{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:07:31Z","timestamp":1792789651879,"version":"4.5.0"},"reference-count":52,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:00:00Z","timestamp":1790726400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Science and Technology of the People\u2019s Republic of China","award":["2023YFA1801902"],"award-info":[{"award-number":["2023YFA1801902"]}],"id":[{"id":"https:\/\/ror.org\/027s68j25","id-type":"ROR","asserted-by":"crossref"}]},{"award":["2023YFA1801902"],"award-info":[{"award-number":["2023YFA1801902"]}],"id":[{"id":"https:\/\/ror.org\/027s68j25","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004826","name":"Beijing Natural Science Foundation","doi-asserted-by":"publisher","award":["QY26292"],"award-info":[{"award-number":["QY26292"]}],"id":[{"id":"10.13039\/501100004826","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Health Commission Capacity Building and Continuing Education Center","award":["GWJJMB202510024224"],"award-info":[{"award-number":["GWJJMB202510024224"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Tumor incidence increases markedly with advancing age, yet the molecular mechanisms linking aging-driven senescence to tumorigenesis remain incompletely understood. The proteasome activator PA200 preserves genomic stability by mediating the degradation of acetylated histones during aging. However, its function in age-associated tumor progression is poorly defined. Here, we demonstrate that PA200 promotes aging-associated tumorigenesis independent of its histone-degrading activity. Elevated PA200 correlates with poor prognosis and advancing age in human lung cancer. PA200-deficient tumor cells exhibit suppressed proliferation and migration, accompanied by aggravated oxidative-stress-triggered cellular senescence. Mechanistically, p53 directly binds and represses PSME4 transcription at its promoter. Reciprocally, PA200 facilitates proteasomal degradation of \u03b2-catenin, thereby sustaining p53 activity and forming a negative feedback loop. In the urethane-induced mouse lung tumor model, PA200 ablation markedly reduces tumor burden, especially in middle-aged mice. This effect is coupled with \u03b2-catenin accumulation, lowered p53 levels, and partial remodeling of the pro-inflammatory tumor microenvironment. Our findings uncover the p53-PA200-\u03b2-catenin feedback axis as a key driver of age-dependent lung tumorigenesis and highlight PA200 as a potential therapeutic target for elderly patients with lung cancer.<\/jats:p>","DOI":"10.3390\/ijms27198783","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T15:20:59Z","timestamp":1790781659000},"page":"8783","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The p53-PA200 Feedback Loop Modulates Age-Dependent Tumorigenesis"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-6492-6047","authenticated-orcid":false,"given":"Chen-Yang","family":"Jiang","sequence":"first","affiliation":[{"name":"Ministry of Education Key Laboratory of Cell Proliferation & Regulation Biology, College of Life Sciences, Beijing Normal University, 19 Xinjiekouwai Avenue, Beijing 100875, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan-Li","family":"Wang","sequence":"additional","affiliation":[{"name":"Ministry of Education Key Laboratory of Cell Proliferation & Regulation Biology, College of Life Sciences, Beijing Normal University, 19 Xinjiekouwai Avenue, Beijing 100875, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nan","family":"Lv","sequence":"additional","affiliation":[{"name":"Ministry of Education Key Laboratory of Cell Proliferation & Regulation Biology, College of Life Sciences, Beijing Normal University, 19 Xinjiekouwai Avenue, Beijing 100875, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing-Kun","family":"Cai","sequence":"additional","affiliation":[{"name":"Ministry of Education Key Laboratory of Cell Proliferation & Regulation Biology, College of Life Sciences, Beijing Normal University, 19 Xinjiekouwai Avenue, Beijing 100875, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6344-8214","authenticated-orcid":false,"given":"Tian-Xia","family":"Jiang","sequence":"additional","affiliation":[{"name":"Ministry of Education Key Laboratory of Cell Proliferation & Regulation Biology, College of Life Sciences, Beijing Normal University, 19 Xinjiekouwai Avenue, Beijing 100875, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1038\/s41571-023-00798-3","article-title":"The global burden of lung cancer: Current status and future trends","volume":"20","author":"Leiter","year":"2023","journal-title":"Nat. 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