{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n eIF4G2, also known as DAP5, NAT1, or p97, is a member of the eIF4G family that plays a central role in cap‐independent translation. Unlike its canonical counterpart eIF4G1, eIF4G2 lacks an eIF4A‐binding site and is specialized to recruit ribosomes for the internal ribosome entry site (IRES)–dependent translation of specific mRNAs. Studies have shown that full‐length eIF4G2 is abundantly expressed in proliferating cells, where it associates with ribosomes and positively regulates overall protein synthesis, cell cycle progression, and survival."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In particular, eIF4G2 promotes the translation of key mRNAs—for example, driving the production of distinct p53 isoforms from its IRES, thereby influencing downstream stress‐response pathways."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Moreover, its expression is tightly controlled at the translational level. Evolutionarily conserved features such as non‐AUG (e.g., GUG) initiation, dictated by optimal Kozak contexts and specific mRNA secondary structures, allow precise regulation of eIF4G2 synthesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " In addition, microRNAs have emerged as critical regulators of eIF4G2. For example, miR‑139 can repress eIF4G2 expression—leading to reduced global protein synthesis and modulation of cell cycle inhibitors—while miR‑379 similarly targets its 3′UTR to influence chemotherapeutic responses."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n eIF4G2 is also subject to regulation by RNA‐binding proteins. Notably, estrogen receptor α (ERα) functions as a noncanonical RNA‐binding protein that can enhance the translation of eIF4G2 mRNA, thereby contributing to stress adaptation and therapeutic resistance in breast cancer."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " In the context of stem cell biology, eIF4G2‐mediated cap‐independent translation is crucial for the downregulation of pluripotency genes and the proper induction of differentiation programs—underscoring its importance in cell fate decisions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Further adding to its complexity, alternative RNA species derived from the EIF4G2 gene, such as the circular RNA circEIF4G2, have been implicated in promoting oncogenic properties in cervical cancer by acting as microRNA sponges."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " In addition, eIF4G2 participates in broader signaling networks—for example, its downregulation has been linked with compromised GNA13–ERK1–eIF4G2 signaling in the prefrontal cortex, a change that may contribute to impaired neuronal axon formation and synaptic plasticity observed in schizophrenia."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Together, these studies highlight the multifaceted functions of eIF4G2 in modulating both global and selective mRNA translation. Its regulation by noncanonical initiation mechanisms, microRNAs, and RNA‐binding proteins as well as its involvement in cell proliferation, stress adaptation, differentiation, and disease pathogenesis illustrate its critical role in cellular homeostasis and as a potential therapeutic target.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Sang Hyun Lee, Frank McCormick "}, {"type": "b", "children": [{"type": "t", "text": "p97/DAP5 is a ribosome-associated factor that facilitates protein synthesis and cell proliferation by modulating the synthesis of cell cycle proteins."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO J (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/sj.emboj.7601268"}], "href": "https://doi.org/10.1038/sj.emboj.7601268"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16932749"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16932749"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "S Weingarten-Gabbay, D Khan, N Liberman, et al. 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