IRES-dependent translation of egr2 is induced under inflammatory conditions

Rübsamen, Daniela; Blees, Johanna S.; Schulz, Kathrin; Döring, Claudia; Hansmann, Martin‐Leo; Heide, Heinrich; Weigert, Andreas; Schmid, Tobias; Brüne, Bernhard

doi:10.1261/rna.033019.112

Cited by 26 publications

(21 citation statements)

References 43 publications

(44 reference statements)

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“…In some cases, an IRES is a special mRNA motif that can form a typical clover leaf-like structure with a length of 150-250 bp [4,31,32]. Therefore, we employed the bioinformatics tools RNAdraw and RNA fold (http://rna.…”

Section: Adar1-301-600 Exhibits Necessary Core Ires-like Activitymentioning

confidence: 99%

“…IRES-dependent translation is critical for physiological and pathological progress and can drive the expression of proteins under conditions where cap-dependent translation is suppressed, which indicates a translation-regulated response to stress environments such as hypoxia, apoptosis, inflammation and tumorigenesis [2][3][4][5]. IRES trans-acting factors (ITAFs) are known to contribute to IRES-mediated translation progress, and a subset of RNA-binding proteins can function as ITAFs, such as polypyrimidine tract binding protein (PTB, also known as PTBP1), upstream of N-ras (UNR, also known as CSDE1) and poly(C)-binding protein (PCBP) [6][7][8].…”

Section: Introductionmentioning

confidence: 99%

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PTBP1 induces ADAR1 p110 isoform expression through IRES-like dependent translation control and influences cell proliferation in gliomas

Yang

Lin

et al. 2015

Cell. Mol. Life Sci.

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Internal ribosomal entry site (IRES)-mediated translation initiation is constitutively activated during stress conditions such as tumorigenesis and hypoxia. The RNA editing enzyme ADAR1 plays an important role in physiology and pathology. Initially, we found that the ADAR1 p150 or p110 transcript levels were decreased in glioma cells compared with normal astrocyte cells. In contrast, protein levels of ADAR1 p110 were significantly upregulated in glioma tissues and cells. This expression pattern indicated translationally controlled regulation. We identified an 885-nt sequence that was located between AUG1 and AUG2 within the ADAR1 mRNA that exhibited IRES-like activity. Furthermore, we confirmed that the translational mode of ADAR1 p110 was mediated by PTBP1 in glioma cells. The protein levels of PTBP1 and ADAR1 were cooperatively expressed in glioma tissues and cells. Knocking down ADAR1 p110 significantly decreased cell proliferation in three types of glioma cells (T98G, U87MG and A172). The removal of a minimal IRES-like sequence in a p150-overexpression construct could effectively abolish p110 induction and resulted in the slight suppression of cell proliferation compared with ADAR1-p150 overexpression in siPTBP1-treated T98G cells. In summary, our study revealed a mechanism whereby ADAR1 p110 can be activated by PTBP1 through an IRES-like element in glioma cells, and ADAR1 is essential for the maintenance of gliomagenesis.

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Section: Adar1-301-600 Exhibits Necessary Core Ires-like Activitymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

PTBP1 induces ADAR1 p110 isoform expression through IRES-like dependent translation control and influences cell proliferation in gliomas

Yang

Lin

et al. 2015

Cell. Mol. Life Sci.

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“…Importantly, we noticed that such inflammatory conditions induce translational changes in MCF7 cells as determined by altered polysomal association of various mRNAs [16]. Polysomal fractionation analyses of MCF7 cells (Figure 1) followed by microarray analyses of polysomal mRNA changes in response to 4 h CM treatment [16], identified cyp24a1 to significantly increase in the polysomal fractions without concomitant change on total RNA level in response to 4 h CM treatment. Since cyp24a1 has been proposed to play a critical role in the development of resistances to tumor therapeutic application of vitamin D 3 , we aimed at further characterizing the translational regulation of cyp24a1.…”

Section: Resultsmentioning

confidence: 95%

“…Yet, mediators within the inflammatory environment such as members of the interleukin-1 family have been shown to control protein expression on a translational level [15], [16]. The present study aimed at characterizing a novel, translationally regulated target during inflammation-associated tumorigenesis.…”

Section: Introductionmentioning

confidence: 99%

Inflammatory Conditions Induce IRES-Dependent Translation of cyp24a1

et al. 2014

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Rapid alterations in protein expression are commonly regulated by adjusting translation. In addition to cap-dependent translation, which is e.g. induced by pro-proliferative signaling via the mammalian target of rapamycin (mTOR)-kinase, alternative modes of translation, such as internal ribosome entry site (IRES)-dependent translation, are often enhanced under stress conditions, even if cap-dependent translation is attenuated. Common stress stimuli comprise nutrient deprivation, hypoxia, but also inflammatory signals supplied by infiltrating immune cells. Yet, the impact of inflammatory microenvironments on translation in tumor cells still remains largely elusive. In the present study, we aimed at identifying translationally deregulated targets in tumor cells under inflammatory conditions. Using polysome profiling and microarray analysis, we identified cyp24a1 (1,25-dihydroxyvitamin D3 24-hydroxylase) to be translationally upregulated in breast tumor cells co-cultured with conditioned medium of activated monocyte-derived macrophages (CM). Using bicistronic reporter assays, we identified and validated an IRES within the 5′ untranslated region (5′UTR) of cyp24a1, which enhances translation of cyp24a1 upon CM treatment. Furthermore, IRES-dependent translation of cyp24a1 by CM was sensitive to phosphatidyl-inositol-3-kinase (PI3K) inhibition, while constitutive activation of Akt sufficed to induce its IRES activity. Our data provide evidence that cyp24a1 expression is translationally regulated via an IRES element, which is responsive to an inflammatory environment. Considering the negative feedback impact of cyp24a1 on the vitamin D responses, the identification of a novel, translational mechanism of cyp24a1 regulation might open new possibilities to overcome the current limitations of vitamin D as tumor therapeutic option.

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“…In times of nutrient deprivation or under stress conditions, cap-dependent translation is inhibited by 4E-BP1. However, a subset of cellular proteins is still translated during these times through cap-independent mechanisms via internal ribosomal entry sites (IRES) (10). IRES elements were first described in poliovirus, where viral proteins degrade translational regulators and inhibit cap-dependent translation, which then promotes the translation of viral proteins under the influence of the IRES sequence (11).…”

mentioning

confidence: 99%

The Human Papillomavirus 16 E7 Oncoprotein Attenuates AKT Signaling To Promote Internal Ribosome Entry Site-Dependent Translation and Expression of c-MYC

Strickland

Pol

2016

J Virol

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While the role of high-risk human papillomavirus (HPV) oncoproteins E6 and E7 in targeting p53 and retinoblastoma (Rb) has been intensively studied, how E6 and E7 manipulate cellular signaling cascades to promote the viral life cycle and cancer development is less understood. Keratinocytes containing the episomal HPV-16 genome had decreased activation of AKT, which was phenocopied by HPV-16 E7 expression alone. Attenuation of phosphorylated AKT (pAKT) by E7 was independent of the Rb degradation function of E7 but could be ablated by a missense mutation in the E7 carboxy terminus, H73E, thereby defining a novel structure-function phenotype for E7. Downstream of AKT, reduced phosphorylation of p70 S6K and 4E-BP1 was also observed in E7-expressing keratinocytes, which coincided with an increase in internal ribosomal entry site (IRES)-dependent translation that enhanced the expression of several cellular proteins, including MYC, Bax, and the insulin receptor. The decrease in pAKT mediated by E7 is in contrast to the widely observed increase of pAKT in invasive cervical cancers, suggesting that the activation of AKT signaling could be acquired during the progression from initial productive infections to invasive carcinomas. IMPORTANCEHPV causes invasive cervical cancers through the dysregulation of the cell cycle regulators p53 and Rb, which are degraded by the viral oncoproteins E6 and E7, respectively. Signaling cascades contribute to cancer progression and cellular differentiation, and how E6 and E7 manipulate those pathways remains unclear. The phosphoinositol 3-kinase (PI3K)/AKT pathway regulates cellular processes, including proliferation, cell survival, and cell differentiation. Surprisingly, we found that HPV-16 decreased the phosphorylation of AKT (pAKT) and that this is a function of E7 that is independent of the Rb degradation function. This is in contrast to the observed increase in AKT signaling in nearly 80% of cervical cancers, which typically show an acquired mutation within the PI3K/AKT cascade leading to constitutive activation of the pathway. Our observations suggest that multiple changes in the activation and effects of AKT signaling occur in the progression from productive HPV infections to invasive cervical cancers.T he causative link between human papillomavirus 16 (HPV-16) infection and the development of cervical cancer is well established (reviewed in reference 1). High-risk alpha genera HPV E6 and E7 oncoproteins interact with and degrade p53 and retinoblastoma (Rb), respectively, to alter cell cycle regulation (reviewed in references 2, 3, and 4). However, less is known about the interaction of E6 and E7 with cellular proteins that manipulate cellular signaling cascades. We sought to examine the role of HPV-16, and specifically E7 (here 16E7), in manipulating cellular signaling pathways critical to the survival of the cell and initially focused upon the phosphoinositol 3-kinase (PI3K)/AKT pathway.AKT was originally identified as the causative agent in the acute transforming retrovi...

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IRES-dependent translation of egr2 is induced under inflammatory conditions

Cited by 26 publications

References 43 publications

PTBP1 induces ADAR1 p110 isoform expression through IRES-like dependent translation control and influences cell proliferation in gliomas

PTBP1 induces ADAR1 p110 isoform expression through IRES-like dependent translation control and influences cell proliferation in gliomas

Inflammatory Conditions Induce IRES-Dependent Translation of cyp24a1

The Human Papillomavirus 16 E7 Oncoprotein Attenuates AKT Signaling To Promote Internal Ribosome Entry Site-Dependent Translation and Expression of c-MYC

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