Activating protein-1 cooperates with steroidogenic factor-1 to regulate 3′,5′-cyclic adenosine 5′-monophosphate-dependent human CYP11A1 transcription in vitro and in vivo

Ing Cherng Guo, Chiung Yi Huang, Chi Kuang Leo Wang, Bon Chu Chung

研究成果: ジャーナルへの寄稿記事

25 引用 (Scopus)

抄録

The CYP11A1 encodes cytochrome P450scc, catalyzing the first step of steroidogenesis in adrenals and gonads under the control of cAMP-mediated hormonal signals. The cAMP-induced activation of human CYP11A1 has been suggested to depend on the transcription factor cAMP-responsive element-binding protein (CREB), but the CREB action cannot explain the chronic cAMP effect on CYP11A1 activation. To further understand the mechanism of human CYP11A1 activation, we dissected the functions of the upstream cAMP responsive sequences (U-CRS) containing a core sequence, U identical to the steroidogenic factor-1 (SF-1)-binding site, and two flanking TPA-responsive element/cAMP-responsive element-like elements, C1 and C2. The EMSA assays showed that the binding activities of U with SF-1 as well as C1 or C2 with activating protein-1 (AP-1)/CREB-like proteins are induced by cAMP. The results from the site-directed mutagenesis analyses revealed that all three elements are required for the U-CRS function and any mutation of C1, C2, or U impairs the response to cAMP stimulation. In transgenic mice, the single or double mutations of C1 and C2 resulted in the reduction of reporter gene expression accompanied with poor hormonal response. The cAMP induction on the U-CRS activity was mimicked and enhanced by the overexpressed c-Jun in the presence of SF-1, but was abolished by the overexpression of an AP-1 dominant-negative mutant, FosB2. Furthermore, we have observed the interdependent transactivation between SF-1 and c-Jun on the U-CRS function. These results collectively demonstrate that SF-1 and AP-1 cooperate to activate CYP11A1 transcription in vitro and in vivo.

元の言語英語
ページ(範囲)1804-1812
ページ数9
ジャーナルEndocrinology
148
発行部数4
DOI
出版物ステータス出版済み - 4 1 2007

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Steroidogenic Factor 1
Cholesterol Side-Chain Cleavage Enzyme
Cyclic AMP
Carrier Proteins
Proteins
Mutation
Gonads
Site-Directed Mutagenesis
Reporter Genes
Transgenic Mice
Transcriptional Activation
In Vitro Techniques
Transcription Factors
Binding Sites
Gene Expression

All Science Journal Classification (ASJC) codes

  • Endocrinology

これを引用

Activating protein-1 cooperates with steroidogenic factor-1 to regulate 3′,5′-cyclic adenosine 5′-monophosphate-dependent human CYP11A1 transcription in vitro and in vivo. / Guo, Ing Cherng; Huang, Chiung Yi; Wang, Chi Kuang Leo; Chung, Bon Chu.

:: Endocrinology, 巻 148, 番号 4, 01.04.2007, p. 1804-1812.

研究成果: ジャーナルへの寄稿記事

Guo, Ing Cherng ; Huang, Chiung Yi ; Wang, Chi Kuang Leo ; Chung, Bon Chu. / Activating protein-1 cooperates with steroidogenic factor-1 to regulate 3′,5′-cyclic adenosine 5′-monophosphate-dependent human CYP11A1 transcription in vitro and in vivo. :: Endocrinology. 2007 ; 巻 148, 番号 4. pp. 1804-1812.
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abstract = "The CYP11A1 encodes cytochrome P450scc, catalyzing the first step of steroidogenesis in adrenals and gonads under the control of cAMP-mediated hormonal signals. The cAMP-induced activation of human CYP11A1 has been suggested to depend on the transcription factor cAMP-responsive element-binding protein (CREB), but the CREB action cannot explain the chronic cAMP effect on CYP11A1 activation. To further understand the mechanism of human CYP11A1 activation, we dissected the functions of the upstream cAMP responsive sequences (U-CRS) containing a core sequence, U identical to the steroidogenic factor-1 (SF-1)-binding site, and two flanking TPA-responsive element/cAMP-responsive element-like elements, C1 and C2. The EMSA assays showed that the binding activities of U with SF-1 as well as C1 or C2 with activating protein-1 (AP-1)/CREB-like proteins are induced by cAMP. The results from the site-directed mutagenesis analyses revealed that all three elements are required for the U-CRS function and any mutation of C1, C2, or U impairs the response to cAMP stimulation. In transgenic mice, the single or double mutations of C1 and C2 resulted in the reduction of reporter gene expression accompanied with poor hormonal response. The cAMP induction on the U-CRS activity was mimicked and enhanced by the overexpressed c-Jun in the presence of SF-1, but was abolished by the overexpression of an AP-1 dominant-negative mutant, FosB2. Furthermore, we have observed the interdependent transactivation between SF-1 and c-Jun on the U-CRS function. These results collectively demonstrate that SF-1 and AP-1 cooperate to activate CYP11A1 transcription in vitro and in vivo.",
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AB - The CYP11A1 encodes cytochrome P450scc, catalyzing the first step of steroidogenesis in adrenals and gonads under the control of cAMP-mediated hormonal signals. The cAMP-induced activation of human CYP11A1 has been suggested to depend on the transcription factor cAMP-responsive element-binding protein (CREB), but the CREB action cannot explain the chronic cAMP effect on CYP11A1 activation. To further understand the mechanism of human CYP11A1 activation, we dissected the functions of the upstream cAMP responsive sequences (U-CRS) containing a core sequence, U identical to the steroidogenic factor-1 (SF-1)-binding site, and two flanking TPA-responsive element/cAMP-responsive element-like elements, C1 and C2. The EMSA assays showed that the binding activities of U with SF-1 as well as C1 or C2 with activating protein-1 (AP-1)/CREB-like proteins are induced by cAMP. The results from the site-directed mutagenesis analyses revealed that all three elements are required for the U-CRS function and any mutation of C1, C2, or U impairs the response to cAMP stimulation. In transgenic mice, the single or double mutations of C1 and C2 resulted in the reduction of reporter gene expression accompanied with poor hormonal response. The cAMP induction on the U-CRS activity was mimicked and enhanced by the overexpressed c-Jun in the presence of SF-1, but was abolished by the overexpression of an AP-1 dominant-negative mutant, FosB2. Furthermore, we have observed the interdependent transactivation between SF-1 and c-Jun on the U-CRS function. These results collectively demonstrate that SF-1 and AP-1 cooperate to activate CYP11A1 transcription in vitro and in vivo.

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