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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.

Dual Specificity Phosphatase 5, a Specific Negative Regulator of ERK Signaling, Is Induced by Serum Response Factor and Elk-1 Transcription Factor