{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTP73, a gene encoding a protein that shares high structural and functional homology with p53, plays pivotal roles in tumor suppression and embryonic development. TP73 is expressed in a highly regulated manner during normal development—from ensuring proper blastocyst mitosis and maternal reproduction to contributing to differentiation of various tissues—and its deregulation has been implicated in several human malignancies. Notably, monoallelic expression of p73 is observed in tumors such as neuroblastoma and head and neck cancers, supporting its candidacy as a tumor suppressor distinct from p53 despite some overlapping functions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn response to DNA damage and cellular stress, TP73 functions as a transcription factor that activates key proapoptotic target genes—including those encoding PUMA, Bax, CD95, and other Bcl-2 family members—to induce cell cycle arrest and apoptosis via both the mitochondrial and death receptor pathways. Furthermore, TP73 is transcriptionally induced by factors such as E2F1 and is acetylated by p300 (in a process promoted by c-Abl activation) to fine-tune its apoptotic potential. These activities underscore its central role in mediating chemo‐induced cell death and in integrating signals from DNA damage response pathways."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nTP73’s activity and stability are delicately modulated by multiple post‐translational modifications. Itch, a HECT domain ubiquitin ligase, selectively ubiquitinates TP73 to promote its proteasomal degradation, whereas phosphorylation events mediated by kinases such as c‐Abl, protein kinase C δ, and Aurora kinase A (which phosphorylates TP73 at Ser-289 or Ser235) have been shown to either enhance its transcriptional activity or lead to its cytoplasmic sequestration. Additional layers of regulation include Pin1-mediated conformational changes, PIAS-1–dependent sumoylation, and even NEDD8 modification that together affect TP73’s subcellular localization and ability to activate downstream apoptotic programs."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "14", "end_ref": "17"}, {"type": "fg_f", "ref": "10"}, {"type": "fg_fs", "start_ref": "18", "end_ref": "20"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nThe TP73 gene produces multiple isoforms with distinct, and sometimes antagonistic, functions. The full-length transactivation-competent TA isoforms exhibit classical tumor suppressor activity by promoting apoptosis and cell cycle arrest, whereas the N-terminally truncated ΔN isoforms can act as dominant-negative inhibitors of both p53 and TA-TP73. This balance between isoforms is critical in determining cellular outcomes, with aberrant ΔN expression being associated with chemoresistance and poorer prognosis in cancers such as head and neck and triple-negative breast carcinomas. Moreover, TP73 can autoregulate its own expression through activation of the ΔN promoter, establishing a negative feedback loop that further fine-tunes the apoptotic response."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "21", "end_ref": "25"}, {"type": "fg_f", "ref": "11"}, {"type": "fg_f", "ref": "26"}, {"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its role in apoptosis, TP73 contributes to cellular differentiation and metabolism. In neuronal cells, TP73 regulates differentiation processes by transcriptionally controlling key metabolic enzymes such as glutaminase-2 (GLS-2), thereby modulating serine biosynthesis and the production of antioxidants like glutathione. In addition, TP73 influences cell cycle progression by interacting with factors such as TP53INP1 and YB-1, and its noncoding RNA counterpart (TP73-AS1) has been implicated in promoting tumor cell proliferation and chemoresistance in hepatocellular carcinoma."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "27", "end_ref": "31"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nGenetic polymorphisms and epigenetic modifications at the TP73 locus further affect its expression and function in tumorigenesis. Certain noncoding polymorphisms have been associated with an increased risk for cancers such as squamous cell carcinomas of the head and neck as well as digestive tract malignancies. In addition, aberrant promoter methylation of TP73 has been observed in specific tumors, including Epstein–Barr virus–associated gastric carcinomas, underscoring the complexity of TP73 regulation in cancer predisposition and progression."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "32", "end_ref": "35"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "M Kaghad, H Bonnet, A Yang, et al. 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