Akt negatively regulates translation of the ternary complex factor Elk-1

Figueroa, Claudia; Vojtek, Anne B.

doi:10.1038/sj.onc.1206496

Cited by 15 publications

(14 citation statements)

References 49 publications

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“…Proteins (60 g) were separated by SDS-PAGE and immunoblotted with anti-phospho-ERK and anti-Akt antibody, respectively. regulate the Elk-1 transcription factor by decreasing either its expression (Figueroa and Vojtek, 2003) or its activation (Galetic et al, 2003). Therefore, the critical step for the negative regulation of ERK1/2 by Akt lies between the cytosolic activation of ERK1/2 and its activity on nuclear substrates, such as Elk-1.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, constitutively active Akt can negatively regulate the Ras/Raf/MEF/ERK1/2 cascade via phosphorylation and inactivation of the kinase Raf , leading to the phenotype modulation of differentiated myotubes (Rommel et al, 1999) or of vascular smooth muscle cells (Reusch et al, 2001). An additional level of interaction between Akt and the ERK1/2 pathway has been reported downstream of Ras, Raf, and MEK that involves the down-regulation of the transcription factor Elk-1 (Figueroa and Vojtek, 2003;Galetic et al, 2003). To date, the molecular mechanisms and the functional cellular consequences of this cross-talk remain poorly investigated.…”

Section: Introductionmentioning

confidence: 99%

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Akt Down-Regulates ERK1/2 Nuclear Localization and Angiotensin II-induced Cell Proliferation through PEA-15

Gervais

Dugourd

Muller

et al. 2006

MBoC

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Angiotensin II (AngII) type 1 receptors (AT1) regulate cell growth through the extracellular signal-regulated kinase (ERK)1/2 and phosphatidylinositol 3-kinase (PI3K) pathways. ERK1/2 and Akt/protein kinase B, downstream of PI3K, are independently activated but both required for mediating AngII-induced proliferation when expressed at endogenous levels. We investigate the effect of an increase in the expression of wild-type Akt1 by using Chinese hamster ovary (CHO)-AT1 cells. Unexpectedly, Akt overexpression inhibits the AT1-mediated proliferation. This effect could be generated by a cross-talk between the PI3K and ERK1/2 pathways. A functional partner is the phosphoprotein enriched in astrocytes of 15 kDa (PEA-15), an Akt substrate known to bind ERK1/2 and to regulate their nuclear translocation. We report that Akt binds to PEA-15 and that Akt activation leads to PEA-15 stabilization, independently of PEA-15 interaction with ERK1/2. Akt cross-talk with PEA-15 does not affect ERK1/2 activation but decreases their nuclear activity as a result of the blockade of ERK1/2 nuclear accumulation. In response to AngII, PEA-15 overexpression displays the same functional consequences on ERK1/2 signaling as Akt overactivation. Thus, Akt overactivation prevents the nuclear translocation of ERK1/2 and the AngII-induced proliferation through interaction with and stabilization of endogenous PEA-15.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Akt Down-Regulates ERK1/2 Nuclear Localization and Angiotensin II-induced Cell Proliferation through PEA-15

Gervais

Dugourd

Muller

et al. 2006

MBoC

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“…However, it was reported that AKT negatively regulated ELK-1 expression at the level of translation and that a region within the first 279 nt of the ELK-1 open reading frame (ORF) was necessary and sufficient for this control (13,14). These latter studies were performed using GST–ELK-1 fusion constructs; i.e.…”

Section: Introductionmentioning

confidence: 99%

Alternatively spliced isoforms of the human elk-1 mRNA within the 5′ UTR: implications for ELK-1 expression

Araud

Genolet

Jaquier-Gubler

et al. 2007

Nucleic Acids Research

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The expression of cellular proteins that play central roles in the regulation of cell growth and differentiation is frequently tightly controlled at the level of translation initiation. In this article, we provide evidence that the ETS domain transcription factor ELK-1 forms part of this class of genes. Its mRNA 5′ UTR is composed of a complexed mosaic of elements, including uAUGs, uORFs and RNA structure, that interplay to modulate ribosomal access to the ELK-1 AUG start codon. Superimposed upon this is the generation of two different 5′ UTRs via alternative splicing. The two spliced isoforms show altered cellular and tissue distributions and behave differently in polysomal recruitment assays in the presence of the drug rapamycin. We propose that repression is therefore the sum of a series of interplaying negative elements within the 5′ UTRs, a situation which may reflect the need for tight translational control of ELK-1 in different tissues and under changing physiological conditions.

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“…AKT can phosphorylate mTOR, and studies in Drosophila have demonstrated that dTOR (Drosophila target of rapamycin) is downstream and epistatic to the phosphatidylinositol 3-kinase/AKT pathway (5,16,17). However, AKT has recently been shown to negatively regulate the translation of the Elk-1 and Sap1a mRNAs independently of mTOR (18), and our prior work (19) also suggests a role for AKT in the regulation of cap-independent translation.…”

mentioning

confidence: 99%

Cyclin D1 and c-myc Internal Ribosome Entry Site (IRES)-dependent Translation Is Regulated by AKT Activity and Enhanced by Rapamycin through a p38 MAPK- and ERK-dependent Pathway

Shi

Sharma

et al. 2005

Journal of Biological Chemistry

143

165

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The macrolide antibiotic rapamycin inhibits the mammalian target of rapamycin protein (mTOR) kinase resulting in the global inhibition of cap-dependent protein synthesis, a blockade in ribosome component biosynthesis, and G 1 cell cycle arrest. G 1 arrest may occur by inhibiting the protein synthesis of critical factors required for cell cycle progression. Hypersensitivity to mTOR inhibitors has been demonstrated in cells having elevated levels of AKT kinase activity, whereas cells containing quiescent AKT activity are relatively resistant. Our previous data suggest that low AKT activity induces resistance by allowing continued cap-independent protein synthesis of cyclin D1 and c-Myc proteins. In support of this notion, the current study demonstrates that the human cyclin D1 mRNA 5 untranslated region contains an internal ribosome entry site (IRES) and that both this IRES and the c-myc IRES are negatively regulated by AKT activity. Furthermore, we show that cyclin D1 and c-myc IRES function is enhanced following exposure to rapamycin and requires both p38 MAPK and RAF/MEK/ERK signaling, as specific inhibitors of these pathways reduce IRES-mediated translation and protein levels under conditions of quiescent AKT activity. Thus, continued IRES-mediated translation initiation may permit cell cycle progression upon mTOR inactivation in cells in which AKT kinase activity is relatively low.The global regulation of cap-dependent translation is mediated via the mTOR 1 signaling cascade (1-3). Activation of mTOR results in phosphorylation of the p70 S6 kinase and the translation repressor 4E-BP1, allowing the formation of functional eIF-4F complexes resulting in cap-dependent mRNA translation initiation and ribosomal component biogenesis (4, 5). The efficiency with which a mRNA can initiate cap-dependent translation is a function of the length and degree of secondary structure present within the 5Ј-UTR as well as the sequence context of the initiation codon (6). Most eukaryotic mRNAs contain 5Ј-UTRs with relatively short and unstructured 5Ј-UTRs (Ͻ100 nucleotides), which allow efficient capdependent ribosomal scanning (6). However, some key regulators of cell proliferation and apoptosis have leaders that are quite long, highly structured, and contain many upstream AUG or CUG codons and, as a result, are inhibitory to scanning ribosomes (7). Translation initiation in a number of these mRNAs is achieved via IRES-mediated mechanisms (8). Protein synthesis via this alternative form of initiation is typically favored under conditions when the default cap-dependent pathway is inhibited (9 -12).The ability of AKT to regulate cap-dependent initiation is mediated via its inhibitory effects on the mTOR inhibitor complex TSC1/TSC2 (13-15). A direct linkage between AKT and the mTOR kinase has also been described. AKT can phosphorylate mTOR, and studies in Drosophila have demonstrated that dTOR (Drosophila target of rapamycin) is downstream and epistatic to the phosphatidylinositol 3-kinase/AKT pathway (5,16,17). However, AKT has rec...

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Akt negatively regulates translation of the ternary complex factor Elk-1

Cited by 15 publications

References 49 publications

Akt Down-Regulates ERK1/2 Nuclear Localization and Angiotensin II-induced Cell Proliferation through PEA-15

Akt Down-Regulates ERK1/2 Nuclear Localization and Angiotensin II-induced Cell Proliferation through PEA-15

Alternatively spliced isoforms of the human elk-1 mRNA within the 5′ UTR: implications for ELK-1 expression

Cyclin D1 and c-myc Internal Ribosome Entry Site (IRES)-dependent Translation Is Regulated by AKT Activity and Enhanced by Rapamycin through a p38 MAPK- and ERK-dependent Pathway

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