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It is also implicated in the mechanisms underlying replicative senescence since p16<jats:sup>INK4A<\/jats:sup> RNA and protein accumulate as cells approach their proscribed limit of population doublings in tissue culture. To obtain further evidence of its role in senescence, we have sought ways of overexpressing p16<jats:sup>INK4A<\/jats:sup> in primary human diploid fibroblasts (HDF). To circumvent the low transfection efficiency of primary cells we have exploited a recombinant form of the full\u2010length p16<jats:sup>INK4A<\/jats:sup> protein fused to a 16 amino acid peptide from the <jats:italic>Drosophila<\/jats:italic> antennapedia protein. This peptide has the capacity to cross both cytoplasmic and nuclear membranes allowing the direct introduction of the active protein to primary cells. Here, we show that antennapedia\u2010tagged wild\u2010type p16<jats:sup>INK4A<\/jats:sup> protein, but not a functionally compromised tumor\u2010specific variant, causes G1 arrest in early passage HDFs by inhibiting the phosphorylation of the retinoblastoma protein. Significantly, the arrested cells display several phenotypic features that are considered characteristic of senescent cells. These data support a role for p16<jats:sup>INK4A<\/jats:sup> in replicative senescence and raise the possibility of using the antennapedia\u2010tagged protein therapeutically.<\/jats:p>","DOI":"10.1016\/s0014-5793(98)00426-8","type":"journal-article","created":{"date-parts":[[2002,7,25]],"date-time":"2002-07-25T19:16:26Z","timestamp":1027624586000},"page":"203-208","source":"Crossref","is-referenced-by-count":74,"title":["Features of replicative senescence induced by direct addition of antennapedia\u2010p16<sup>INK4A<\/sup> fusion protein to human diploid fibroblasts"],"prefix":"10.1002","volume":"427","author":[{"given":"Daishiro","family":"Kato","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazuhiro","family":"Miyazawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marugarida","family":"Ruas","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Starborg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ikuo","family":"Wada","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takahiro","family":"Oka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toshiyuki","family":"Sakai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gordon","family":"Peters","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eiji","family":"Hara","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[1998,12,18]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/366704a0"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.8153634"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/368753a0"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(94)90540-1"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(94)90543-6"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/375503a0"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/375506a0"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.9.10.1149"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.15.5.2672"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.274.5293.1672"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.91.23.11045"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.2421407"},{"key":"e_1_2_6_14_1","unstructured":"Campisi J. 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