DAX1 and its network partners: exploring complexity in development

Clipsham, Robert C.; McCabe, Edward R.B.

doi:10.1016/j.ymgme.2003.08.023

Cited by 43 publications

(32 citation statements)

References 417 publications

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“…27,33 Thus, we compared the levels of DAX1 expression in Ewing tumors to those observed in a panel of 21 human normal tissues by quantitative real time qRT-PCR (Fig. 5b).…”

Section: Resultsmentioning

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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“…27,33 Thus, we compared the levels of DAX1 expression in Ewing tumors to those observed in a panel of 21 human normal tissues by quantitative real time qRT-PCR (Fig. 5b).…”

Section: Resultsmentioning

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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“…Besides the increased expression of esrs resulting in estrogen induced sexual differentiation, other possible mechanisms for differential estrogen exposure are through the increased expression of steroidogenic enzymes, steroid receptor cofactors and nuclear receptors upstream of aromatase, which could potentially create sex differences in the availability of androgenic substrate for aromatase. In support of this hypothesis, steroidogenic factor-1 (nr5a2) has been reported to play a key role in the development and differentiation of the reproductive system and nr0b1 has been reported to act as a coregulatory protein that inhibits the transcriptional activity of other nuclear receptors including nr5a2 (Crawford et al, 1998;Clipsham and McCabe, 2003), esr (Zhang et al, 2000), ar (Holter et al, 2002), star, and steroidogenic enzymes (cyp11a1, cyp17, and cyp19) (Lalli et al, 1998;Lalli and Sassone-Corsi, 2003;Nakamoto et al, 2007). Both nr5a2 and nr0b1 has been reported to be independently important for normal male gonadal differentiation and development (Park and Jameson, 2005;Wu et al, 2008b).…”

Section: Discussionmentioning

confidence: 96%

Age‐dependent differential expression of genes involved in steroid signalling pathway in the brain of protandrous black porgy, Acanthopagrus schlegeli

Tomy

Huang

et al. 2009

Developmental Neurobiology

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ABSTRACT:The mechanisms underlying brain sex differentiation in animals are poorly understood. In the present study, using black porgy, Acanthopagrus schlegeli, as primary experimental model, we investigated the temporal expression patterns of receptors for androgen (ar) and estrogen (esr1 and esr2a) in the brain during posthatching ages and analyzed them against the timing of gonadal germ cell development. We hypothesized that endogenous estrogens naturally masculinize the brain of black porgy. The expression of sex steroid receptors was studied in relation to a wider suite of other related genes (nr5a2, nr0b1, star, and cyp19a1b) to provide some insight into the monomale sex differentiation pattern observed in this species. Our results revealed a highly significant increase in esr1 together with the increase in esr2a at 120 dph (days posthatching), suggesting a significant role for esr in sex differentiation in this species. Temporal expression patterns of nr5a2, nr0b1, star, sex steroid receptors, and cyp19a1b in the brain provided evidence for their physiological roles in the monomale sex differentiation in this species. The expression of nr5a2, star, ar, esr1, esr2a, and cyp19a1b increased at 120 dph, a period when brain sex differentiation probably occurs in this species. The study also suggests that neurosteroidogenesis in black porgy may be regulated by both nr5a2-dependent and nr5a2-independent mechanisms. The results demonstrated striking differences in the abundance of the gene transcripts in discrete brain region throughout ontogeny. In addition, the sex steroid hormone levels and aromatase activity in brain at different developmental states and the changes in the gene expression patterns in response to aromatase inhibitor treatment are also discussed. ' 2009 Wiley Periodicals, Inc. Develop Neurobiol

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“…Despite that DAX1 has been identified as a nuclear receptor, its annotated function is that of a transcriptional repressor [155]. In liver metabolism, it has been shown that DAX1 inhibited HNF4-alpha trans-activation capacities and negatively regulated gluconeogenic gene expression [156].…”

Section: Dax1mentioning

confidence: 99%

Transcriptional co-factors and hepatic energy metabolism

Sommerfeld

Krones-Herzig

Herzig

2011

Molecular and Cellular Endocrinology

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After binding to their cognate DNA-binding partner, transcriptional co-factors exert their function through the recruitment of enzymatic, chromatin-modifying activities. In turn, the assembly of co-factor-associated multi-protein complexes efficiently impacts target gene expression. Recent advances have established transcriptional co-factor complexes as a critical regulatory level in energy homeostasis and aberrant co-factor activity has been linked to the pathogenesis of severe metabolic disorders including obesity, type 2 diabetes and other components of the Metabolic Syndrome. The liver represents the key peripheral organ for the maintenance of systemic energy homeostasis, and aberrations in hepatic glucose and lipid metabolism have been causally linked to the manifestation of disorders associated with the Metabolic Syndrome. Therefore, this review focuses on the role of distinct classes of transcriptional co-factors in hepatic glucose and lipid homeostasis, emphasizing pathwayspecific functions of these co-factors under physiological and pathophysiological conditions.

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DAX1 and its network partners: exploring complexity in development

Cited by 43 publications

References 417 publications

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

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

Age‐dependent differential expression of genes involved in steroid signalling pathway in the brain of protandrous black porgy, Acanthopagrus schlegeli

Transcriptional co-factors and hepatic energy metabolism

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