EIF4EBP3 Human
Description
Molecular Structure and Functional Domains
EIF4EBP3 shares 57–59% sequence homology with other family members (EIF4EBP1 and EIF4EBP2), particularly in the central eIF4E-binding motif . Key structural features include:
Regulation of Translation
EIF4EBP3 inhibits cap-dependent translation by sequestering EIF4E, preventing its interaction with eIF4G and subsequent ribosome recruitment . This repression is critical under stress conditions (e.g., serum starvation), where it modulates cell growth and survival .
mTORC1 Signaling Integration
EIF4EBP3 is transcriptionally induced by TFE3 during prolonged mTORC1 inhibition, acting as a compensatory mechanism to sustain translational control . Unlike EIF4EBP1/2, which are regulated via phosphorylation, EIF4EBP3 expression is driven by mTORC1-TFE3 signaling .
Activity-Dependent Muscle Growth
In zebrafish, the homolog eif4ebp3L regulates myofibrilogenesis by suppressing mef2ca mRNA translation during muscle inactivity, linking mechanical activity to protein synthesis .
Tumor Suppressor Activity
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Gastric Cancer: Promoter methylation silences EIF4EBP3, correlating with advanced stage, liver metastasis, and poor survival. Restoring EIF4EBP3 inhibits proliferation and invasion via β-catenin downregulation .
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Cervical Cancer: EIF4EBP3 overexpression induces apoptosis and reduces viability in C33a and SiHa cells, with ultrastructural changes (organelle loss, apoptotic bodies) observed .
Biomarker Potential
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Reduced EIF4EBP3 levels in peripheral blood cells serve as a marker for CDC73-related parathyroid tumors, distinguishing them from MEN1-associated cases .
Epigenetic and Transcriptional Regulation
Therapeutic Implications
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mTOR Inhibitor Resistance: CRISPR-Cas9 knockout of EIF4EBP3 mitigates mTOR inhibitor effects on translation and proliferation, highlighting its role in drug response .
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Targeting Methylation: Demethylating agents could reactivate EIF4EBP3 in gastric cancer, offering a strategy to curb metastasis .
Comparative Analysis with Other EIF4EBPs
| Feature | EIF4EBP3 | EIF4EBP1/2 |
|---|---|---|
| Regulation | Transcriptional (TFE3-dependent) | Post-translational (phosphorylation) |
| Stress Response | Induced during prolonged mTORC1 inhibition | Rapidly phosphorylated upon mTORC1 activation |
| Cancer Role | Tumor suppressor in gastric/parathyroid cancers | Context-dependent oncogenic roles |
Product Specs
Product Science Overview
eIF4E is a key player in the initiation of translation, the process by which ribosomes synthesize proteins from mRNA. It recognizes and binds to the 7-methylguanosine cap structure at the 5’ end of mRNAs, facilitating the recruitment of ribosomes to the mRNA . This cap-binding activity is essential for the formation of the eIF4F complex, which includes eIF4E, eIF4G (a scaffolding protein), and eIF4A (an RNA helicase) .
The activity of eIF4E is tightly regulated by 4E-BPs. Under normal conditions, 4E-BPs bind to eIF4E, preventing its interaction with eIF4G and thus inhibiting the formation of the eIF4F complex . This inhibition is relieved when 4E-BPs are phosphorylated by the mechanistic target of rapamycin complex 1 (mTORC1) in response to various signals such as nutrients, growth factors, and energy status . Phosphorylation of 4E-BPs causes their dissociation from eIF4E, allowing eIF4E to bind to eIF4G and initiate cap-dependent translation .
4E-BP3, like its family members, contains multiple phosphorylation sites that are targeted by mTORC1 . The phosphorylation of these sites is hierarchical, meaning that certain sites must be phosphorylated before others . This hierarchical phosphorylation is crucial for the regulation of 4E-BP3’s binding affinity to eIF4E and its subsequent release .
Recombinant 4E-BP3 is a form of the protein that is produced through recombinant DNA technology. This involves inserting the gene encoding 4E-BP3 into a host organism, such as bacteria or yeast, which then expresses the protein. Recombinant proteins are often used in research to study protein function, interactions, and regulation under controlled conditions.
The study of 4E-BP3 and its interactions with eIF4E is important for understanding the regulation of protein synthesis. Dysregulation of this pathway is implicated in various diseases, including cancer, where increased eIF4E activity can lead to the overproduction of proteins that promote tumor growth . By studying 4E-BP3, researchers aim to develop therapeutic strategies that can modulate eIF4E activity and potentially treat diseases associated with its dysregulation.
