{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T00:16:01Z","timestamp":1791850561017,"version":"4.3.4"},"reference-count":81,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2017,1,23]],"date-time":"2017-01-23T00:00:00Z","timestamp":1485129600000},"content-version":"vor","delay-in-days":22,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP16K12983"],"award-info":[{"award-number":["JP16K12983"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP26460398"],"award-info":[{"award-number":["JP26460398"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["16ek0109015s0303"],"award-info":[{"award-number":["16ek0109015s0303"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancer Science"],"published-print":{"date-parts":[[2017,1]]},"abstract":"<jats:p>On July 10, 2016, Alfred G. Knudson, Jr., <jats:styled-content style=\"fixed-case\">MD<\/jats:styled-content>, PhD, a leader in cancer research, died at the age of 93 years. We deeply mourn his loss. Knudson's two\u2010hit hypothesis, published in 1971, has been fundamental for understanding tumor suppressor genes and familial tumor\u2010predisposing syndromes. To understand the molecular mechanism of two\u2010hit\u2010initiated tumorigenesis, Knudson used an animal model of a dominantly inherited tumor, the Eker rat. From the molecular identification of <jats:italic>Tsc2<\/jats:italic> germline mutations, the Eker rat became a model for tuberous sclerosis complex (<jats:styled-content style=\"fixed-case\">TSC<\/jats:styled-content>), a familial tumor\u2010predisposing syndrome. Animal models, including the fly, have greatly contributed to <jats:styled-content style=\"fixed-case\">TSC<\/jats:styled-content> research. Because the product of the <jats:italic><jats:styled-content style=\"fixed-case\">TSC<\/jats:styled-content>2<\/jats:italic>\/<jats:italic>Tsc2<\/jats:italic> gene (tuberin) together with hamartin, the product of another <jats:styled-content style=\"fixed-case\">TSC<\/jats:styled-content> gene (<jats:italic><jats:styled-content style=\"fixed-case\">TSC<\/jats:styled-content>1<\/jats:italic>\/<jats:italic>Tsc1<\/jats:italic>), suppresses mammalian\/mechanistic target of rapamycin complex 1 (<jats:styled-content style=\"fixed-case\">mTORC<\/jats:styled-content>1), rapalogs have been used as therapeutic drugs for <jats:styled-content style=\"fixed-case\">TSC<\/jats:styled-content>. Although significant activity of these drugs has been reported, there are still problems such as recurrence of residual tumors and adverse effects. Recent studies indicate that there are <jats:styled-content style=\"fixed-case\">mTORC<\/jats:styled-content>1\u2010independent signaling pathways downstream of hamartin\/tuberin, which may represent new therapeutic targets. The establishment of cellular models, such as pluripotent stem cells with <jats:italic><jats:styled-content style=\"fixed-case\">TSC<\/jats:styled-content>2<\/jats:italic>\/<jats:italic>Tsc2<\/jats:italic> gene mutations, will facilitate the understanding of new aspects of <jats:styled-content style=\"fixed-case\">TSC<\/jats:styled-content> pathogenesis and the development of novel treatment options. In this review, we look back at the history of Knudson and animal models of <jats:styled-content style=\"fixed-case\">TSC<\/jats:styled-content> and introduce recent progress in <jats:styled-content style=\"fixed-case\">TSC<\/jats:styled-content> research.<\/jats:p>","DOI":"10.1111\/cas.13116","type":"journal-article","created":{"date-parts":[[2016,11,14]],"date-time":"2016-11-14T16:54:16Z","timestamp":1479142456000},"page":"5-11","source":"Crossref","is-referenced-by-count":50,"title":["Mourning Dr. Alfred G. 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