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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

SF-1, an orphan nuclear receptor. A- Canonical nuclear receptor and SF-1 structure comparison. AF1 : activation function 1; DBD : DNA binding domain; LBD : ligand binding domain; AF2 : activation function 2. SF-1 does not harbor a classical AF-1 domain. B- SF-1 functional domains. Zn I and Zn II : zinc fingers of the DBD; Ftz-F1 : Ftz-F1 box ; NLS : nuclear localization signal ; P-rich : proline-rich region ; FP : functional region encompassing the Ftz-F1 box and the proline-rich region ; pAF : proximal activation function ; pRD : proximal repression domain ; H1 : helix 1 of the LBD ; dRD : distal repression domain; AF2 AH : activation function 2 activation hexamer; S203 * serine at position 203, implicated in SF-1 responsiveness to the MAPK pathway. Factors interacting with SF-1 that have allowed delineation of the functional domains are shown. Their interaction sites are figured by the grey bars.
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Figure 1: SF-1, an orphan nuclear receptor. A- Canonical nuclear receptor and SF-1 structure comparison. AF1 : activation function 1; DBD : DNA binding domain; LBD : ligand binding domain; AF2 : activation function 2. SF-1 does not harbor a classical AF-1 domain. B- SF-1 functional domains. Zn I and Zn II : zinc fingers of the DBD; Ftz-F1 : Ftz-F1 box ; NLS : nuclear localization signal ; P-rich : proline-rich region ; FP : functional region encompassing the Ftz-F1 box and the proline-rich region ; pAF : proximal activation function ; pRD : proximal repression domain ; H1 : helix 1 of the LBD ; dRD : distal repression domain; AF2 AH : activation function 2 activation hexamer; S203 * serine at position 203, implicated in SF-1 responsiveness to the MAPK pathway. Factors interacting with SF-1 that have allowed delineation of the functional domains are shown. Their interaction sites are figured by the grey bars.

Mentions: Nuclear receptors usually display common features such as a DNA-binding domain (DBD), a ligand binding domain (LBD) and two activation domains, amino-terminal AF-1 (activation function 1) and carboxyterminal AF-2, whose activity is normaly dependent on the presence of a ligand [10] (figure 1A). In all the species studied so far, SF-1 harbors a classical DBD characterized by two Cys2-Cys2 zinc fingers in the N-terminal region [11]. However, as opposed to a majority of nuclear receptors, SF-1 binds DNA as a monomer, in a manner reminiscent of NGFI-B (Nur 77), ROR or LRH-1/CPF binding [10,12,13]. This binding is stabilized by an A box or Ftz-F1 box which recognizes nucleotides flanking the AGGTCA nuclear receptor core binding sequence on its 5' side (figure 1B). This protein domain defines the binding specificity of a nuclear receptor, as a function of its responsive element [12,14]. The role of A box in SF-1 activity is illustrated by a human mutation that results in sex reversal and adrenal failure [15]. Nuclear receptors usually shuttle from the cytoplasm where they bind their cognate ligands to the nucleus where they activate transcription. This shuttling is dependent on nuclear localisation signals (NLS). One NLS is present on SF-1, downstream of the DBD (amino acids 89 à 101). It is required for transcriptional activity [14]. Although SF-1 harbors a putative LBD highly conserved across species, it is classified as an orphan receptor because no bona fide SF-1 ligand was identified so far [16,17]. Recent experiments show that SF-1 LBD helices 1 and 12 can adopt an active conformation independently of a ligand, in response to phosphorylation of a serine residue at position 203 [18]. A conserved AF-2 domain that recruits coactivators, is present in SF-1. It is necessary but not sufficient for SF-1 transcativating activity [14,19-21]. In a majority of nuclear receptors, the AF-2 domain cooperates with the constitutive amino-terminal AF-1 domain in order to activate transcription. Such N to C interactions are essential for ligand-activated nuclear receptors function such as PPARγ [22] or AR [23,24]. SF-1 amino-terminal region upstream of the DBD is very short and does not possess a classical AF-1. In fact SF-1 AF-2 cooperates with two activating domains downstream of the DBD. The proximal activation domain (pAF: proximal activation function) overlapping the hinge region and helix H1 of the putative LBD (amino acids 187–245) is required for maximal SF-1 activity with the coactivator SRC-1. It harbors a serine residue at 203, the phosphorylation of which is essential for SF-1 activity [18,20,25]. The FP region (amino acids 78 to 172), composed of the Ftz-F1 box and of a proline-rich region, interacts with c-jun and TFIIB for maximal activity [14].


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)

SF-1, an orphan nuclear receptor. A- Canonical nuclear receptor and SF-1 structure comparison. AF1 : activation function 1; DBD : DNA binding domain; LBD : ligand binding domain; AF2 : activation function 2. SF-1 does not harbor a classical AF-1 domain. B- SF-1 functional domains. Zn I and Zn II : zinc fingers of the DBD; Ftz-F1 : Ftz-F1 box ; NLS : nuclear localization signal ; P-rich : proline-rich region ; FP : functional region encompassing the Ftz-F1 box and the proline-rich region ; pAF : proximal activation function ; pRD : proximal repression domain ; H1 : helix 1 of the LBD ; dRD : distal repression domain; AF2 AH : activation function 2 activation hexamer; S203 * serine at position 203, implicated in SF-1 responsiveness to the MAPK pathway. Factors interacting with SF-1 that have allowed delineation of the functional domains are shown. Their interaction sites are figured by the grey bars.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 1: SF-1, an orphan nuclear receptor. A- Canonical nuclear receptor and SF-1 structure comparison. AF1 : activation function 1; DBD : DNA binding domain; LBD : ligand binding domain; AF2 : activation function 2. SF-1 does not harbor a classical AF-1 domain. B- SF-1 functional domains. Zn I and Zn II : zinc fingers of the DBD; Ftz-F1 : Ftz-F1 box ; NLS : nuclear localization signal ; P-rich : proline-rich region ; FP : functional region encompassing the Ftz-F1 box and the proline-rich region ; pAF : proximal activation function ; pRD : proximal repression domain ; H1 : helix 1 of the LBD ; dRD : distal repression domain; AF2 AH : activation function 2 activation hexamer; S203 * serine at position 203, implicated in SF-1 responsiveness to the MAPK pathway. Factors interacting with SF-1 that have allowed delineation of the functional domains are shown. Their interaction sites are figured by the grey bars.
Mentions: Nuclear receptors usually display common features such as a DNA-binding domain (DBD), a ligand binding domain (LBD) and two activation domains, amino-terminal AF-1 (activation function 1) and carboxyterminal AF-2, whose activity is normaly dependent on the presence of a ligand [10] (figure 1A). In all the species studied so far, SF-1 harbors a classical DBD characterized by two Cys2-Cys2 zinc fingers in the N-terminal region [11]. However, as opposed to a majority of nuclear receptors, SF-1 binds DNA as a monomer, in a manner reminiscent of NGFI-B (Nur 77), ROR or LRH-1/CPF binding [10,12,13]. This binding is stabilized by an A box or Ftz-F1 box which recognizes nucleotides flanking the AGGTCA nuclear receptor core binding sequence on its 5' side (figure 1B). This protein domain defines the binding specificity of a nuclear receptor, as a function of its responsive element [12,14]. The role of A box in SF-1 activity is illustrated by a human mutation that results in sex reversal and adrenal failure [15]. Nuclear receptors usually shuttle from the cytoplasm where they bind their cognate ligands to the nucleus where they activate transcription. This shuttling is dependent on nuclear localisation signals (NLS). One NLS is present on SF-1, downstream of the DBD (amino acids 89 à 101). It is required for transcriptional activity [14]. Although SF-1 harbors a putative LBD highly conserved across species, it is classified as an orphan receptor because no bona fide SF-1 ligand was identified so far [16,17]. Recent experiments show that SF-1 LBD helices 1 and 12 can adopt an active conformation independently of a ligand, in response to phosphorylation of a serine residue at position 203 [18]. A conserved AF-2 domain that recruits coactivators, is present in SF-1. It is necessary but not sufficient for SF-1 transcativating activity [14,19-21]. In a majority of nuclear receptors, the AF-2 domain cooperates with the constitutive amino-terminal AF-1 domain in order to activate transcription. Such N to C interactions are essential for ligand-activated nuclear receptors function such as PPARγ [22] or AR [23,24]. SF-1 amino-terminal region upstream of the DBD is very short and does not possess a classical AF-1. In fact SF-1 AF-2 cooperates with two activating domains downstream of the DBD. The proximal activation domain (pAF: proximal activation function) overlapping the hinge region and helix H1 of the putative LBD (amino acids 187–245) is required for maximal SF-1 activity with the coactivator SRC-1. It harbors a serine residue at 203, the phosphorylation of which is essential for SF-1 activity [18,20,25]. The FP region (amino acids 78 to 172), composed of the Ftz-F1 box and of a proline-rich region, interacts with c-jun and TFIIB for maximal activity [14].

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