Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Normal endocrine development and function require nuclear hormone receptor SF-1 (steroidogenic factor 1). To understand the molecular mechanism of SF-1 action, we have investigated its domain function by mutagenesis and functional analyses. Our mutant studies show that the putative AF2 (activation function 2) helix located at the C-terminal end is indispensable for gene activation. SF-1 does not have an N-terminal AF1 domain. Instead, it contains a unique FP region, composed of the Ftz-F1 box and the proline cluster, after the zinc finger motif. The FP region interacts with transcription factor IIB (TFIIB) in vitro. This interaction requires residues 178-201 of TFIIB, a domain capable of binding several transcription factors. The FP region also mediates physical interaction with c-Jun, and this interaction greatly enhances SF-1 activity. The putative SF-1 ligand, 25-hydroxycholesterol, has no effects on these bindings. In addition, the Ftz-F1 box contains a bipartite nuclear localization signal (NLS). Removing the basic residues at either end of the key nuclear localization sequence NLS2.2 abolishes the nuclear transport. Expression of mutants containing only the FP region or lacking the AF2 domain blocks wild-type SF-1 activity in cells. By contrast, the mutant having a truncated nuclear localization signal lacks this dominant negative effect. These results delineate the importance of the FP and AF2 regions in nuclear localization, protein-protein interaction, and transcriptional activation.
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PMID:Function of steroidogenic factor 1 domains in nuclear localization, transactivation, and interaction with transcription factor TFIIB and c-Jun. 1047 48

The CYP11A1 gene encodes cytochrome P450scc, the enzyme catalyzing the first step of steroid biosynthesis in the adrenal and gonad. We generated transgenic mice containing 2.3 kb of the 5'-flanking region of CYP11A1 driving LacZ reporter gene expression, in order to study hormonal control of CYP11A1 gene expression in different tissues. This 2.3 kb fragment contains information for hormonal control; by ACTH and hCG which increased reporter gene expression, in the adrenal and testis of transgenic mice respectively, while dexamethasone administration decreased reporter activity in the adrenal. The 5'-fragment of CYP11A1 has appreciable promoter activities in mouse adrenal Y1 cells but not in non-steroidogenic COS-1 cells, showing cell-type specificity. Transcription factor SF-1 activates the 2.3 kb promoter, which can be potentiated by cotransfection with c-Jun in steroidogenic JEG3 cells but not in COS-1 cells. We conclude that the 2.3 kb region of CYP11A1 contains elements controlling hormonal-dependent, cell-type-specific expression. In addition, c-Jun and SF-1 could act synergistically to activate CYP11A1 gene expression.
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PMID:Action of hormone responsive sequence in 2.3 kb promoter of CYP11A1. 1132 30

Steroid hormones are important physiological regulators that control our glucose and salt balance, as well as sexual characteristics. The synthesis of steroid hormones is under tight control; disturbed secretion of steroids often leads to diseases. The mechanism controlling the secretion of steroids, namely steroidogenesis, has been the focus of intensive studies. CYP11A1 controls the first and rate-limiting step of steroid biosynthesis. It is expressed in the adrenal cortex and gonads, under the control of pituitary hormones, through the cAMP-signaling pathway. The promoter of the CYP11A1 gene contains sequences that bind to transcription factor SF-1, which plays an important role in the tissue-specific and hormonally regulated expression of steroidogenic genes. Detailed transcriptional analysis documents the importance of SF-1 in activating CYP11A1 in vitro and in vivo. Other factors like c-Jun are also involved. The assembly of various transcription factors forming protein-DNA complexes appears to be the key step in CYP11A1 transcription.
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PMID:Transcriptional regulation of CYP11A1. 1457 61

Steroids are synthesized in adrenal glands and gonads under the control of pituitary peptides. These peptides bind to cell surface receptors to activate the cyclic AMP (cAMP) signaling pathway leading to an increase of steroidogenic gene expression. Exactly how cAMP activates steroidogenic gene expression is not clear, except for the knowledge that transcription factor SF-1 plays a key role. Investigating the factors participating in SF-1 action, we found that c-Jun and homeodomain-interacting protein kinase 3 (HIPK3) were required for basal and cAMP-stimulated expression of one major steroidogenic gene, CYP11A1. HIPK3 enhanced SF-1 activity, and c-Jun was required for the functional interaction of HIPK3 with SF-1. Furthermore, after cAMP stimulation, both c-Jun and Jun N-terminal kinase (JNK) were phosphorylated through HIPK3. These phosphorylations were important for SF-1 activity and CYP11A1 expression. Thus, we have defined HIPK3-mediated JNK activity and c-Jun phosphorylation as important events that increase SF-1 activity for CYP11A1 transcription in response to cAMP. This finding has linked three common factors, HIPK3, JNK, and c-Jun, to the cAMP signaling pathway leading to increased steroidogenic gene expression.
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PMID:Cyclic AMP stimulates SF-1-dependent CYP11A1 expression through homeodomain-interacting protein kinase 3-mediated Jun N-terminal kinase and c-Jun phosphorylation. 1721 Jun 46

The CYP11A1 gene encodes the cholesterol side-chain cleavage enzyme, also termed cytochrome P450scc, which catalyzes the conversion of cholesterol to pregnenolone in the first step of steroid biosynthesis in mitochondria. The adrenal- and gonad-selective, hormonally and developmentally regulated expression of CYP11A1 is principally driven by its 2.3 kb promoter. Multiple trans-acting factors like SF-1, Sp1, AP-2, TReP-132, LBP-1b, LBP-9, AP-1, NF-1, and Ets control CYP11A1 transcription either through DNA-protein interaction with their specific cis-acting elements or through protein-protein interaction between each other, wherein SF-1 plays a central role in adrenals and testes. In addition to binding with its proximal and upstream motifs, SF-1 also physically interacts with TFIIB, CBP/p300, TReP-132, and c-Jun/AP-1 to specifically transmit the regulatory signals of cAMP. Other factors like Sp1 family members, AP-2, and LBP-1b/LBP-9 may be other factors that play a role in CYP11A1 transcription, particularly in placental cells. The TATA sequence could also contribute to tissue-specificity and hormonal regulation of CYP11A1 transcription. This article reviews recent studies focusing on adrenals and gonads.
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PMID:Transcriptional regulation of human CYP11A1 in gonads and adrenals. 1759 37

SF-1 is a key transcription factor for all steroidogenic genes. It up-regulates the expression of the steroidogenic Cyp11a1 gene in the adrenal in a pathway stimulated by cAMP through HIPK3-mediated JNK/c-Jun phosphorylation. In the present study, we have investigated the factors mediating cAMP-dependent HIPK3 action to potentiate the activity of SF-1 for Cyp11a1 transcription in mouse adrenocortical Y1 cells. We found Daxx, a HIPK kinase substrate in the apoptosis pathway, was phosphorylated by HIPK3 at Ser-669 in response to cAMP stimulation. Daxx participated in SF-1-dependent Cyp11a1 expression as shown by experiments involving both overexpression and down-regulation via a dominant negative Daxx mutant. The S669A mutant of Daxx, which could not be phosphorylated by HIPK3, lost the ability to potentiate SF-1 activity for Cyp11a1 expression. The enhancement of SF-1 activity by Daxx required JNK and c-Jun phosphorylation. Thus, Daxx functioned as a signal transducer linking cAMP-stimulated HIPK3 activity with JNK/c-Jun phosphorylation and SF-1-dependent Cyp11a1 transcription for steroid synthesis.
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PMID:Death-associated protein 6 (Daxx) mediates cAMP-dependent stimulation of Cyp11a1 (P450scc) transcription. 2219 61