scholarly journals Systematic Analysis of Gene Expression Alteration and Co-Expression Network of Eukaryotic Initiation Factor 4A-3 in Cancer

2018 ◽  
Vol 9 (24) ◽  
pp. 4568-4577 ◽  
Author(s):  
Yan Lin ◽  
Jinyan Zhang ◽  
Junying Cai ◽  
Rong Liang ◽  
Guoying Chen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Initiation Factor ◽  
Eukaryotic Initiation Factor ◽  
Systematic Analysis ◽  
Gene Expression Alteration

scholarly journals Activating Transcription Factor 3 Is Integral to the Eukaryotic Initiation Factor 2 Kinase Stress Response

2004 ◽  
Vol 24 (3) ◽  
pp. 1365-1377 ◽  
Author(s):  
Hao-Yuan Jiang ◽  
Sheree A. Wek ◽  
Barbara C. McGrath ◽  
Dan Lu ◽  
Tsonwin Hai ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Amino Acid ◽  
Stress Response ◽  
Amino Acid Starvation ◽  
Initiation Factor ◽  
Activating Transcription Factor 3 ◽  
Eukaryotic Initiation Factor ◽  
Initiation Factor 2 ◽  
Activating Transcription Factor

ABSTRACT In response to environmental stress, cells induce a program of gene expression designed to remedy cellular damage or, alternatively, induce apoptosis. In this report, we explore the role of a family of protein kinases that phosphorylate eukaryotic initiation factor 2 (eIF2) in coordinating stress gene responses. We find that expression of activating transcription factor 3 (ATF3), a member of the ATF/CREB subfamily of basic-region leucine zipper (bZIP) proteins, is induced in response to endoplasmic reticulum (ER) stress or amino acid starvation by a mechanism requiring eIF2 kinases PEK (Perk or EIF2AK3) and GCN2 (EIF2AK4), respectively. Increased expression of ATF3 protein occurs early in response to stress by a mechanism requiring the related bZIP transcriptional regulator ATF4. ATF3 contributes to induction of the CHOP transcriptional factor in response to amino acid starvation, and loss of ATF3 function significantly lowers stress-induced expression of GADD34, an eIF2 protein phosphatase regulatory subunit implicated in feedback control of the eIF2 kinase stress response. Overexpression of ATF3 in mouse embryo fibroblasts partially bypasses the requirement for PEK for induction of GADD34 in response to ER stress, further supporting the idea that ATF3 functions directly or indirectly as a transcriptional activator of genes targeted by the eIF2 kinase stress pathway. These results indicate that ATF3 has an integral role in the coordinate gene expression induced by eIF2 kinases. Given that ATF3 is induced by a very large number of environmental insults, this study supports involvement of eIF2 kinases in the coordination of gene expression in response to a more diverse set of stress conditions than previously proposed.

scholarly journals Mutations Causing Childhood Ataxia with Central Nervous System Hypomyelination Reduce Eukaryotic Initiation Factor 2B Complex Formation and Activity

2004 ◽  
Vol 24 (6) ◽  
pp. 2352-2363 ◽  
Author(s):  
Jonathan P. Richardson ◽  
Sarah S. Mohammad ◽  
Graham D. Pavitt
Keyword(s):  
Gene Expression ◽  
Central Nervous System ◽  
Nervous System ◽  
Prion Diseases ◽  
State Level ◽  
Initiation Factor ◽  
Temperature Sensitive ◽  
Eukaryotic Initiation Factor ◽  
Brain Disorder ◽  
Childhood Ataxia

ABSTRACT Childhood ataxia with central nervous system hypomyelination (CACH), or vanishing white matter leukoencephalopathy (VWM), is a fatal brain disorder caused by mutations in eukaryotic initiation factor 2B (eIF2B). eIF2B is essential for protein synthesis and regulates translation in response to cellular stresses. We performed mutagenesis to introduce changes equivalent to 12 human CACH/VWM mutations in three subunits of the equivalent factor from yeast (Saccharomyces cerevisiae) and analyzed effects on cell growth, translation, and gene expression in response to stresses. None of the mutations is lethal or temperature sensitive, but almost all confer some defect in eIF2B function significant enough to alter growth or gene expression under normal or stress conditions. Biochemical analyses indicate that mutations analyzed in eIF2Bα and -ε reduce the steady-state level of the affected subunit, while the most severe mutant tested, eIF2BβV341D (human eIF2BβV316D), forms complexes with reduced stability and lower eIF2B activity. eIF2Bδ is excluded from eIF2BβV341D complexes. eIF2Bβv341D function can be rescued by overexpression of eIF2Bδ alone. Our findings imply CACH/VWM mutations do not specifically impair responses to eIF2 phosphorylation, but instead cause protein structure defects that impair eIF2B activity. Altered protein folding is characteristic of other diseases, including cystic fibrosis and neurodegenerative disorders such as Huntington, Alzheimer's, and prion diseases.

scholarly journals Inhibition of HIV-1 gene expression by Ciclopirox and Deferiprone, drugs that prevent hypusination of eukaryotic initiation factor 5A

Retrovirology ◽  
2009 ◽  
Vol 6 (1) ◽  
pp. 90 ◽  
Author(s):  
Mainul Hoque ◽  
Hartmut M Hanauske-Abel ◽  
Paul Palumbo ◽  
Deepti Saxena ◽  
Darlene D'Alliessi Gandolfi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Initiation Factor ◽  
Eukaryotic Initiation Factor ◽  
Hiv 1

scholarly journals Eukaryotic initiation factor 5A is a cellular target of the human immunodeficiency virus type 1 Rev activation domain mediating trans-activation.

1993 ◽  
Vol 123 (6) ◽  
pp. 1309-1320 ◽  
Author(s):  
M Ruhl ◽  
M Himmelspach ◽  
G M Bahr ◽  
F Hammerschmid ◽  
H Jaksche ◽  
...  
Keyword(s):  
Gene Expression ◽  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Initiation Factor ◽  
Eukaryotic Initiation Factor ◽  
Activation Domain ◽  
Immunodeficiency Virus ◽  
Hiv 1

Expression of human immunodeficiency virus type 1 (HIV-1) structural proteins requires the presence of the viral trans-activator protein Rev. Rev is localized in the nucleus and binds specifically to the Rev response element (RRE) sequence in viral RNA. Furthermore, the interaction of the Rev activation domain with a cellular cofactor is essential for Rev function in vivo. Using cross-linking experiments and Biospecific Interaction Analysis (BIA) we identify eukaryotic initiation factor 5A (eIF-5A) as a cellular factor binding specifically to the HIV-1 Rev activation domain. Indirect immunofluorescence studies demonstrate that a significant fraction of eIF-5A localizes to the nucleus. We also provide evidence that Rev transactivation is functionally mediated by eIF-5A in Xenopus oocytes. Furthermore, we are able to block Rev function in mammalian cells by antisense inhibition of eIF-5A gene expression. Thus, regulation of HIV-1 gene expression by Rev involves the targeting of RRE-containing RNA to components of the cellular translation initiation complex.

Translational dysregulation in cancer: eIF4A isoforms and sequence determinants of eIF4A dependence

2015 ◽  
Vol 43 (6) ◽  
pp. 1227-1233 ◽  
Author(s):  
Farheen Raza ◽  
Joseph Alexander Waldron ◽  
John Le Quesne
Keyword(s):  
Gene Expression ◽  
Initiation Factor ◽  
Transformed Cells ◽  
Helicase Activity ◽  
Eukaryotic Initiation Factor ◽  
Malignant Phenotype ◽  
Detailed Understanding ◽  
Specific Mrnas ◽  
Global Increase ◽  
Made In

The malignant phenotype is largely the consequence of dysregulated gene expression. Transformed cells depend upon not just a global increase in protein synthesis but an altered translational landscape in which pro-oncogenic mRNAs are translationally up-regulated. Such mRNAs have been shown to possess longer and more structured 5′-UTRs requiring high levels of eukaryotic initiation factor 4A (eIF4A) helicase activity for efficient translation. As such there is a developing focus on targeting eIF4A as a cancer therapy. In order for such treatments to be successful, we must develop a detailed understanding of the mechanisms which make specific mRNAs more dependent on eIF4A activity than others. It is also crucial to fully characterize the potentially distinct roles of eIF4A1 and eIF4A2, which until recently were thought to be functionally interchangeable. This review will highlight the recent advances made in this field that address these issues.

Sign in / Sign up

Export Citation Format

Share Document