Snail1, in turn, binds to the ER promoter to Salubrinal complete the negative feedback loop [27,28]. In a similar fashion, Egr-1 and Snail1 relate via a negative feedback loop. Egr-1, another zinc-finger transcription

factor, binds to the Snail1 promoter at four sites between -450 and -50 bp. This process necessitates the presence of HGF and is mediated by the MAPK pathway, and it ultimately results in Snail1 upregulation. Snail1, in turn, Veliparib represses Egr-1 [29]. YY1 and Snail1 itself are two special instances of transcriptional Snail1 regulation. YY1 binds to the 3’ enhancer, rather than the promoter, and knockdown of YY1 has been shown to decrease Snail1 expression [30]. Furthermore, Snail1 is capable of binding to its own promoter and upregulating itself [31]. Snail1 binds to the E box region within the Snail ILK Responsive Element (SIRE); PARP-1 also binds to the SIRE, which is located between -134 and -69 bp, when induced by ILK [23] (Figure 2). Figure Ro 61-8048 concentration 2 Regulation at the Snail1 promoter. This figure depicts the regulatory interactions at the human Snail1 promoter. The central line represents the base-paired sequence, with -750 to -1 bp shown. The relative locations of interactions with various transcription factors are then spatially compared using blocks to represent each regulator’s binding

site. Each block, with the base pairs involved denoted at the top, shows where that particular protein binds the Snail1 promoter. Experiments conducted to elucidate the relationship between p53, a tumor suppressor protein, and Snail1 have shown that p53 acts via miR-34a, -34b, and -34c to repress Snail1 at a 3’ untranslated region (UTR). Consequently,

when p53 is repressed, the repression of Snail1 is lifted, and the expression of Snail1 rises [32]. Translational regulation Two instances of phosphorylation are crucial Bay 11-7085 to Snail1’s post-transcriptional regulation. GSK-3β phosphorylates Snail1 at two consensus motifs in serine-rich regions. The first phosphorylation, at motif 2 (S107, S111, S115, S119), results in Snail1’s being exported to the cytoplasm. The second instance of phosphorylation (S96, S100, S104) leads to its ubiquitination by β-Trcp, which recognizes the destruction motif D95SGxxS100 and ubiquitinates Lys98, 137, and 146. Consequential proteasomal degradation follows [33,34]. In conditions that prevent GSK-3β from phosphorylating Snail1, the F-box E3 ubiquitin ligase FBXL14 appears to cause proteasomal degradation by ubiquitinating the same lysine residues as β-Trcp [35]. P21-activated kinase 1 (PAK1) also phosphorylates Snail1 at S246 [36]. Phosphorylation determines Snail1’s subcellular location, as GSK-3β -mediated phosphorylation induces Snail1’s export to the cytoplasm through exportins such as chromosome region maintenance 1 (CRM1) [33,37].