Last update 01 Nov 2024

EIF4G1

Last update 01 Nov 2024

Basic Info

Synonyms

eIF-4-gamma 1, eIF-4G 1, eIF-4G1

+ [7]

Introduction

Component of the protein complex eIF4F, which is involved in the recognition of the mRNA cap, ATP-dependent unwinding of 5'-terminal secondary structure and recruitment of mRNA to the ribosome (PubMed:29987188). Exists in two complexes, either with EIF1 or with EIF4E (mutually exclusive) (PubMed:29987188). Together with EIF1, is required for leaky scanning, in particular for avoiding cap-proximal start codon (PubMed:29987188). Together with EIF4E, antagonizes the scanning promoted by EIF1-EIF4G1 and locates the start codon (through a TISU element) without scanning (PubMed:29987188). As a member of the eIF4F complex, required for endoplasmic reticulum stress-induced ATF4 mRNA translation (PubMed:29062139).

Drugs associated with EIF4G1

4EGI-1

Target

EIF4E x EIF4G1

Mechanism

EIF4E inhibitors [+1]

Active Org.

Harvard Medical School

Originator Org.

Harvard Medical School

Active Indication

Neoplasms

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

FEP-633

Target

EIF4E x EIF4G1

Mechanism

EIF4E inhibitors [+1]

Active Org.

PRISM BioLab Co., Ltd.

Originator Org.

PRISM BioLab Co., Ltd.

Active Indication

Bladder Cancer

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

SBI-0640756

Target

EIF4G1

Mechanism

EIF4G1 inhibitors

Active Org.-

Originator Org.

Sanford Burnham Prebys Medical Discovery Institute

Active Indication-

Inactive Indication

Melanoma

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with EIF4G1

100 Translational Medicine associated with EIF4G1

0 Patents (Medical) associated with EIF4G1

1,473

Literatures (Medical) associated with EIF4G1

01 Nov 2024·Gut

KLHL21 suppresses gastric tumourigenesis via maintaining STAT3 signalling equilibrium in stomach homoeostasis

Article

Author: Huang, Xiao-Bo ; Wang, Jia-Bin ; Lu, Jun ; Wang, Hua-Gen ; Xie, Jian-Wei ; Huang, Qiang ; Zheng, Chao-Hui ; Huang, Zhi-Hong ; Li, Ping ; Huang, Ze-Ning ; Jiang, Mei-Chen ; Zhong, Qing ; Lin, Jian-Xian ; Huang, Chang-Ming ; Lin, Mi ; Liu, Zhi-Yu ; Que, Jian-Wen ; Xu, Kai-Xiang ; Li, Yi-Fan ; Chen, Qi-Yue ; Zheng, Hua-Long

ObjectivePrecancerous metaplasia transition to dysplasia poses a risk for subsequent intestinal-type gastric adenocarcinoma. However, the molecular basis underlying the transformation from metaplastic to cancerous cells remains poorly understood.Design An integrated analysis of genes associated with metaplasia, dysplasia was conducted, verified and characterised in the gastric tissues of patients by single-cell RNA sequencing and immunostaining. Multiple mouse models, including homozygous conditional knockout Klhl21 -floxed mice, were generated to investigate the role of Klhl21 deletion in stemness, DNA damage and tumour formation. Mass-spectrometry-based proteomics and ribosome sequencing were used to elucidate the underlying molecular mechanisms. Results Kelch-like protein 21 (KLHL21) expression progressively decreased in metaplasia, dysplasia and cancer. Genetic deletion of Klhl21 enhances the rapid proliferation of Mist1 + cells and their descendant cells. Klhl21 loss during metaplasia facilitates the recruitment of damaged cells into the cell cycle via STAT3 signalling. Increased STAT3 activity was confirmed in cancer cells lacking KLHL21, boosting self-renewal and tumourigenicity. Mechanistically, the loss of KLHL21 promotes PIK3CB mRNA translation by stabilising the PABPC1-eIF4G complex, subsequently causing STAT3 activation. Pharmacological STAT3 inhibition by TTI-101 elicited anticancer effects, effectively impeding the transition from metaplasia to dysplasia. In patients with gastric cancer, low levels of KLHL21 had a shorter survival rate and a worse response to adjuvant chemotherapy. ConclusionsOur findings highlighted that KLHL21 loss triggers STAT3 reactivation through PABPC1-mediated PIK3CB translational activation, and targeting STAT3 can reverse preneoplastic metaplasia in KLHL21-deficient stomachs.

07 Oct 2024·GENETICS

Tdh3 and Rom2 are functional modulators of a conserved condensate-resident RNA-binding protein, Scd6, in Saccharomyces cerevisiae

Article

Author: Rajyaguru, Purusharth I ; Dhage, Riya ; Togra, Chitra

AbstractArginine–glycine–glycine motif proteins play a crucial role in determining mRNA fate. Suppressor of clathrin deficiency 6 (Scd6) is a conserved arginine–glycine–glycine motif containing ribonucleoprotein (RNP) condensate–resident, translation repressor, and decapping activator protein in Saccharomyces cerevisiae. Identifying protein factors that can modulate Scd6 function is critical to understanding the regulation of mRNA fate by Scd6. In this study, using an approach that combined mRNA tethering assay with flow cytometry, we screened 50 genes for their role in modulating the translation repression activity of Scd6. We identified 8 conserved modulators with human homologs. Of these, we further characterized in detail guanine nucleotide exchange factor Rho1 multicopy suppressor 2 (Rom2) and glycolytic enzyme triose phosphate dehydrogenase 3 (Tdh3), which, respectively, impede and promote translation repression activity of Scd6. Our study reveals that Rom2 negatively regulates the arginine methylation of Scd6 and antagonizes its localization to P-bodies. Tdh3, on the other hand, promotes Scd6 interaction with Hmt1, thereby promoting the arginine methylation of Scd6 and enhanced eIF4G1 interaction, which is known to promote its repression activity. Identifying these novel modulators provides exciting new insights into the role of a metabolic enzyme of the glycolytic pathway and guanine nucleotide exchange factor implicated in the cell wall integrity pathway in regulating Scd6 function and, thereby, cytoplasmic mRNA fate.

01 Oct 2024·Journal of Biological Chemistry

Mechanistic differences in eukaryotic initiation factor requirements for eIF4GI-driven cap-independent translation of structured mRNAs

Article

Author: Goss, Dixie J. ; Goss, Dixie J ; Haizel, Solomon A ; Saha, Baishakhi ; Haizel, Solomon A.

Protein translation is globally downregulated under stress conditions. Many proteins that are synthesized under stress conditions use a cap-independent translation initiation pathway. A subset of cellular mRNAs that encode for these proteins contain stable secondary structures within their 5' untranslated region (5'UTR), and initiate cap-independent translation using elements called Cap-Independent Translation Enhancers (CITEs) or Internal Ribosome Entry Sites (IRESs) within their 5'UTRs. The interaction among initiation factors such as eIF4E, eIF4A and eIF4GI, especially in regulating the eIF4F complex during non-canonical translation initiation of different 5'UTR mRNAs, is poorly understood. Here, equilibrium-binding assays, circular dichroism studies and in vitro translation assays were employed to elucidate the recruitment of these initiation factors to the highly structured 5'UTRs of fibroblast-growth factor 9 (FGF-9) and hypoxia inducible factor 1 subunit alpha (HIF-1α) encoding mRNAs. We showed that eIF4A and eIF4E enhanced eIF4GI's binding affinity to the uncapped 5'UTR of HIF-1α mRNA, inducing conformational changes in the protein/RNA complex. In contrast, these factors have no effect on the binding of eIF4GI to the 5'UTR of FGF-9 mRNA. Recently, Izidoro, M. S. et al. reported that the interaction of 42nt unstructured RNA to human eIF4F complex is dominated by eIF4E and ATP-bound state of eIF4A. Here we show that structured 5'UTR mRNA binding mitigates this requirement. Based on these observations, we describe two possible cap-independent translation mechanisms for FGF-9 and HIF-1α encoding mRNAs employed by cells to mitigate cellular stress conditions.

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EIF4G1

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