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Last update 23 Jan 2025

EIF4EBP1

Last update 23 Jan 2025

Basic Info

Synonyms

4E-BP1, eIF4E-binding protein 1, EIF4EBP1

+ [4]

Introduction

Repressor of translation initiation that regulates EIF4E activity by preventing its assembly into the eIF4F complex: hypophosphorylated form competes with EIF4G1/EIF4G3 and strongly binds to EIF4E, leading to repress translation. In contrast, hyperphosphorylated form dissociates from EIF4E, allowing interaction between EIF4G1/EIF4G3 and EIF4E, leading to initiation of translation. Mediates the regulation of protein translation by hormones, growth factors and other stimuli that signal through the MAP kinase and mTORC1 pathways.

Drugs associated with EIF4EBP1

RMC-5552

Target

EIF4EBP1 x mTORC1

Mechanism

EIF4EBP1 inhibitors [+1]

Active Org.

Revolution Medicines, Inc.

Originator Org.

Revolution Medicines, Inc.

Active Indication

Recurrent Glioblastoma

Inactive Indication-

Drug Highest PhasePhase 1

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with EIF4EBP1

NCT05557292

/ RecruitingPhase 1IIT

A Phase I/Ib, Open-Label, Dose-Escalation Study of RMC-5552 Monotherapy in Adult Subjects with Recurrent Glioblastoma

This phase I/Ib trial tests the side effects, best dose, tolerability, and effectiveness of RMC-5552 in treating patients with glioblastoma that has come back (recurrent). RMC-5552 is a type of medicine called an mechanistic target of rapamycin (mTOR) inhibitor. These types of drugs prevent the formation of a specific group of proteins called mTOR. This protein controls cancer cell growth, and the study doctors believe stopping mTOR from forming may help to kill tumor cells.

Start Date03 Apr 2023

Sponsor / Collaborator

The University of California, San Francisco

[+2]

NCT04774952

/ Active, not recruitingPhase 1

A Phase 1/1b, Open-Label, Multicenter, Dose-Escalation Study of RMC 5552 Monotherapy in Adult Subjects With Relapsed/Refractory Solid Tumors

The purpose of this study is to evaluate the safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) profiles of escalating doses of RMC-5552 monotherapy in adult participants with relapsed/refractory solid tumors and to identify the recommended Phase 2 dose (RP2D).

Start Date07 Apr 2021

Sponsor / Collaborator

Revolution Medicines, Inc.

100 Clinical Results associated with EIF4EBP1

100 Translational Medicine associated with EIF4EBP1

0 Patents (Medical) associated with EIF4EBP1

2,850

Literatures (Medical) associated with EIF4EBP1

01 Mar 2025·Journal of Hazardous Materials

Sulfur dioxide increases testosterone biosynthesis by activating ERK1/2 pathway and disrupting autophagy in Leydig cells

Article

Author: Xiao, Haoran ; Feng, Zhiyuan ; Bai, Jian ; Li, Rui ; Zhang, Jianhai ; Liu, Sha ; Shi, Yan ; Li, Xiang ; Liang, Chen ; Zhang, Xinyue ; Han, Yongli ; Wang, Jundong ; Li, Zirou

Sulfur dioxide (SO₂) is a ubiquitous environmental pollutant that has been shown to be toxic to the male reproductive system, but the underlying mechanism remains unclear. Therefore, the SO₂-treated mice and primary Leydig cell models were established to investigate the effects of SO₂ on the production of testosterone and its specific mechanism. The results demonstrated that SO₂ activated the ERK1/2 signaling pathway, leading to increased key proteins expression of testosterone biosynthesis and elevated testosterone levels. The addition of ERK1/2 inhibitor U0126 attenuated SO₂-induced increases in key testosterone biosynthetic gene mRNA levels of Star, Cyp17a1, Hsd3b1, and testosterone. Low doses of SO₂ reduced the expression of BECLIN1 and LC3 proteins, increased P-4E-BP1 protein expression, and decreased autophagy in Leydig cells. Moreover, increasing doses of SO₂ correlate with enhanced Leydig cell autophagy and testosterone levels initially. However, increasing the dose of SO₂ resulted in a significant decrease in cell viability and ultimately decreased testosterone levels. These findings suggest that SO₂ promotes testosterone production by activating ERK1/2 and disrupting autophagy. This study enriched the dose-effect relationship of SO₂ on the male reproductive system and provided a theoretical reference for us to have a comprehensive and dynamic understanding of the SO₂ toxic mechanism.

03 Jan 2025·Journal of Proteome Research

Quantitative Top-down Proteomics Revealed Kinase Inhibitor-Induced Proteoform-Level Changes in Cancer Cells

Article

Author: Burgett, Anthony ; Guo, Yanting ; Wu, Si ; Chowdhury, Trishika ; Zhao, Zhitao ; Cupp-Sutton, Kellye A. ; Gao, Kevin

Quantitative analysis of proteins and their post-translational modifications (PTMs) in complex biological samples is critical to understanding cellular biology as well as disease detection and treatment. Top-down proteomics methods provide a "bird's eye" view of the proteome by directly detecting and quantifying intact proteoforms. Here, we developed a high-throughput quantitative top-down proteomics platform to probe intact proteoform and phosphoproteoform abundance changes in HeLa cells as a result of treatment with staurosporine (STS), a broad-spectrum kinase inhibitor. In total, we identified and quantified 1187 proteoforms from 215 proteoform families. Among them, 55 proteoforms from 37 proteoform families were significantly changed upon STS treatment. These proteoforms were primarily related to catabolic, metabolic, and apoptotic pathways that are expected to be impacted as a result of kinase inhibition. In addition, we manually evaluated 25 proteoform families that expressed one or more phosphorylated proteoforms. We observed that phosphorylated proteoforms in the same proteoform family, such as eukaryotic initiation factor 4E binding protein 1 (4EBP1), were differentially regulated relative to the unphosphorylated proteoforms. Combining relative profiling of proteoforms within these proteoform families with individual proteoform profiling results in a more comprehensive picture of STS treatment-induced proteoform abundance changes that cannot be achieved using bottom-up methods.

01 Jan 2025·Life Sciences

Poststroke hyperglycemia dysregulates cap-dependent translation in neural cells

Article

Author: Geldenhuys, Werner J ; Huber, Jason D ; BaniArdalan, Soha ; Ghahremani, Pargol Tayefeh ; Parveen, Arshi ; Ishrat, Tauheed ; Alehossein, Parsa ; Nasoohi, Sanaz ; Jorjani, Masoumeh ; Brown, Candice M

AIMSPost stroke hyperglycemia has been shown to deter functional recovery. Earlier findings have indicated the cap-dependent translation regulator 4E-BP1 is detrimentally upregulated in hyperglycemic conditions. The present study aims to test the hypothesis that hyperglycemic ischemic reperfusion injury (I/R) affects normal protein translation poststroke.METHODSRat primary cortical neurons (PCNs) were exposed to oxygen glucose deprivation (OGD) followed by increasing glucose concentration (0, 5, 10, 25 mM) at reoxygenation. In vivo, adult rats were subjected to two hours transient distal middle cerebral artery occlusion (t-dMCAO) and hyperglycemic reperfusion.KEY FINDINGSIn PCN cultures, high glucose levels impaired normal neurite growth at 24 h I/R where it drastically depressed S6 ribosomal protein phosphorylation at serine 235/236 residues in 40S ribosomal subunit. This concurred with substantial hypoxia inducible factor-1α (HIF-1α) destabilization and sustained vascular endothelial growth factor (VEGF). Our immunoblotting findings indicated HIF-1α stabilization and AMPK activation rely on glucose availability. Incremental glucose concentrations above the physiological levels, induced a shift towards 4E-BP1, eIF-4E hypo-phosphorylated forms leading to reduced eIF-4E availability and efficacy, as the key to recruit the 40S ribosomal subunit to the 5' end of mRNA. In vivo, immunostaining of t-dMCAO rat brains showed remarkable decrease in phosphorylated 4E-BP1 and particularly s6 ribosomal protein in the marginal cortical tissue of hyperglycemic compared to normoglycemic animals.SIGNIFICANCEThese findings suggest a remarkable association between hyperglycemic I/R injury with dysregulated cap-dependent translation poststroke. Further loss/gain of function experiment may elucidate the potential therapeutic targets in regulation of HIF-1α/translation in hyperglycemic I/R injury.

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