{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T20:32:59Z","timestamp":1761597179445},"reference-count":54,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2009,12,28]],"date-time":"2009-12-28T00:00:00Z","timestamp":1261958400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Journal Cellular Physiology"],"published-print":{"date-parts":[[2010,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Herein we used single\u2010cell observation methods to gain insight into the roles of p16<jats:sup>INK4A<\/jats:sup> and p21<jats:sup>WAF1<\/jats:sup> (hereafter p16 and p21) in replicative senescence and ionizing radiation\u2010induced accelerated senescence in human [normal, ataxia telangiectasia (AT) and Li\u2010Fraumeni syndrome (LFS)] fibroblast strains. Cultures of all strains entered a state of replicative senescence at late passages, as evident from inhibition of growth, acquisition of flattened and enlarged cell morphology, and positive staining for senescence\u2010associated \u03b2\u2010galactosidase. In addition, proliferating early\u2010passage cultures of these strains exhibited accelerated senescence in response to ionizing radiation. Immunofluorescence microscopy revealed the heterogeneous expression of p16 in normal and AT fibroblast strains, with the majority of the cells exhibiting undetectable levels of p16 irrespective of <jats:italic>in vitro<\/jats:italic> culture age. Importantly, replicative senescence as well as accelerated senescence triggered by ionizing radiation were accompanied by sustained nuclear accumulation of p21, but did not correlate with p16 expression in p53\u2010proficient (normal and AT) fibroblasts. In p53\u2010deficient (LFS) fibroblasts, on the other hand, replicative senescence and ionizing radiation\u2010triggered accelerated senescence strongly correlated with expression of p16 but not of p21. Furthermore, senescence in LFS fibroblasts was associated with genomic instability encompassing polyploidy. Our findings are compatible with a model in which p16 serves as a backup regulator of senescence, triggering this response preferentially in the absence of wild\u2010type p53 activity. The possibility that one of the tumor\u2010suppressor functions of p16 may be associated with genomic instability, preventing the emergence of malignant progeny from polyploid giant cells, is also supported by these results. J. Cell. Physiol. 223: 57\u201367, 2010. \u00a9 2009 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/jcp.22002","type":"journal-article","created":{"date-parts":[[2009,12,28]],"date-time":"2009-12-28T14:59:56Z","timestamp":1262012396000},"page":"57-67","source":"Crossref","is-referenced-by-count":39,"title":["Single\u2010cell analysis of p16<sup>INK4a<\/sup> and p21<sup>WAF1<\/sup> expression suggests distinct mechanisms of senescence in normal human and Li\u2010Fraumeni Syndrome fibroblasts"],"prefix":"10.1002","volume":"223","author":[{"given":"Razmik","family":"Mirzayans","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bonnie","family":"Andrais","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"April","family":"Scott","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Malcolm 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