Negative Regulation of ERK and Elk by Protein Kinase B Modulates c-fos Transcription

Galetic, Ivana; Maira, Sauveur‐Michel; Andjelković, Mirjana; Hemmings, Brian A.

doi:10.1074/jbc.m210578200

Cited by 37 publications

(33 citation statements)

References 43 publications

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“…In contrast, this result suggests that Akt acted downstream of ERK1/2 activation in the cytosol. In agreement with our data, a recent study reported that constitutively active Akt does not modify ERK1/2 phosphorylation (Galetic et al, 2003). In our study, the inhibition of ERK1/2 nuclear activity by overexpressed Akt resulted in a decrease in Elk-1-dependent transcription with a subsequent abolition of cFos expression.…”

Section: Discussionsupporting

confidence: 82%

“…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: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

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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“…72 Studies in human glioblastoma cells show: (i) protein kinase B inhibits Elk-1 expression by downregulation of the MEK-ERK pathway; 73 and (ii) activation and nuclear translocation of ERK1/2 induces activation of Elk-1. 74 Parallel with these findings, 73,74 we demonstrated that the reduction of ERK1/2 phosphorylation by RAMH results in decreased Elk-1 phosphorylation.…”

Section: Histamine Regulation Of Cholangiocyte Growthsupporting

confidence: 67%

H3 histamine receptor agonist inhibits biliary growth of BDL rats by downregulation of the cAMP-dependent PKA/ERK1/2/ELK-1 pathway

Francis

Franchitto

Ueno

et al. 2007

Laboratory Investigation

152

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Histamine regulates many functions by binding to four histamine G-coupled receptor proteins (H1R, H2R, H3R and H4R). As H3R exerts their effects by coupling to Ga i/o proteins reducing adenosine 3 0 , 5 0 -monophosphate (cAMP) levels (a key player in the modulation of cholangiocyte hyperplasia/damage), we evaluated the role of H3R in the regulation of biliary growth. We posed the following questions: (1) Do cholangiocytes express H3R? (2) Does in vivo administration of (R)-(a)-(À)-methylhistamine dihydrobromide (RAMH) (H3R agonist), thioperamide maleate (H3R antagonist) or histamine, in the absence/presence of thioperamide maleate, to bile duct ligated (BDL) rats regulate cholangiocyte proliferation? and (3) Does RAMH inhibit cholangiocyte proliferation by downregulation of cAMP-dependent phosphorylation of protein kinase A (PKA)/extracellular signal-regulated kinase 1/2 (ERK1/2)/ets-like gene-1 (Elk-1)? The expression of H3R was evaluated in liver sections by immunohistochemistry and immunofluorescence, and by real-time PCR in cholangiocyte RNA from normal and BDL rats. BDL rats (immediately after BDL) were treated daily with RAMH, thioperamide maleate or histamine in the absence/presence of thioperamide maleate for 1 week. Following in vivo treatment of BDL rats with RAMH for 1 week, and in vitro stimulation of BDL cholangiocytes with RAMH, we evaluated cholangiocyte proliferation, cAMP levels and PKA, ERK1/2 and Elk-1 phosphorylation. Cholangiocytes from normal and BDL rats express H3R. The expression of H3R mRNA increased in BDL compared to normal cholangiocytes. Histamine decreased cholangiocyte growth of BDL rats to a lower extent than that observed in BDL RAMH-treated rats; histamine-induced inhibition of cholangiocyte growth was partly blocked by thioperamide maleate. In BDL rats treated with thioperamide maleate, cholangiocyte hyperplasia was slightly higher than that of BDL rats. In vitro, RAMH inhibited the proliferation of BDL cholangiocytes. RAMH inhibition of cholangiocyte growth was associated with decreased cAMP levels and PKA/ERK1/2/Elk-1 phosphorylation. Downregulation of cAMP-dependent PKA/ERK1/2/Elk-1 phosphorylation (by activation of H3R) is important in the inhibition of cholangiocyte growth in liver diseases.

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“…Although c-fos expression was maintained at an elevated level through a mechanism independent of increased MAPK activity, constitutive SRE activity could be either because of deficient antagonistic phosphatase function (59,60) or by stimuli-independent phosphorylation by other kinases (61). Alternatively, SRE activity could be also regulated by a pathway involving the Rho family GTPases (62).…”

Section: Discussionmentioning

confidence: 99%

Loss of Net as Repressor Leads to Constitutive Increased c-fos Transcription in Cervical Cancer Cells

Riggelen¹,

Buchwalter²,

Soto³

et al. 2005

Journal of Biological Chemistry

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We have investigated the expression of c-fos in cervical carcinoma cells and in somatic cell hybrids derived therefrom. In malignant cells, c-fos was constitutively expressed even after serum starvation. Dissection of the c-fos promoter showed that expression was mainly controlled by the SRE motif, which was active in malignant cells, but repressed in their non-malignant counterparts. Constitutive SRE activity was not mediated by sustained mitogen-activated protein kinase activity but because of inefficient expression of the ternary complex factor Net, which was either very low or even barely discernible. Chromatin immunoprecipitation assays re-

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Negative Regulation of ERK and Elk by Protein Kinase B Modulates c-fos Transcription

Cited by 37 publications

References 43 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

H3 histamine receptor agonist inhibits biliary growth of BDL rats by downregulation of the cAMP-dependent PKA/ERK1/2/ELK-1 pathway

Loss of Net as Repressor Leads to Constitutive Increased c-fos Transcription in Cervical Cancer Cells

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