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Cells expressing p16<jats:sup>INK4a<\/jats:sup> accumulate in aging tissues and appear in premalignant lesions, yet their physiologic effects are poorly understood. We found that prolonged expression of transgenic p16<jats:sup>INK4a<\/jats:sup> in the mouse epidermis induces hyperplasia and dysplasia, involving high proliferation rates of keratinocytes not expressing the transgene. Continuous p16<jats:sup>INK4a<\/jats:sup> expression increases the number of epidermal papillomas formed after carcinogen treatment. Wnt-pathway ligands and targets are activated upon prolonged p16<jats:sup>INK4a<\/jats:sup> expression, and Wnt inhibition suppresses p16<jats:sup>INK4a<\/jats:sup>-induced hyperplasia. Senolytic treatment reduces p16<jats:sup>INK4a<\/jats:sup>-expressing cell numbers, and inhibits Wnt activation and hyperplasia. In human actinic keratosis, a precursor of squamous cell carcinoma, p16<jats:sup>INK4a<\/jats:sup>-expressing cells are found adjacent to dividing cells, consistent with paracrine interaction. These findings reveal that chronic p16<jats:sup>INK4a<\/jats:sup> expression is sufficient to induce hyperplasia through Wnt-mediated paracrine stimulation, and suggest that this tumor suppressor can promote early premalignant epidermal lesion formation.<\/jats:p>","DOI":"10.1038\/s41467-020-16475-3","type":"journal-article","created":{"date-parts":[[2020,6,1]],"date-time":"2020-06-01T10:03:14Z","timestamp":1591005794000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":56,"title":["Chronic expression of p16INK4a in the epidermis induces Wnt-mediated hyperplasia and promotes tumor initiation"],"prefix":"10.1038","volume":"11","author":[{"given":"Narmen","family":"Azazmeh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Assouline","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eitan","family":"Winter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shmuel","family":"Ruppo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuval","family":"Nevo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Maly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Meir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnieszka K.","family":"Witkiewicz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Cohen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophia V.","family":"Rizou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eli","family":"Pikarsky","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Luxenburg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9001-4112","authenticated-orcid":false,"given":"Vassilis G.","family":"Gorgoulis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7815-1165","authenticated-orcid":false,"given":"Ittai","family":"Ben-Porath","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,6,1]]},"reference":[{"key":"16475_CR1","doi-asserted-by":"publisher","first-page":"703","DOI":"10.1038\/nrm2241","volume":"8","author":"NE Sharpless","year":"2007","unstructured":"Sharpless, N. 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