{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMDM2 is a pivotal negative regulator of the p53 tumor‐suppressor pathway. It binds directly to p53 and, depending on its own level and post‐translational modifications, can promote either monoubiquitination—leading to nuclear export—or polyubiquitination that earmarks p53 for proteasomal degradation. Moreover, naturally occurring polymorphisms such as SNP309 can enhance Sp1 binding to the MDM2 promoter, elevating MDM2 expression and attenuating p53 responses to stress, thereby accelerating tumor formation. Activating signals, for example via Akt‐mediated phosphorylation at Ser186, further bolster MDM2’s ubiquitin ligase activity toward p53. In addition, MDM2 recruits co‐factors such as HDAC1, which deacetylates p53 on critical lysines that overlap with its ubiquitination sites, thereby favoring p53 degradation. MDM2 also influences p53 synthesis by promoting alternative translation initiation events, generating p53 isoforms that differ in their MDM2 binding capacity and function. Its interplay with the p53 negative regulator MDMX underscores the balanced, dynamic control of p53 activity under both normal and stress conditions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "8"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its direct regulation of p53, MDM2 functions as a central node integrating multiple cellular signals through interactions with a variety of ribosomal and regulatory proteins. In response to nucleolar or ribosomal stress, proteins such as L11, L5, L23, and L26 bind to MDM2 and attenuate its ubiquitin ligase activity toward p53, thereby promoting p53 stabilization and cell cycle arrest. In parallel, MDM2 engages with ribosomal protein S7 to form complexes that further modulate p53 levels. The regulatory influence of MDM2 extends to other critical proteins involved in cell proliferation and survival: it can promote degradation of the retinoblastoma protein (Rb) and the cyclin-dependent kinase inhibitor p21 through mechanisms that, in some cases, bypass classical ubiquitination. In addition, deubiquitinases like USP15 and HAUSP interact with MDM2 (or its partners) to either stabilize MDM2 or counteract its activity, thereby fine-tuning the overall p53 response."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "20"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the clinical arena, dysregulation and amplification of MDM2 contribute both to tumor progression and to therapeutic outcomes. MDM2/MDMX amplification has been associated with hyperprogressive disease in patients receiving checkpoint inhibitors and serves as an important diagnostic marker in malignancies such as adipocytic tumors. Moreover, DNA damage–induced stress signals activate specific kinases (including ATM, Chk2, and casein kinase I) that phosphorylate and target MDM2 for degradation through β‐TRCP–dependent ubiquitination, thereby enabling p53 stabilization and downstream apoptotic responses. Notably, MDM2 also regulates non–p53 targets, exemplified by its role in controlling androgen receptor turnover—an effect modulated by long noncoding RNAs like HOTAIR in castration‐resistant prostate cancer. From a therapeutic perspective, small‐molecule inhibitors that disrupt the MDM2–p53 (and MDMX–p53) interaction, such as stapled α‐helical peptides, have demonstrated potent antitumor activity by reactivating p53 function."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "21", "end_ref": "29"}]}, {"type": "t", "text": "\n"}]}]}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Gareth L Bond, Wenwei Hu, Elisabeth E Bond, et al. 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