{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T13:21:13Z","timestamp":1791897673703,"version":"4.3.4"},"reference-count":44,"publisher":"National Academy of Sciences","issue":"26","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[1998,12,22]]},"abstract":"<jats:p>\n                    Tuberous sclerosis is an autosomal dominant disorder characterized by the development of aberrant growths in many tissues and organs. Linkage analysis revealed two disease-determining genes on chromosome 9 and chromosome 16. The tuberous sclerosis complex gene-2 (\n                    <jats:italic>TSC2<\/jats:italic>\n                    ) on chromosome 16 encodes the tumor suppressor protein tuberin. We have shown earlier that loss of\n                    <jats:italic>TSC2<\/jats:italic>\n                    is sufficient to induce quiescent cells to enter the cell cycle. Here we show that\n                    <jats:italic>TSC2<\/jats:italic>\n                    -negative fibroblasts exhibit a shortened G\n                    <jats:sub>1<\/jats:sub>\n                    phase. Although the expression of cyclin E, cyclin A, p21, or Cdc25A is unaffected,\n                    <jats:italic>TSC2<\/jats:italic>\n                    -negative cells express much lower amounts of the cyclin-dependent kinase (CDK) inhibitor p27 because of decreased protein stability. In\n                    <jats:italic>TSC2<\/jats:italic>\n                    mutant cells the amount of p27 bound to CDK2 is diminished, accompanied with elevated kinase activity. Ectopic expression studies revealed that the aforementioned effects can be reverted by transfecting\n                    <jats:italic>TSC2<\/jats:italic>\n                    in\n                    <jats:italic>TSC2<\/jats:italic>\n                    -negative cells. High ectopic levels of p27 have cell cycle inhibitory effects in\n                    <jats:italic>TSC2<\/jats:italic>\n                    -positive cells but not in\n                    <jats:italic>TSC2<\/jats:italic>\n                    -negative counterparts, although the latter still depend on CDK2 activity. Loss of\n                    <jats:italic>TSC2<\/jats:italic>\n                    induces soft agar growth of fibroblasts, a process that cannot be inhibited by high levels of p27. Both phenotypes of\n                    <jats:italic>TSC2<\/jats:italic>\n                    -negative cells, their resistance to the activity of ectopic p27, and the instability of endogenous p27, could be explained by our observation that the nucleoprotein p27 is mislocated into the cytoplasm upon loss of\n                    <jats:italic>TSC2<\/jats:italic>\n                    . These findings provide insights into the molecular mechanism of how loss of\n                    <jats:italic>TSC2<\/jats:italic>\n                    induces cell cycle entry and allow a better understanding of its tumor suppressor function.\n                  <\/jats:p>","DOI":"10.1073\/pnas.95.26.15653","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T10:40:52Z","timestamp":1027680052000},"page":"15653-15658","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":138,"title":["Inactivation of the cyclin-dependent kinase inhibitor p27 upon loss of the tuberous sclerosis complex gene-2"],"prefix":"10.1073","volume":"95","author":[{"given":"Thomas","family":"Soucek","sequence":"first","affiliation":[{"name":"Obstetrics and Gynecology, University of Vienna, Department of Prenatal Diagnosis and Therapy, W\u00e4hringer G\u00fcrtel 18\u201320, A-1090 Vienna, Austria; and University of Washington Medical Center, Seattle, WA 98195"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raymond S.","family":"Yeung","sequence":"additional","affiliation":[{"name":"Obstetrics and Gynecology, University of Vienna, Department of Prenatal Diagnosis and Therapy, W\u00e4hringer G\u00fcrtel 18\u201320, A-1090 Vienna, Austria; and University of Washington Medical Center, Seattle, WA 98195"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Hengstschl\u00e4ger","sequence":"additional","affiliation":[{"name":"Obstetrics and Gynecology, University of Vienna, Department of Prenatal Diagnosis and Therapy, W\u00e4hringer G\u00fcrtel 18\u201320, A-1090 Vienna, Austria; and University of Washington Medical Center, Seattle, WA 98195"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[1998,12,22]]},"reference":[{"key":"e_1_3_3_1_2","volume-title":"Tuberous Sclerosis","author":"Gomez M 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