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PMID:17664281

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Citation

Li, D, Urs, AN, Allegood, J, Leon, A, Merrill, AH Jr and Sewer, MB (2007) Cyclic AMP-stimulated interaction between steroidogenic factor 1 and diacylglycerol kinase theta facilitates induction of CYP17. Mol. Cell. Biol. 27:6669-85

Abstract

In the human adrenal cortex, adrenocorticotropin (ACTH) activates CYP17 transcription by promoting the binding of the nuclear receptor steroidogenic factor 1 (SF1) (Ad4BP, NR5A1) to the promoter. We recently found that sphingosine is an antagonist for SF1 and inhibits cyclic AMP (cAMP)-dependent CYP17 gene transcription. The aim of the current study was to identify phospholipids that bind to SF1 and to characterize the mechanism by which ACTH/cAMP regulates the biosynthesis of this molecule(s). Using tandem mass spectrometry, we show that in H295R human adrenocortical cells, SF1 is bound to phosphatidic acid (PA). Activation of the ACTH/cAMP signal transduction cascade rapidly increases nuclear diacylglycerol kinase (DGK) activity and PA production. PA stimulates SF1-dependent transcription of CYP17 reporter plasmids, promotes coactivator recruitment, and induces the mRNA expression of CYP17 and several other steroidogenic genes. Inhibition of DGK activity attenuates the binding of SF1 to the CYP17 promoter, and silencing of DGK-theta expression inhibits cAMP-dependent CYP17 transcription. LXXLL motifs in DGK-theta mediate a direct interaction of SF1 with the kinase and may facilitate binding of PA to the receptor. We conclude that ACTH/cAMP stimulates PA production in the nucleus of H295R cells and that this increase in PA concentrations facilitates CYP17 induction.

Links

PubMed PMC2099220 Online version:10.1128/MCB.00355-07

Keywords

Adrenal Cortex/cytology; Adrenal Cortex/physiology; Adrenocorticotropic Hormone/metabolism; Animals; Cell Line; Cell Nucleus/metabolism; Cyclic AMP/metabolism; Diacylglycerol Kinase/genetics; Diacylglycerol Kinase/metabolism; Enzyme Induction; Gene Expression Regulation; Genes, Reporter; Humans; Isoenzymes/genetics; Isoenzymes/metabolism; Phosphatidic Acids/metabolism; Phospholipids/metabolism; Promoter Regions, Genetic; RNA Polymerase II/metabolism; Signal Transduction/physiology; Steroid 17-alpha-Hydroxylase/genetics; Steroid 17-alpha-Hydroxylase/metabolism; Steroidogenic Factor 1/genetics; Steroidogenic Factor 1/metabolism; Two-Hybrid System Techniques

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:NR5A2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q92830

F

Seeded From UniProt

complete

HUMAN:DGKQ

involved_in

GO:0019933: cAMP-mediated signaling

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:DGKQ

enables

GO:0140297: DNA-binding transcription factor binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q13285

F

Seeded From UniProt

complete

HUMAN:DGKQ

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:DGKQ

involved_in

GO:0006357: regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:STF1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q92830

F

Seeded From UniProt

complete

HUMAN:STF1

enables

GO:0019899: enzyme binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q13574

F

Seeded From UniProt

complete

HUMAN:STF1

enables

GO:0019899: enzyme binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P52824

F

Seeded From UniProt

complete

HUMAN:STF1

enables

GO:0005543: phospholipid binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:STF1

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:STF1

involved_in

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:DGKZ

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q13285

F

Seeded From UniProt

complete

HUMAN:DGKZ

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:KAT2A

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O00482

F

Seeded From UniProt

complete

HUMAN:KAT2A

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q13285

F

Seeded From UniProt

complete


See also

References

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