The E-box Binding Factors Max/Mnt, MITF, and USF1 Act Coordinately with FoxO to Regulate Expression of Proapoptotic and Cell Cycle Control Genes by Phosphatidylinositol 3-Kinase/Akt/Glycogen Synthase Kinase 3 Signaling

Terragni, Jolyon; Nayak, Gauri; Banerjee, Swati; Medrano, Jose-Luis; Graham, James G.; Brennan, James F.; Sepulveda, Sean; Cooper, Geoffrey M.

doi:10.1074/jbc.m111.246116

Cited by 38 publications

(48 citation statements)

References 55 publications

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“…Although some similarities between USF1 and USF2 exist, they appear to have different functions, and different target genes which is also substantiated by significantly different phenotypes of USF1 and USF2 knockout mice. Moreover, like in the present study there is also no priming phosphorylation at the amino acid in +4 position of USF1 S186 [18]. These findings are conform to other studies in which for example the transcription factors c-Jun [67], p53 [68] and c-Myb [69] were found to be phosphorylated by GSK3β at sites not matching the minimal recognition motif.…”

Section: Discussionsupporting

confidence: 91%

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GSK3β-Dependent Phosphorylation Alters DNA Binding, Transactivity and Half-Life of the Transcription Factor USF2

et al. 2014

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The upstream stimulatory factor 2 (USF2) is a regulator of important cellular processes and is supposed to have also a role during tumor development. However, the knowledge about the mechanisms that control the function of USF2 is limited. The data of the current study show that USF2 function is regulated by phosphorylation and identified GSK3β as an USF2-phosphorylating kinase. The phosphorylation sites within USF2 could be mapped to serine 155 and threonine 230. In silico analyses of the 3-dimensional structure revealed that phosphorylation of USF2 by GSK3β converts it to a more open conformation which may influence transactivity, DNA binding and target gene expression. Indeed, experiments with GSK-3β-deficient cells revealed that USF2 transactivity, DNA binding and target gene expression were reduced upon lack of GSK3β. Further, experiments with USF2 variants mimicking GSK3β phosphorylated USF2 in GSK3β-deficient cells showed that phosphorylation of USF2 by GSK3β did not affect cell proliferation but increased cell migration. Together, this study reports a new mechanism by which USF2 may contribute to cancerogenesis.

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Section: Discussionsupporting

confidence: 91%

“…Although not strictly required, priming phosphorylation seems to increase substrate phosphorylation by GSK3β [18]. Within the minimal GSK3 recognition motif, the first S/T is the proper GSK3β target site, X is any amino acid and the C-terminal S/T residue is the site of priming phosphorylation [28].…”

Section: Discussionmentioning

confidence: 99%

GSK3β-Dependent Phosphorylation Alters DNA Binding, Transactivity and Half-Life of the Transcription Factor USF2

et al. 2014

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“…16, 18 The role of representative p53 target genes ( Atrogin-1, Gadd45A, Nupr1, Tp53inp1 and Txnip) in apoptosis induced by PI 3-kinase inhibition was tested by siRNA knockdowns (Figure 2c). Inhibition of PI 3-kinase for 24 h resulted in 50–55% cell death (Figure 2c).…”

Section: Resultsmentioning

confidence: 99%

p53 is a major component of the transcriptional and apoptotic program regulated by PI 3-kinase/Akt/GSK3 signaling

Nayak

Cooper

2012

Cell Death Dis

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The phosphatidylinositol (PI) 3-kinase/Akt signaling pathway has a prominent role in cell survival and proliferation, in part, by regulating gene expression at the transcriptional level. Previous work using global expression profiling identified FOXOs and the E-box-binding transcription factors MITF and USF1 as key targets of PI 3-kinase signaling that lead to the induction of proapoptotic and cell cycle arrest genes in response to inhibition of PI 3-kinase. In this study, we investigated the role of p53 downstream of PI 3-kinase signaling by analyzing the effects of inhibition of PI 3-kinase in Rat-1 cells, which have wild-type p53, compared with Rat-1 cells expressing a dominant-negative p53 mutant. Expression of dominant-negative p53 conferred partial resistance to apoptosis induced by inhibition of PI 3-kinase. Global gene expression profiling combined with computational and experimental analysis of transcription factor binding sites demonstrated that p53, along with FOXO, MITF and USF1, contributed to gene induction in response to PI 3-kinase inhibition. Activation of p53 was mediated by phosphorylation of the histone acetyltransferase Tip60 by glycogen synthase kinase (GSK) 3, leading to activation of p53 by acetylation. Many of the genes targeted by p53 were also targeted by FOXO and E-box-binding transcription factors, indicating that p53 functions coordinately with these factors to regulate gene expression downstream of PI 3-kinase/Akt/GSK3 signaling.

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“…Our result that Zn 2C ions induce gastrin expression through the activation of an E-box binding transcription factor via the phosphorylation of AKT raises the possibility that Zn 2C may induce the EMT through direct activation of E-boxbinding transcription factors. Although further studies of the transcription factors involved are warranted, in the light of evidence that many known (Longo et al 2008, Terragni et al 2011 and as yet uncharacterized transcription factors (Biggs et al 2007) can bind E-boxes it is beyond the scope of the current study to identify one single transcription factor which activates gastrin expression in response to Zn 2C . What does our finding that gastrin is induced by Zn 2C ions imply about normal gastric physiology?…”

Section: Discussionmentioning

confidence: 99%

Zinc ions upregulate the hormone gastrin via an E-box motif in the proximal gastrin promoter

Xiao

Kovac

Chang

et al. 2014

Journal of Molecular Endocrinology

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Gastrin and its precursors act as growth factors for the normal and neoplastic gastrointestinal mucosa. As the hypoxia mimetic cobalt chloride upregulates the gastrin gene, the effect of other metal ions on gastrin promoter activity was investigated. Gastrin mRNA was measured by real-time PCR, gastrin peptides by RIA, and gastrin promoter activity by dual-luciferase reporter assay. Exposure to Zn 2C ions increased gastrin mRNA concentrations in the human gastric adenocarcinoma cell line AGS in a dose-dependent manner, with a maximum stimulation of 55G14-fold at 100 mM (P!0.05). . Deletional mutation of the gastrin promoter identified an 11 bp DNA sequence, which contained an E-box motif, as necessary for Zn 2C -dependent gastrin induction. The fact that E-box binding transcription factors play a crucial role in the epithelial-mesenchymal transition (EMT), together with our observation that Zn 2C ions upregulate the gastrin gene in AGS cells by an E-box-dependent mechanism, suggests that Zn 2C ions may induce an EMT, and that gastrin may be involved in the transition.

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The E-box Binding Factors Max/Mnt, MITF, and USF1 Act Coordinately with FoxO to Regulate Expression of Proapoptotic and Cell Cycle Control Genes by Phosphatidylinositol 3-Kinase/Akt/Glycogen Synthase Kinase 3 Signaling

Cited by 38 publications

References 55 publications

GSK3β-Dependent Phosphorylation Alters DNA Binding, Transactivity and Half-Life of the Transcription Factor USF2

GSK3β-Dependent Phosphorylation Alters DNA Binding, Transactivity and Half-Life of the Transcription Factor USF2

p53 is a major component of the transcriptional and apoptotic program regulated by PI 3-kinase/Akt/GSK3 signaling

Zinc ions upregulate the hormone gastrin via an E-box motif in the proximal gastrin promoter

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