García³

et al. 2005

Int. J. Cancer

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The Ewing family of tumors harbors chromosomal translocations that join the N-terminal region of the EWS gene with the C-terminal region of several transcription factors of the ETS family, mainly FLI1, resulting in chimeric transcription factors that play a pivotal role in the pathogenesis of Ewing tumors. To identify downstream targets of the EWS/FLI1 fusion protein, we established 293 cells expressing constitutively either the chimeric EWS/ FLI1 or wild type FLI1 proteins and used cDNA arrays to identify genes differentially regulated by EWS/FLI1. DAX1 (NR0B1), an unusual orphan nuclear receptor involved in gonadal development, sex determination and steroidogenesis, showed a consistent up-regulation by EWS/FLI1 oncoprotein, but not by wild type FLI1. Specific induction of DAX1 by EWS/FLI1 was confirmed in two independent cell systems with inducible expression of EWS/ FLI1. We also analyzed the expression of DAX1 in Ewing tumors and derived cell lines, as well as in other nonrelated small round cell tumors. DAX1 was expressed in all Ewing tumor specimens analyzed, and in seven out of eight Ewing tumor cell lines, but not in any neuroblastoma or embryonal rhabdomyosarcoma. Furthermore, silencing of EWS/FLI1 by RNA interference in a Ewing tumor cell line markedly reduced the levels of DAX1 mRNA and protein, confirming that DAX1 up-regulation is dependent upon EWS/FLI1 expression. The high levels of DAX1 found in Ewing tumors and its potent transcriptional repressor activity suggest that the oncogenic effect of EWS/FLI1 may be mediated, at least in part, by the up-regulation of DAX1 expression. ' 2005 Wiley-Liss, Inc.Key words: Ewing tumors; EWS/FLI1 oncoprotein; orphan nuclear receptor DAX1; cDNA arrays Ewing sarcoma and peripheral primitive neuroectodermal tumors (PNETs) are referred to as the Ewing family of tumors, a group of highly malignant tumors arising in children, adolescents and young adults. 1 Ewing tumors are characterized by specific balanced chromosomal translocations, leading to the formation of chimeric proteins that join the N-terminal region from the EWS gene product in frame with the C-terminal portion of out of five different members of the ETS family of transcription factors: FLI1, ERG or FEV (ERG subfamily) and E1AF or ETV1 (PEA3 subfamily). The EWS/FLI1 combination is most frequent and is present in nearly 85% of all cases. 2 A large body of evidence has shown the oncogenic potential of EWS/FLI1 protein. Thus, the ectopic expression of EWS/FLI1 in murine fibroblasts promotes anchorage-independent growth in vitro 3 and accelerates tumorigenesis in vivo. 4 Moreover, EWS/FLI1 knock-down using a variety of techniques inhibits the growth of Ewing tumor-derived cell lines both in vitro and in vivo. 5-9 These data, together with the observation that EWS/ETS chimeric proteins are present in virtually all Ewing tumors, have provided strong evidence that these fusion genes are necessary for the development of these neoplasms. However, EWS/FLI1 appears to be toxic for mouse embryo fibroblasts 10 and p...

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Section: Discussionmentioning

confidence: 99%

The orphan nuclear receptor DAX1 is up-regulated by the EWS/FLI1 oncoprotein and is highly expressed in Ewing tumors

Mendiola¹,

Carrillo²,

García³

et al. 2005

Int. J. Cancer

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“…In fact, although most studies have focused on the developmental and tissular distribution of DAX-1 expression in various species (32,33), on its mechanism of action (25,34,35), and on the incidence of mutations in the DAX-1 gene on adrenal and reproductive functions (23,24,36,37), information on the regulation of DAX-1 expression in steroidogenic tissues is practically non-existent. In our hands, the aldosterone response was correlated with the extent of the repression of DAX-I, the highest amounts of the mineralocorticoid being produced when DAX-1 protein levels were the lowest.…”

Section: Discussionmentioning

confidence: 99%

Repression of DAX-1 and Induction of SF-1 Expression

Osman

Murigande

Nadakal

et al. 2002

Journal of Biological Chemistry

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Angiotensin II (Ang II) and adrenocorticotropic hormone stimulate aldosterone biosynthesis in the zona glomerulosa of the adrenal cortex through induction of the expression of the steroidogenic acute regulatory (StAR) protein, which promotes intramitochondrial cholesterol transfer. To understand the mechanism of this induction of the StAR protein, we have examined the effect of Ang II and forskolin, a mimicker of adrenocorticotropic hormone action, on two transcription factors known to modulate StAR gene expression in opposite ways, DAX-1 and SF-1, in bovine adrenal glomerulosa cells in primary culture. Ang II markedly inhibited DAX-1 protein expression in a time-and concentrationdependent manner (to 38.7 ؎ 12.9% of controls at 3 nM after 6 h, p < 0.01), an effect that required de novo protein synthesis and ERK2/1 activation. This effect was associated with a concomitant decrease in DAX-1 mRNA and an increase in mitochondrial StAR protein levels. Similarly, forskolin dramatically repressed DAX-1 protein and mRNA expression (to 19.6 ؎ 1.8 and 50.3 ؎ 4.7% of controls, respectively, p < 0.01). Neither Ang II nor forskolin affected DAX-1 protein and mRNA stability. The aldosterone response to Ang II was markedly reduced (to 59 ؎ 4% of controls, p < 0.01) in transiently transfected cells overexpressing DAX-1. Whereas Ang II was without effect on SF-1 expression, forskolin significantly increased SF-1 protein and mRNA levels in a cycloheximide-sensitive manner (to 167.4 ؎ 16.6 and 173.1 ؎ 25.1% of controls after 6 h, respectively, p < 0.01). These results demonstrate that the balance between repressor and inducer function of DAX-1 and SF-1 are of critical importance in the regulation of adrenal aldosterone biosynthesis.

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“…While some studies reported similar SF-1 levels in normal adrenal compared to cortisol-producing adenomas (Sasano et al 1995, Shibata et al 2001 and in adrenocortical adenomas and carcinomas (Kiiveri et al 2005), others described increased SF-1 mRNA expression in aldosterone-and cortisol-producing adenomas (Bassett et al 2005), and in adenomas relative to carcinomas (Lefrançois- Martinez et al 2004). Possible explanations for these discrepancies are differences between the methods used to measure SF-1 expression at the mRNA or protein level.…”

Section: Sf-1 Dosage and Acts In Micementioning

confidence: 98%