scholarly journals Vasohibin1, a new IRES trans-acting factor for induction of (lymph)angiogenic factors in early hypoxia

2018 ◽  
Author(s):  
Fransky Hantelys ◽  
Anne-Claire Godet ◽  
Florian David ◽  
Florence Tatin ◽  
Edith Renaud-Gabardos ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Synthesis ◽  
Growth Factors ◽  
Ischemic Heart ◽  
Transcriptional Level ◽  
Angiogenic Growth Factors ◽  
Internal Ribosome Entry ◽  
Global Protein Synthesis ◽  
Specific Mrnas ◽  
Angiogenic Genes

ABSTRACTHypoxia, a major inducer of angiogenesis, is known to trigger major changes of gene expression at the transcriptional level. Furthermore, global protein synthesis is blocked while internal ribosome entry sites (IRES) allow specific mRNAs to be translated. Here we report the transcriptome and translatome signatures of (lymph)angiogenic genes in hypoxic HL-1 cardiomyocytes: most genes are not induced at the transcriptome-, but at the translatome level, including all IRES-containing mRNAs. Our data reveal activation of (lymph)angiogenic mRNA IRESs in early hypoxia. We identify vasohibin1 (VASH1) as an IRES trans-acting factor (ITAF) able to activate FGF1 and VEGFD IRESs in hypoxia while it inhibits several IRESs in normoxia. Thus this new ITAF may have opposite effects on IRES activities. These data suggest a generalized process of IRES-dependent translational induction of (lymph)angiogenic growth factors expression in early hypoxia, whose pathophysiological relevance is to trigger formation of new functional vessels in ischemic heart. VASH1 is not always required, indicating that the IRESome composition is variable, thus allowing subgroups of IRESs to be activated under the control of different ITAFs.

scholarly journals Vasohibin1, a new mouse cardiomyocyte IRES trans-acting factor that regulates translation in early hypoxia

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Fransky Hantelys ◽  
Anne-Claire Godet ◽  
Florian David ◽  
Florence Tatin ◽  
Edith Renaud-Gabardos ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Synthesis ◽  
Translational Control ◽  
Ischemic Heart ◽  
Angiogenic Factor ◽  
Transcriptional Level ◽  
Internal Ribosome Entry ◽  
Global Protein Synthesis ◽  
Specific Mrnas ◽  
Angiogenic Genes

Hypoxia, a major inducer of angiogenesis, triggers major changes in gene expression at the transcriptional level. Furthermore, under hypoxia, global protein synthesis is blocked while internal ribosome entry sites (IRES) allow specific mRNAs to be translated. Here, we report the transcriptome and translatome signatures of (lymph)angiogenic genes in hypoxic HL-1 mouse cardiomyocytes: most genes are induced at the translatome level, including all IRES-containing mRNAs. Our data reveal activation of (lymph)angiogenic factor mRNA IRESs in early hypoxia. We identify vasohibin1 (VASH1) as an IRES trans-acting factor (ITAF) that is able to bind RNA and to activate the FGF1 IRES in hypoxia, but which tends to inhibit several IRESs in normoxia. VASH1 depletion has a wide impact on the translatome of (lymph)angiogenesis genes, suggesting that this protein can regulate translation positively or negatively in early hypoxia. Translational control thus appears as a pivotal process triggering new vessel formation in ischemic heart.

Internal Ribosome Entry Site-Mediated Translation in Neuronal Protein Synthesis

2018 ◽  
Author(s):  
Martin Holcik
Keyword(s):  
Protein Synthesis ◽  
Internal Ribosome Entry Site ◽  
Normal Function ◽  
Entry Site ◽  
Alternative Mode ◽  
Internal Ribosome Entry ◽  
Neuronal Protein ◽  
Global Protein Synthesis ◽  
Cellular Mrnas ◽  
Specific Mrnas

While the majority of cellular mRNAs are translated by a cap-dependent mechanism, a subset of mRNAs can use an alternative mode of translation that, instead of cap, relies on discreet RNA elements that help to recruit the ribosome. This mode of translation, termed Internal Ribosome Entry Site (IRES)–dependent translation, is particularly important during conditions of compromised global protein synthesis or for a local, precisely timed translation of specific mRNAs. This latter purpose is of considerable importance in cells of the CNS for their normal function. Recently, the disruption of the IRES-mediated translation has also been linked to pathological processes, suggesting that full understanding and targeting of this peculiar mechanism could be used for therapeutic intervention.

scholarly journals The hnRNA-Binding Proteins hnRNP L and PTB Are Required for Efficient Translation of the Cat-1 Arginine/Lysine Transporter mRNA during Amino Acid Starvation

2009 ◽  
Vol 29 (10) ◽  
pp. 2899-2912 ◽  
Author(s):  
Mithu Majumder ◽  
Ibrahim Yaman ◽  
Francesca Gaccioli ◽  
Vladimir V. Zeenko ◽  
Chuanping Wang ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Amino Acid ◽  
Binding Protein ◽  
Mrna Translation ◽  
Amino Acid Starvation ◽  
Entry Site ◽  
Internal Ribosome Entry ◽  
Polypyrimidine Tract Binding Protein ◽  
Global Protein Synthesis

ABSTRACT The response to amino acid starvation involves the global decrease of protein synthesis and an increase in the translation of some mRNAs that contain an internal ribosome entry site (IRES). It was previously shown that translation of the mRNA for the arginine/lysine amino acid transporter Cat-1 increases during amino acid starvation via a mechanism that utilizes an IRES in the 5′ untranslated region of the Cat-1 mRNA. It is shown here that polypyrimidine tract binding protein (PTB) and an hnRNA binding protein, heterogeneous nuclear ribonucleoprotein L (hnRNP L), promote the efficient translation of Cat-1 mRNA during amino acid starvation. Association of both proteins with Cat-1 mRNA increased during starvation with kinetics that paralleled that of IRES activation, although the levels and subcellular distribution of the proteins were unchanged. The sequence CUUUCU within the Cat-1 IRES was important for PTB binding and for the induction of translation during amino acid starvation. Binding of hnRNP L to the IRES or the Cat-1 mRNA in vivo was independent of PTB binding but was not sufficient to increase IRES activity or Cat-1 mRNA translation during amino acid starvation. In contrast, binding of PTB to the Cat-1 mRNA in vivo required hnRNP L. A wider role of hnRNP L in mRNA translation was suggested by the decrease of global protein synthesis in cells with reduced hnRNP L levels. It is proposed that PTB and hnRNP L are positive regulators of Cat-1 mRNA translation via the IRES under stress conditions that cause a global decrease of protein synthesis.

Co-Culture of Myeloma and Endothelial Cells: Defibrotide Downregulates Heparanase and Pro-Angiogenic Growth Factors.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2513-2513 ◽  
Author(s):  
Cinara Echart ◽  
Maria Distaso ◽  
Laura Ferro ◽  
Mario Boccadoro ◽  
Antonio Palumbo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Endothelial Cells ◽  
Growth Factors ◽  
Growth Factor ◽  
Conditioned Media ◽  
Angiogenic Growth Factors ◽  
Factor Expression ◽  
Key Factor ◽  
Growth Factor Expression ◽  
Rpmi 8226

Abstract Introduction: Heparanase (HPSE) expression in humans has been associated with advanced progression and metastasis of many tumor types, including multiple myeloma (MM), where its activity is correlated with altered gene expression that may promote an aggressive tumor phenotype with high microvessel density (ref). These findings indicate an important role of HPSE in regulating metastasis, angiogenesis and progression of MM. Defibrotide (DF) is an orally bio-available polydisperse oligonucleotide with anti-thrombotic, pro-fibrinolytic, anti-adhesive and anti-angiogenic properties. Recently, we have shown that DF is able to downregulate HPSE gene expression and activity in MM cell lines (International myeloma workshop, Greece, 2007). Methods: We investigated whether the expression of HPSE and angiogenic growth factors (FGF-2 and VEGF) in human microvascular endothelial cells (HMEC) are modified by co-culture with MM cells or by growing in the media of MM cells. In addition, we evaluated whether DF has activity in regulating the expression of HPSE, FGF-2 and VEGF in HMEC co-cultured with MM cells. We then tested the effect of DF on the invasiveness of MM cells activated with HPSE. HMEC cells were co-cultured with RPMI 8226 MM cells for 48h in the presence and absence of DF (at dose of 150μg/ml). HMEC was also grown alone for 48h in MM cell-conditioned media. The expression of HPSE and angiogenic growth factors (FGF-2 and VEGF) present in endothelial cells were examined through real time polymerase chain reaction (RT-PCR) of cDNA prepared from HMEC. Tumor invasion was evaluated using the BD BioCoat MatrigelTM invasion system (BD Bioscience). Results: Coculture with RPMI 8226 cells substantially induced the expression of HPSE (7.2 fold) and angiogenic growth factors (3-5 fold) in HMEC compared with endothelial cells growing alone. DF was able to downregulate HPSE, FGF-2 and VEGF gene expression in HMEC co-cultured with RPMI 8226 cells (4.0; 6.0-8.0 fold, respectively). Surprisingly, addition of conditioned media in absence of MM cells resulted in 6.5 fold of elevation of HPSE but not growth factors expression in HMEC. These results show that components released by MM cells are sufficient to modulate HPSE. However, to alter growth factor expression, HMEC needed to be culture in the presence of RPMI 8226 cells. Additionally, HPSE increased the invasiveness of RPMI 8226 cells and DF was able to significantly decrease MM invasiveness in the Matrigel assay by 50% (p<0.05). Conclusion: Taken together, these results suggest that cross-talk between MM and endothelial cells leads to enhanced angiogenesis. HPSE is a key factor in this process, correlating with both angiogenic stimulus and MM progression. Moreover, DF is able to downregulate HSPE and growth factor expression in activated HMEC induced by MM, as well as reducing the invasiveness of MM in this system. These observations suggest a potent potential anti-tumor effect of DF and support further preclinical evaluation in MM models as well as ongoing clinical studies in this setting.

scholarly journals Borrelia burgdorferi Alters Its Gene Expression and Antigenic Profile in Response to CO2 Levels

2006 ◽  
Vol 189 (2) ◽  
pp. 437-445 ◽  
Author(s):  
Jenny A. Hyde ◽  
Jerome P. Trzeciakowski ◽  
Jonathan T. Skare
Keyword(s):  
Gene Expression ◽  
Protein Synthesis ◽  
Borrelia Burgdorferi ◽  
Growth Conditions ◽  
Etiologic Agent ◽  
Complex Life Cycle ◽  
Mammalian Host ◽  
Transcriptional Level ◽  
Virulence Determinants

ABSTRACT The etiologic agent of Lyme disease, Borrelia burgdorferi, must adapt to the distinct environments of its arthropod vector and mammalian host during its complex life cycle. B. burgdorferi alters gene expression and protein synthesis in response to temperature, pH, and other uncharacterized environmental factors. The hypothesis tested in this study is that dissolved gases, including CO2, serve as a signal for B. burgdorferi to alter protein production and gene expression. In this study we focused on characterization of in vitro anaerobic (5% CO2, 3% H2, 0.087 ppm O2) and microaerophilic (1% CO2, 3.48 ppm O2) growth conditions and how they modulate protein synthesis and gene expression in B. burgdorferi. Higher levels of several immunoreactive proteins, including BosR, NapA, DbpA, OspC, BBK32, and RpoS, were synthesized under anaerobic conditions. Previous studies demonstrated that lower levels of NapA were produced when microaerophilic cultures were purged with nitrogen gas to displace oxygen and CO2. In this study we identified CO2 as a factor contributing to the observed change in NapA synthesis. Specifically, a reduction in the level of dissolved CO2, independent of O2 levels, resulted in reduced NapA synthesis. BosR, DbpA, OspC, and RpoS synthesis was also decreased with the displacement of CO2. Quantitative reverse transcription-PCR indicated that the levels of the dbpA, ospC, and BBK32 transcripts are increased in the presence of CO2, indicating that these putative borrelial virulence determinants are regulated at the transcriptional level. Thus, dissolved CO2 may be an additional cue for borrelial host adaptation and gene regulation.

scholarly journals Active Translation Control of CD4 T Cell Activation by Regulatory T Cells

2021 ◽  
Author(s):  
Lomon So ◽  
Kazushige Obata-Ninomiya ◽  
Alex Hu ◽  
Virginia Muir ◽  
Ayako Takamori ◽  
...  
Keyword(s):  
T Cells ◽  
Protein Synthesis ◽  
Regulatory T Cells ◽  
Cell Activation ◽  
Peripheral Tolerance ◽  
Transcriptional Level ◽  
Translation Control ◽  
Teff Cell ◽  
Protein Synthesis Machinery ◽  
Global Protein Synthesis

Increased protein synthesis is a hallmark of lymphocyte activation. Regulatory T cells (Tregs) suppress the activation and subsequent effector functions of CD4 effector T cells (Teff). Molecular mechanisms that enforce suppression on CD4 Teff cell function are unclear. Control of CD4 Teff cell activation by Tregs has largely been defined at the transcriptional level, which does not reflect changes in post-transcriptional control. We found that Tregs suppressed activation-induced global protein synthesis in CD4 Teff cells prior to cell division. We analyzed genome-wide changes in the transcriptome and translatome of activated CD4 Teff cells using two independent approaches. We show that mRNAs encoding for the protein synthesis machinery are regulated at the level of translation in activated Teff cells. Strikingly, Tregs suppressed global protein synthesis of CD4 Teff cells by specifically inhibiting mRNAs of the translation machinery at the level of mTORC1-mediated translation control. Lastly, we found that the RNA helicase eIF4A inhibitor rocaglamide A (RocA) can suppress CD4 Teff activation in vitro to alleviate inflammatory CD4 Teff activation caused by acute Treg depletion in vivo. These data provide evidence that peripheral tolerance is enforced by Tregs, mediated by IL-10, through mRNA translational control in CD4 Teff cells. Therefore, therapeutic targeting of the protein synthesis machinery can mitigate inflammatory responses invoked by Treg loss of function.

Nerve growth factor regulates gene expression by several distinct mechanisms

1989 ◽  
Vol 9 (1) ◽  
pp. 135-143
Author(s):  
K O Cho ◽  
W C Skarnes ◽  
B Minsk ◽  
S Palmieri ◽  
L Jackson-Grusby ◽  
...  
Keyword(s):  
Gene Expression ◽  
Growth Factors ◽  
Nerve Growth Factor ◽  
Growth Factor ◽  
Cholera Toxin ◽  
Phorbol Myristate Acetate ◽  
Kinase Inhibitor ◽  
Transcriptional Level ◽  
Myristate Acetate ◽  
Nerve Growth

To help elucidate the mechanisms by which nerve growth factor (NGF) regulates gene expression, we have identified and studied four genes (a-2, d-2, d-4, and d-5) that are positively regulated by NGF in PC12 cells, including one (d-2) which has previously been identified as a putative transcription factor (NGF I-A). Three of these genes, including d-2, were induced very rapidly at the transcriptional level, but the relative time courses of transcription and mRNA accumulation of each of these three genes were distinct. The fourth gene (d-4) displayed no apparent increase in transcription that corresponded to the increase in its mRNA, suggesting that NGF may regulate its expression at a posttranscriptional level. Thus, NGF positively regulates gene expression by more than one mechanism. These genes could also be distinguished on the basis of their response to cyclic AMP. The expression of d-2 and a-2 was increased by cholera toxin and further augmented by NGF; however, cholera toxin not only failed to increase the levels of d-5 and d-4 mRNA but also actually inhibited the NGF-dependent increase. The expression of each of these genes, including d-2 (NGF I-A), was also increased by fibroblast growth factor, epidermal growth factor (EGF), phorbol myristate acetate, and in some cases insulin, showing that the regulation of these genes is not unique to NGF. Because each of these genes was expressed in response to phorbol myristate acetate and EGF, their expression may be necessary but is certainly not sufficient for neurite formation. The protein kinase inhibitor K-252a prevented the NGF-associated, but not the acidic FGF-associated, induction of d-2 and d-5 gene expression, suggesting that these two growth factors may regulate gene expression via different cellular pathways. The study of the regulation of the expression of these and other NGF-inducible genes should valuable new information concerning how NGF and other growth factors cause neural differentiation.

Abstract 13522: Vascular Healing in Drug-Eluting Stents: Differential Response of Limus-Eluting Stents in a Preclinical Model of Stent Implantation

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Kazuko Tajiri ◽  
Akira Sato ◽  
Tomoya Hoshi ◽  
Taizo Kimura ◽  
Yoshihiro Seo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Growth Factors ◽  
Stent Implantation ◽  
Late Phase ◽  
Bare Metal Stents ◽  
Metal Stents ◽  
Preclinical Model ◽  
Cobalt Chromium ◽  
Angiogenic Growth Factors ◽  
The Difference

Introduction: Recently, several clinical studies suggest that second-generation cobalt-chromium everolimus-eluting stents (CoCr-EES) lead to more favorable vascular healing than first-generation sirolimus-eluting stents (SES). However, it remains unclear the difference of vascular responses between CoCr-EES and SES. Methods: A total of 42 stents (14 bare-metal stents [BMS], 13 CoCr-EES, and 15 SES) were deployed in the iliac arteries of 31 Japanese White rabbits. Qquantitative real-time reverse-transcription polymerase chain reaction (QRT-PCR) analyses of the neointima were performed on days 30 and 90 after the stent implantation. Results: On day 30, the gene expression of the angiogenic growth factors (hepatocyte and basic fibroblast growth factors) and proteoglycans (decorin, biglycan and lumican) were more upregulated in the BMS than in the SES. However, at 90 days after stenting, the gene expression of proteoglycans and collagen was more upregulated in the SES than in the CoCr-EES and BMS. Conclusions: In contrast to CoCr-EES and BMS, SES strongly suppresses the vascular healing-related gene expression in the early phase, and then upregulates it in the late phase. These differences may lead to different clinical outcomes in humans.

scholarly journals mTOR signaling regulates myotube hypertrophy by modulating protein synthesis, rDNA transcription, and chromatin remodeling

2016 ◽  
Vol 311 (4) ◽  
pp. C663-C672 ◽  
Author(s):  
Ferdinand von Walden ◽  
Chang Liu ◽  
Nicole Aurigemma ◽  
Gustavo A. Nader
Keyword(s):  
Gene Expression ◽  
Protein Synthesis ◽  
Chromatin Remodeling ◽  
Muscle Hypertrophy ◽  
Muscle Protein ◽  
Mtor Signaling ◽  
Transcriptional Level ◽  
Rdna Transcription ◽  
Pol Ii ◽  
Pol I

Ribosome production is an early event during skeletal muscle hypertrophy and precedes muscle protein accretion. Signaling via mTOR is crucial for ribosome production and hypertrophy; however, the mechanisms by which it regulates these processes remain to be identified. Herein, we investigated the activation of mTOR signaling in hypertrophying myotubes and determined that mTOR coordinates various aspects of gene expression important for ribosome production. First, inhibition of translation with cycloheximide had a more potent effect on protein synthesis than rapamycin indicating that mTOR function during hypertrophy is not on general, but rather on specific protein synthesis. Second, blocking Pol II transcription had a similar effect as Rapamycin and, unexpectedly, revealed the necessity of Pol II transcription for Pol I transcription, suggesting that mTOR may regulate ribosome production also by controlling Class II genes at the transcriptional level. Third, Pol I activity is essential for rDNA transcription and, surprisingly, for protein synthesis as selective Pol I inhibition blunted rDNA transcription, protein synthesis, and the hypertrophic response of myotubes. Finally, mTOR has nuclear localization in muscle, which is not sensitive to rapamycin. Inhibition of mTOR signaling by rapamycin disrupted mTOR-rDNA promoter interaction and resulted in altered histone marks indicative of repressed transcription and formation of higher-order chromatin structure. Thus mTOR signaling appears to regulate muscle hypertrophy by affecting protein synthesis, Class I and II gene expression, and chromatin remodeling.

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