{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,7]],"date-time":"2026-02-07T22:33:21Z","timestamp":1770503601671,"version":"3.49.0"},"reference-count":47,"publisher":"Proceedings of the National Academy of Sciences","issue":"25","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2003,12,9]]},"abstract":"<jats:p>\n            Deregulation of the p16\n            <jats:sup>INK4a<\/jats:sup>\n            \u2013cyclin D:cyclin-dependent kinases (cdk) 4\/6 \u2013retinoblastoma (pRB) pathway is a common paradigm in the oncogenic transformation of human cells and suggests that this pathway functions linearly in malignant transformation. However, it is not understood why p16\n            <jats:sup>INK4a<\/jats:sup>\n            and cyclin D:cdk4\/6 mutations are disproportionately more common than the rare genetic event of\n            <jats:italic>RB<\/jats:italic>\n            inactivation in human malignancies such as melanoma. To better understand how these complexes contribute to altered tissue homeostasis, we blocked cdk4\/6 activation and acutely inactivated\n            <jats:italic>Rb<\/jats:italic>\n            by conditional mutagenesis during mouse hair follicle cycling. Inhibition of cdk4\/6 in the skin by subcutaneous administration of a membrane-transducible TAT-p16\n            <jats:sup>INK4a<\/jats:sup>\n            protein completely blocked hair follicle growth and differentiation. In contrast, acute disruption of\n            <jats:italic>Rb<\/jats:italic>\n            in the skin of homozygous\n            <jats:italic>\n              Rb\n              <jats:sup>LoxP\/LoxP<\/jats:sup>\n            <\/jats:italic>\n            mice via subcutaneous administration of TAT-Cre recombinase failed to affect hair growth. However, loss of\n            <jats:italic>Rb<\/jats:italic>\n            resulted in severe depigmentation of hair follicles. Further analysis of follicular melanocytes\n            <jats:italic>in vivo<\/jats:italic>\n            and in primary cell culture demonstrated that pRB plays a cell-autonomous role in melanocyte survival. Moreover, functional inactivation of all three\n            <jats:italic>Rb<\/jats:italic>\n            family members (\n            <jats:italic>Rb<\/jats:italic>\n            ,\n            <jats:italic>p107<\/jats:italic>\n            , and\n            <jats:italic>p130<\/jats:italic>\n            ) in primary melanocytes by treatment with a transducible TAT-E1A protein did not rescue the apoptotic phenotype. These findings suggest that deregulated cyclin D:cdk4\/6 complexes and pRB perform nonoverlapping functions\n            <jats:italic>in vivo<\/jats:italic>\n            and provide a cellular mechanism that accounts for the low incidence of\n            <jats:italic>RB<\/jats:italic>\n            inactivation in cancers such as melanoma.\n          <\/jats:p>","DOI":"10.1073\/pnas.2431391100","type":"journal-article","created":{"date-parts":[[2003,12,9]],"date-time":"2003-12-09T18:17:48Z","timestamp":1070993868000},"page":"14881-14886","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":32,"title":["Distinct and nonoverlapping roles for pRB and cyclin D:cyclin-dependent kinases 4\/6 activity in melanocyte survival"],"prefix":"10.1073","volume":"100","author":[{"given":"Benjamin D.","family":"Yu","sequence":"first","affiliation":[{"name":"Howard Hughes Medical Institute and Department of Cellular and Molecular Medicine, University of California at San Diego School of Medicine, La Jolla, CA 92093-0686; Division of Dermatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110; and Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands"}]},{"given":"Michelle","family":"Becker-Hapak","sequence":"additional","affiliation":[{"name":"Howard Hughes Medical Institute and Department of Cellular and Molecular Medicine, University of California at San Diego School of Medicine, La Jolla, CA 92093-0686; Division of Dermatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110; and Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands"}]},{"given":"Eric L.","family":"Snyder","sequence":"additional","affiliation":[{"name":"Howard Hughes Medical Institute and Department of Cellular and Molecular Medicine, University of California at San Diego School of Medicine, La Jolla, CA 92093-0686; Division of Dermatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110; and Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands"}]},{"given":"Marc","family":"Vooijs","sequence":"additional","affiliation":[{"name":"Howard Hughes Medical Institute and Department of Cellular and Molecular Medicine, University of California at San Diego School of Medicine, La Jolla, CA 92093-0686; Division of Dermatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110; and Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands"}]},{"given":"Catherine","family":"Denicourt","sequence":"additional","affiliation":[{"name":"Howard Hughes Medical Institute and Department of Cellular and Molecular Medicine, University of California at San Diego School of Medicine, La Jolla, CA 92093-0686; Division of Dermatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110; and Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands"}]},{"given":"Steven F.","family":"Dowdy","sequence":"additional","affiliation":[{"name":"Howard Hughes Medical Institute and Department of Cellular and Molecular Medicine, University of California at San Diego School of Medicine, La Jolla, CA 92093-0686; Division of Dermatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110; and Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands"}]}],"member":"341","published-online":{"date-parts":[[2003,11,20]]},"reference":[{"key":"e_1_3_2_1_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.280.5366.1035"},{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.813200"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0959-437X(01)00263-5"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc795"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1067\/mjd.2000.104687"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.1998.16.2.670"},{"key":"e_1_3_2_7_2","first-page":"3200","volume":"62","year":"2002","unstructured":"Sauter, E. 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