152918-18-8 citations phosphorylation of ERK1/2 by MEK1/two is needed for the dissociation of the MEK/ERK complex. Because our modern data demonstrate that flotillin-one is a novel MAPK scaffolder that is essential for complete ERK activation and straight interacts with equally MEK1 and ERK2 [thirteen], it may possibly also control the localization of the MEK/ ERK intricate. Therefore, transcriptional regulation of flotillins by MAPK pathway may possibly give a opinions loop that affects the activation status and length of MAPK signaling. Activated ERK1/2 dimerize and translocate to the nucleus exactly where they bind to and phosphorylate transcription elements this kind of as Elk-1 [391], c-Myc [forty two], and c-Fos [43], which then induce the transcription of numerous goal genes. Elk-1 is one particular of the beststudied ERK1/two-activated transcription elements and belongs to the group of Ets ternary complex elements (overview in [forty four]). Immediate phosphorylation of Elk-1 at the C-terminus by ERK1/2 occurs quickly at six websites [forty five]. In addition, a MAPK-unbiased phosphorylation of Elk-1 in reaction to FGF stimulation or Raf activation has been explained [forty six]. Elk-1 types a complicated with serum response element (SRF) and binds to the serum reaction aspect (SRE) in promoters of a number of immediate early genes such as c-Fos [forty seven] or Egr1 [48]. SRF is essential for the activation via the SRE, because mutations that abolish the SRF-binding inhibit the activation of gene expression [49]. The SRF gene by itself is induced in reaction to serum stimulation [fifty]. ERK1/2 are crucial contributors to mobile proliferation, because frequent downstream targets of the three ERK1/two substrates cFos, Elk-1, and c-Myc are genes that control cell cycle progression, such as cyclin D1 (summarized in [fifty one]). In line with this, we recently identified that flotillins are required for cyclin 
D1 expression, given that a knockdown of flotillin-one in HeLa cells resulted in a lowered basal as properly as EGF-induced cyclin D1 expression [13] and also in an arrest of the cell cycle in G1 (our unpublished observations), indicating that flotillins are necessary for a sustained signaling downstream of ERK1/two. In standard, activation of the Raf/MEK/ERK cascade is associated with increased proliferation, and a dysregulation thereof is a hallmark of several tumors. In truth, activating mutations of upstream elements of ERK1/2 are liable for many human cancers, as summarized in [fifty two]. Other common ERK1/2 downstream goal genes are “early response genes” this kind of as the transcription factor c-Fos and the early growth response gene Egr1. Egr1, at first described as NGFI-A [53], is a zinc-finger transcription element whose expression is reduced in resting cells, but is quickly induced upon EGFR activation [fifty four] in an ERK1/2dependent manner [fifty five] and soon after therapy with PMA, EGF or serum [56]. In25374505 this examine, we display that all these stimuli also outcome in flotillin promoter activation, more pointing to ERK1/two and Egr1 as essential regulators of flotillin expression. The Egr1 promoter consists of five SREs [48] that are sure by Elk-one/SRF dimers. Accordingly, overexpression of SRF in HeLa cells final results in an enhanced expression of Egr1 (our unpublished info). Egr1 controls the expression of a large quantity of focus on genes, most of which are associated to cell growth and apoptosis, this sort of as p53, TGF and PTEN [579]. In addition, Egr1 downregulates its very own expression [sixty], ensuing in termination of Egr1regulated gene expression, as a result generating confident that the signaling is only transient. The potential function of Egr1 in cancer is not entirely recognized, since Egr1 has been demonstrated to either encourage [61] or suppress mobile proliferation and/or most cancers progression in a cell and tissue specific way (overview in [sixty two]). Listed here we present that Egr1 overexpression final results in transcriptional activation of flotillins and improve in the cellular flotillin protein quantity, suggesting that flotillins are Egr1-regulated genes.