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SF-1 a key player in the development and differentiation of steroidogenic tissues.

Val P, Lefrançois-Martinez AM, Veyssière G, Martinez A - Nucl. Recept. (2003)

Bottom Line: SF-1 is also an essential regulator of genes involved in the sex determination cascade.In particular, the role of SF-1 in the hormonal responsiveness of steroidogenic genes promoters is still a subject of debate.It also summarizes the pros and cons regarding the presumed role of SF-1 in cAMP signalling.

View Article: PubMed Central - HTML - PubMed

Affiliation: UMR CNRS 6547, Physiologie Comparée et Endocrinologie Moléculaire, Université Blaise Pascal, Clermont II, Complexe Universitaire des Cézeaux, 24 avenue des Landais, 63177 Aubiere Cedex, France. a-marie.lefrancois-martinez@univ-bpclermont.fr

ABSTRACT
Since its discovery in the early 1990s, the orphan nuclear receptor SF-1 has been attributed a central role in the development and differentiation of steroidogenic tissues. SF-1 controls the expression of all the steroidogenic enzymes and cholesterol transporters required for steroidogenesis as well as the expression of steroidogenesis-stimulating hormones and their cognate receptors. SF-1 is also an essential regulator of genes involved in the sex determination cascade. The study of SF-1 mice and of human mutants has been of great value to demonstrate the essential role of this factor in vivo, although the complete adrenal and gonadal agenesis in knock-out animals has impeded studies of its function as a transcriptional regulator. In particular, the role of SF-1 in the hormonal responsiveness of steroidogenic genes promoters is still a subject of debate. This extensive review takes into account recent data obtained from SF-1 haploinsufficient mice, pituitary-specific knock-outs and from transgenic mice experiments carried out with SF-1 target gene promoters. It also summarizes the pros and cons regarding the presumed role of SF-1 in cAMP signalling.

No MeSH data available.


Related in: MedlinePlus

Presumed effect of the coactivators p/CIP and TIF2 on SF-1 transactivation. (After Borud et al., Ref. [188]). In the absence of PKA, p/CIP and TIF2 potentiate SF-1 transcriptional activity. When SF-1 is associated to p/CIP, overexpression of PKA induces a marked increase in SF-1 transcriptional activity. On the contrary, PKA overexpression prevents TIF2-dependent potentiation of SF-1 activity. The decrease of TIF2 protein accumulation caused by PKA overexpression may explain these observations. SFRE : SF-1 responsive element.
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Figure 5: Presumed effect of the coactivators p/CIP and TIF2 on SF-1 transactivation. (After Borud et al., Ref. [188]). In the absence of PKA, p/CIP and TIF2 potentiate SF-1 transcriptional activity. When SF-1 is associated to p/CIP, overexpression of PKA induces a marked increase in SF-1 transcriptional activity. On the contrary, PKA overexpression prevents TIF2-dependent potentiation of SF-1 activity. The decrease of TIF2 protein accumulation caused by PKA overexpression may explain these observations. SFRE : SF-1 responsive element.

Mentions: Ligand-dependent nuclear receptors activate their target genes transcription through interactions with coactivators and/ or corepressors that link receptors to the transcription machinery. Accordingly, SF-1 harbors an AF2 activation domain in its LBD (figure 1B). This motif (LLIEML, consensus LLXXL) is necessary but not sufficient for transactivation [14,19-21] which also depends on two amino-terminal regions of the protein, the FP region [14] and a proximal activation domain [20,25]. SF-1 proteins bearing mutations in their AF2 domain have dominant negative properties on CYP17 promoter activation by PKA in Y1 cells. This suggests that SF-1 AF2 is implicated in the transduction of the cAMP signal [83]. As ligand-activated nuclear receptors, SF-1 interacts with numerous coactivators such as SRC1 [19,20], RIP140 [142], PNRC and PNRC2 [143,144], hMBF1 [145], TIF2 [25], p/CIP [146] and GCN5 [147]. These interactions, independent of an exogenous ligand, are dependent on AF-2 and for some of them, on proximal interaction domain integrity. Most of these interactions are mediated by LXXLL motifs found on coactivators. PNRC and PNRC2 are quite unique in that they interact with SF-1 and other nuclear receptors through SH3 proline-rich motifs [143,144]. None of these coactivators is specific for SF-1 and none of them shows a steroidogenic tissue-restricted pattern of expression. Nonetheless, two of them may be required for integration of the cAMP signalling (figure 5). TIF2 and p/CIP interact with SF-1 through the AF-2 and proximal activation domain [25,146]. Overexpression of TIF2 or p/CIP in heterologous or Y1 cells, stimulates transcription of a reporter gene driven by four copies of a SF-1 responsive-sequence of the bovine CYP17 promoter. However, whereas p/CIP increases sensitivity to PKA overexpression in the presence of SF-1, overexpression of the catalytic subunit of the PKA inhibits potentiation of SF-1 activity by TIF2, through a decrease in TIF2 protein accumulation [146]. In a more physiological system, one might imagine that on the sites where it participates to cAMP-responsiveness, SF-1 would preferentially associate to p/CIP, whereas where it participates to basal promoter activity, SF-1 would rather associate to TIF2. What could allow SF-1 to choose between those two coactivators? Although the sequence of the SF-1 responsive element may participate to this choice, it is possible that adjacent transcription factors, endowed with cAMP sensing capacity, may modulate cofactors recruitment by SF-1. This would allow modulation of SF-1 activity in response to extra-cellular signals.


SF-1 a key player in the development and differentiation of steroidogenic tissues.

Val P, Lefrançois-Martinez AM, Veyssière G, Martinez A - Nucl. Recept. (2003)

Presumed effect of the coactivators p/CIP and TIF2 on SF-1 transactivation. (After Borud et al., Ref. [188]). In the absence of PKA, p/CIP and TIF2 potentiate SF-1 transcriptional activity. When SF-1 is associated to p/CIP, overexpression of PKA induces a marked increase in SF-1 transcriptional activity. On the contrary, PKA overexpression prevents TIF2-dependent potentiation of SF-1 activity. The decrease of TIF2 protein accumulation caused by PKA overexpression may explain these observations. SFRE : SF-1 responsive element.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC240021&req=5

Figure 5: Presumed effect of the coactivators p/CIP and TIF2 on SF-1 transactivation. (After Borud et al., Ref. [188]). In the absence of PKA, p/CIP and TIF2 potentiate SF-1 transcriptional activity. When SF-1 is associated to p/CIP, overexpression of PKA induces a marked increase in SF-1 transcriptional activity. On the contrary, PKA overexpression prevents TIF2-dependent potentiation of SF-1 activity. The decrease of TIF2 protein accumulation caused by PKA overexpression may explain these observations. SFRE : SF-1 responsive element.
Mentions: Ligand-dependent nuclear receptors activate their target genes transcription through interactions with coactivators and/ or corepressors that link receptors to the transcription machinery. Accordingly, SF-1 harbors an AF2 activation domain in its LBD (figure 1B). This motif (LLIEML, consensus LLXXL) is necessary but not sufficient for transactivation [14,19-21] which also depends on two amino-terminal regions of the protein, the FP region [14] and a proximal activation domain [20,25]. SF-1 proteins bearing mutations in their AF2 domain have dominant negative properties on CYP17 promoter activation by PKA in Y1 cells. This suggests that SF-1 AF2 is implicated in the transduction of the cAMP signal [83]. As ligand-activated nuclear receptors, SF-1 interacts with numerous coactivators such as SRC1 [19,20], RIP140 [142], PNRC and PNRC2 [143,144], hMBF1 [145], TIF2 [25], p/CIP [146] and GCN5 [147]. These interactions, independent of an exogenous ligand, are dependent on AF-2 and for some of them, on proximal interaction domain integrity. Most of these interactions are mediated by LXXLL motifs found on coactivators. PNRC and PNRC2 are quite unique in that they interact with SF-1 and other nuclear receptors through SH3 proline-rich motifs [143,144]. None of these coactivators is specific for SF-1 and none of them shows a steroidogenic tissue-restricted pattern of expression. Nonetheless, two of them may be required for integration of the cAMP signalling (figure 5). TIF2 and p/CIP interact with SF-1 through the AF-2 and proximal activation domain [25,146]. Overexpression of TIF2 or p/CIP in heterologous or Y1 cells, stimulates transcription of a reporter gene driven by four copies of a SF-1 responsive-sequence of the bovine CYP17 promoter. However, whereas p/CIP increases sensitivity to PKA overexpression in the presence of SF-1, overexpression of the catalytic subunit of the PKA inhibits potentiation of SF-1 activity by TIF2, through a decrease in TIF2 protein accumulation [146]. In a more physiological system, one might imagine that on the sites where it participates to cAMP-responsiveness, SF-1 would preferentially associate to p/CIP, whereas where it participates to basal promoter activity, SF-1 would rather associate to TIF2. What could allow SF-1 to choose between those two coactivators? Although the sequence of the SF-1 responsive element may participate to this choice, it is possible that adjacent transcription factors, endowed with cAMP sensing capacity, may modulate cofactors recruitment by SF-1. This would allow modulation of SF-1 activity in response to extra-cellular signals.

Bottom Line: SF-1 is also an essential regulator of genes involved in the sex determination cascade.In particular, the role of SF-1 in the hormonal responsiveness of steroidogenic genes promoters is still a subject of debate.It also summarizes the pros and cons regarding the presumed role of SF-1 in cAMP signalling.

View Article: PubMed Central - HTML - PubMed

Affiliation: UMR CNRS 6547, Physiologie Comparée et Endocrinologie Moléculaire, Université Blaise Pascal, Clermont II, Complexe Universitaire des Cézeaux, 24 avenue des Landais, 63177 Aubiere Cedex, France. a-marie.lefrancois-martinez@univ-bpclermont.fr

ABSTRACT
Since its discovery in the early 1990s, the orphan nuclear receptor SF-1 has been attributed a central role in the development and differentiation of steroidogenic tissues. SF-1 controls the expression of all the steroidogenic enzymes and cholesterol transporters required for steroidogenesis as well as the expression of steroidogenesis-stimulating hormones and their cognate receptors. SF-1 is also an essential regulator of genes involved in the sex determination cascade. The study of SF-1 mice and of human mutants has been of great value to demonstrate the essential role of this factor in vivo, although the complete adrenal and gonadal agenesis in knock-out animals has impeded studies of its function as a transcriptional regulator. In particular, the role of SF-1 in the hormonal responsiveness of steroidogenic genes promoters is still a subject of debate. This extensive review takes into account recent data obtained from SF-1 haploinsufficient mice, pituitary-specific knock-outs and from transgenic mice experiments carried out with SF-1 target gene promoters. It also summarizes the pros and cons regarding the presumed role of SF-1 in cAMP signalling.

No MeSH data available.


Related in: MedlinePlus