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We now report that the Rho\u2010associated protein kinase (ROCK) signaling pathway is a critical regulator of oncogene\u2010induced senescence in skin carcinogenesis. Transformation of mouse keratinocytes with oncogenic RAS upregulates ROCK activity and initiates a senescence response characterized by cell enlargement, growth inhibition, upregulation of senescence associated \u03b2\u2010galactosidase (SA\u03b2gal) expression, and release of multiple pro\u2010inflammatory factors comprising the senescence\u2010associated secretory phenotype (SASP). The addition of the ROCK inhibitor Y\u201027632 and others prevents these senescence responses and maintains proliferating confluent RAS transformed keratinocyte cultures indefinitely. Mechanistically, oncogenic RAS transformation is associated with upregulation of cell cycle inhibitors p15<jats:sup>Ink4b<\/jats:sup>, p16<jats:sup>Ink4a<\/jats:sup>, and p19<jats:sup>Arf<\/jats:sup> and downregulation of p\u2010AKT, all of which are reversed by Y\u201027632. RNA\u2010seq analysis of Y\u201027632 treated RAS\u2010transformed keratinocytes indicated that the inhibitor reduced growth\u2010inhibitory gene expression profiles and maintained expression of proliferative pathways. Y\u201027632 also reduced the expression of NF\u2010\u03baB effector genes and the expression of I\u03baB\u03b6 downstream mediators. The senescence inhibition from Y\u201027632 was reversible, and upon its removal, senescence reoccurred in vitro with rapid upregulation of cell cycle inhibitors, SASP expression, and cell detachment. Y\u201027632 treated cultured RAS\u2010keratinocytes formed tumors in the absence of the inhibitor when placed in skin orthografts suggesting that factors in the tumor microenvironment can overcome the drive to senescence imparted by overactive ROCK activity.<\/jats:p>","DOI":"10.1002\/mc.23351","type":"journal-article","created":{"date-parts":[[2021,9,17]],"date-time":"2021-09-17T19:44:12Z","timestamp":1631907852000},"page":"799-812","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["RAS induced senescence of skin keratinocytes is mediated through Rho\u2010associated protein kinase (ROCK)"],"prefix":"10.1002","volume":"60","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1825-2439","authenticated-orcid":false,"given":"Alex J.","family":"Lee","sequence":"first","affiliation":[{"name":"Laboratory of Cancer Biology and Genetics, Center for Cancer Research National Cancer Institute Bethesda Maryland 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