title: Dual Specificity Phosphatase 5, a Specific Negative Regulator of ERK Signaling, Is Induced by Serum Response Factor and Elk-1 Transcription Factor.
abstract: Serum stimulation of mammalian cells induces, via the MAPK pathway, the nuclear protein DUSP5 (dual-specificity phosphatase 5), which specifically interacts with and inactivates the ERK1/2 MAP kinases. However, molecular mechanisms underlying DUSP5 induction are not well known. Here, we found that the DUSP5 mRNA induction depends on a transcriptional regulation by the MAPK pathway, without any modification of the mRNA stability. Two contiguous CArG boxes that bind serum response factor (SRF) were found in a 1 Kb promoter region, as well as several E twenty-six transcription factor family binding sites (EBS). These sites potentially bind Elk-1, a transcription factor activated by ERK1/2. Using wild type or mutated DUSP5 promoter reporters, we demonstrated that SRF plays a crucial role in serum induction of DUSP5 promoter activity, the proximal CArG box being important for SRF binding in vitro and in living cells. Moreover, in vitro and in vivo binding data of Elk-1 to the same promoter region further demonstrate a role for Elk-1 in the transcriptional regulation of DUSP5. SRF and Elk-1 form a ternary complex (Elk-1-SRF-DNA) on DUSP5 promoter, consequently providing a link to an important negative feedback tightly regulating phosphorylated ERK levels.
authors.affiliation: Endocrinology-Metabolism-Diabetes Department, Institut Cochin, Université Paris Descartes, CNRS (UMR8104), INSERM U1016, Paris, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Buffet
authors.affiliation: Endocrinology-Metabolism-Diabetes Department, Institut Cochin, Université Paris Descartes, CNRS (UMR8104), INSERM U1016, Paris, France.
authors.forename: Maria-Grazia
authors.initials: MG
authors.lastname: Catelli
authors.affiliation: Endocrinology-Metabolism-Diabetes Department, Institut Cochin, Université Paris Descartes, CNRS (UMR8104), INSERM U1016, Paris, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Hecale-Perlemoine
authors.affiliation: Endocrinology-Metabolism-Diabetes Department, Institut Cochin, Université Paris Descartes, CNRS (UMR8104), INSERM U1016, Paris, France.
authors.forename: Léopoldine
authors.initials: L
authors.lastname: Bricaire
authors.affiliation: Endocrinology-Metabolism-Diabetes Department, Institut Cochin, Université Paris Descartes, CNRS (UMR8104), INSERM U1016, Paris, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Garcia
authors.affiliation: Endocrinology-Metabolism-Diabetes Department, Institut Cochin, Université Paris Descartes, CNRS (UMR8104), INSERM U1016, Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Gallet-Dierick
authors.affiliation: Endocrinology-Metabolism-Diabetes Department, Institut Cochin, Université Paris Descartes, CNRS (UMR8104), INSERM U1016, Paris, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Rodriguez
authors.affiliation: Endocrinology-Metabolism-Diabetes Department, Institut Cochin, Université Paris Descartes, CNRS (UMR8104), INSERM U1016, Paris, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Cormier
authors.affiliation: Endocrinology-Metabolism-Diabetes Department, Institut Cochin, Université Paris Descartes, CNRS (UMR8104), INSERM U1016, Paris, France.|Department of Endocrinology, Cochin Hospital, Paris, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Groussin
mesh_terms: D000818:Animals; D001665:Binding Sites; D054637:Dual-Specificity Phosphatases / Q000235:genetics* / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D006207:Half-Life; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D009154:Mutation; D041681:NIH 3T3 Cells; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D027602:Serum Response Element; D026362:Serum Response Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D050807:ets-Domain Protein Elk-1 / Q000235:genetics / Q000378:metabolism*
chemical_list: C494113:Elk1 protein, mouse; D012333:RNA, Messenger; D026362:Serum Response Factor; D050807:ets-Domain Protein Elk-1; D054637:Dual-Specificity Phosphatases; C546197:Dusp5 protein, mouse