{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n GSPT1, also known as eRF3a, is a multifunctional protein that plays a central role in translation termination by functioning as a GTPase in complex with eRF1 to promote accurate stop‐codon recognition and peptidyl‐tRNA hydrolysis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In addition to its canonical function in translation, a processed isoform of GSPT1 harbors a conserved IAP‐binding motif that facilitates caspase activation by promoting IAP ubiquitination and proteasomal degradation, thereby potentiating apoptotic signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " Moreover, GSPT1 has emerged as an important regulator in oncogenesis: its expression is modulated by microRNAs (e.g., miR‑144) and transcriptional regulators such as ID1, with alterations in GSPT1 levels contributing to enhanced proliferation, invasion, and migration in colorectal and other cancers."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Furthermore, polymorphic variations in its N‑terminal GGC repeat, particularly the longer (12‐GGC) allele, are correlated with increased mRNA expression and have been associated with heightened cancer risk in various tumor types."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " In the context of protein quality control and drug response, GSPT1 is also targeted for CRL4CRBN‐mediated degradation—a process that is relevant to the action of immunomodulatory drugs in hematologic malignancies."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " Finally, additional interactions of GSPT1 with factors such as RNase L reveal its capacity to modulate translation fidelity by affecting stop codon readthrough and frameshifting, while its enhancement of ASK1 kinase activity further links GSPT1 to the regulation of apoptotic cascades."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these findings underscore the dual roles of GSPT1 in ensuring proper termination during protein biosynthesis and in modulating apoptosis and cell cycle progression, thereby positioning it as a critical nexus in both normal cellular homeostasis and oncogenic processes.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Céline Chauvin, Samia Salhi, Catherine Le Goff, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Involvement of human release factors eRF3a and eRF3b in translation termination and regulation of the termination complex formation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biol (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/MCB.25.14.5801-5811.2005"}], "href": "https://doi.org/10.1128/MCB.25.14.5801-5811.2005"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15987998"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15987998"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Guennadi Kozlov, Kalle Gehring "}, {"type": "b", "children": [{"type": "t", "text": "Molecular basis of eRF3 recognition by the MLLE domain of poly(A)-binding protein."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0010169"}], "href": "https://doi.org/10.1371/journal.pone.0010169"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20418951"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20418951"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Ramesh Hegde, Srinivasa M Srinivasula, Pinaki Datta, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The polypeptide chain-releasing factor GSPT1/eRF3 is proteolytically processed into an IAP-binding protein."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M303179200"}], "href": "https://doi.org/10.1074/jbc.M303179200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12865429"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12865429"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "J A Lee, J E Park, D H Lee, et al. "}, {"type": "b", "children": [{"type": "t", "text": "G1 to S phase transition protein 1 induces apoptosis signal-regulating kinase 1 activation by dissociating 14-3-3 from ASK1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/sj.onc.1210740"}], "href": "https://doi.org/10.1038/sj.onc.1210740"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17700517"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17700517"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Ruilin Xiao, Cui Li, Baofeng Chai "}, {"type": "b", "children": [{"type": "t", "text": "miRNA-144 suppresses proliferation and migration of colorectal cancer cells through GSPT1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biomed Pharmacother (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.biopha.2015.08.006"}], "href": "https://doi.org/10.1016/j.biopha.2015.08.006"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26349975"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26349975"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Sajitha Nair, Namrata Bora-Singhal, Deepak Perumal, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Nicotine-mediated invasion and migration of non-small cell lung carcinoma cells by modulating STMN3 and GSPT1 genes in an ID1-dependent manner."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cancer (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/1476-4598-13-173"}], "href": "https://doi.org/10.1186/1476-4598-13-173"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25028095"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25028095"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Joana Malta-Vacas, Celine Chauvin, Lucilia Gonçalves, et al. "}, {"type": "b", "children": [{"type": "t", "text": "eRF3a/GSPT1 12-GGC allele increases the susceptibility for breast cancer development."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncol Rep (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3892/or_00000387"}], "href": "https://doi.org/10.3892/or_00000387"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19424636"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19424636"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Joana Malta-Vacas, Paula Ferreira, Carolino Monteiro, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Differential expression of GSPT1 GGCn alleles in cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Genet Cytogenet (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cancergencyto.2009.08.010"}], "href": "https://doi.org/10.1016/j.cancergencyto.2009.08.010"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19963113"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19963113"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Thang Van Nguyen, Jing Li, Chin-Chun Jean Lu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "p97/VCP promotes degradation of CRBN substrate glutamine synthetase and neosubstrates."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1700949114"}], "href": "https://doi.org/10.1073/pnas.1700949114"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28320958"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28320958"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Florence Le Roy, Tamim Salehzada, Catherine Bisbal, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A newly discovered function for RNase L in regulating translation termination."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Struct Mol Biol (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nsmb944"}], "href": "https://doi.org/10.1038/nsmb944"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15908960"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15908960"}]}]}]}