{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n FBXO4 is a pivotal F‐box protein that acts as the substrate recognition subunit of an SCF (Skp1–Cullin1–F‐box protein) E3 ubiquitin ligase complex. In several studies, FBXO4 has been shown to target key cell cycle and telomere regulatory proteins for ubiquitin‐dependent proteolysis. For example, FBXO4 recognizes cyclin D1 that has been phosphorylated on Thr‑286, especially in cooperation with cofactors such as αB‑crystallin, to facilitate timely ubiquitination and degradation. This degradation process ensures proper G1–S phase progression and suppresses aberrant cell proliferation, with defects in FBXO4 function leading to cyclin D1 accumulation, genomic instability, and ultimately contributing to tumorigenesis in cancers such as melanoma."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition to cyclin D1 regulation, FBXO4 (also known as PinX3 in early studies) mediates the ubiquitination of telomere‐associated proteins such as TRF1 (also called Pin2), thereby contributing to the control of telomere length and the maintenance of genomic stability."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "7"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n The activity of FBXO4 is itself tightly regulated. Dimerization of FBXO4, which is essential for its ligase activity, is modulated by phosphorylation events that create a docking site for proteins such as 14‑3‑3ε. Mutations that disrupt FBXO4 dimerization impair its ability to ubiquitinate substrates like cyclin D1, thereby promoting oncogenic signaling"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "and enhancing susceptibility to malignant transformation, as observed in studies on melanoma."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these findings establish FBXO4 as a tumor suppressor factor that maintains cellular homeostasis by regulating the degradation of key proteins involved in cell cycle progression and telomere integrity. Dysfunction of FBXO4, whether by mutation or altered regulatory mechanisms, can lead to uncontrolled cell proliferation and contribute to cancer development.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Douglas I Lin, Olena Barbash, K G Suresh Kumar, et al. 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