{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T11:12:52Z","timestamp":1791112372815,"version":"4.1.0"},"reference-count":27,"publisher":"National Academy of Sciences","issue":"15","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2001,7,17]]},"abstract":"<jats:p>\n                    Tuberous sclerosis (TS) is characterized by the development of hamartomas in various organs and is caused by a germ-line mutation in either\n                    <jats:italic>TSC1<\/jats:italic>\n                    or\n                    <jats:italic>TSC2<\/jats:italic>\n                    tumor suppressor genes. From the symptomatic resemblance among TS patients, involvement of TSC1 and TSC2 products in a common pathway has been suggested. Here, to analyze the function of the Tsc1 product, we established a line of\n                    <jats:italic>Tsc1<\/jats:italic>\n                    (\n                    <jats:italic>TSC1<\/jats:italic>\n                    homologue) knockout mouse by gene targeting. Heterozygous\n                    <jats:italic>Tsc1<\/jats:italic>\n                    mutant (\n                    <jats:italic>Tsc1<\/jats:italic>\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                    ) mice developed renal and extra-renal tumors such as hepatic hemangiomas. In these tumors, loss of wild-type\n                    <jats:italic>Tsc1<\/jats:italic>\n                    allele was observed. Homozygous\n                    <jats:italic>Tsc1<\/jats:italic>\n                    mutants died around embryonic days 10.5\u201311.5, frequently associated with neural tube unclosure. As a whole, phenotypes of\n                    <jats:italic>Tsc1<\/jats:italic>\n                    knockout mice resembled those of\n                    <jats:italic>Tsc2<\/jats:italic>\n                    knockout mice previously reported, suggesting that the presumptive common pathway for Tsc1 and Tsc2 products may also exist in mice. Notably, however, development of renal tumors in\n                    <jats:italic>Tsc1<\/jats:italic>\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                    mice was apparently slower than that in\n                    <jats:italic>Tsc2<\/jats:italic>\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                    mice. The\n                    <jats:italic>Tsc1<\/jats:italic>\n                    knockout mouse described here will be a useful model to elucidate the function of Tsc1 and Tsc2 products as well as pathogenesis of TS.\n                  <\/jats:p>","DOI":"10.1073\/pnas.151033798","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T10:34:10Z","timestamp":1027679650000},"page":"8762-8767","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":212,"title":["A germ-line\n                    <i>Tsc1<\/i>\n                    mutation causes tumor development and embryonic lethality that are similar, but not identical to, those caused by\n                    <i>Tsc2<\/i>\n                    mutation in mice"],"prefix":"10.1073","volume":"98","author":[{"given":"Toshiyuki","family":"Kobayashi","sequence":"first","affiliation":[{"name":"Departments of Experimental Pathology and Cell Biology, Cancer Institute, Japanese Foundation for Cancer Research, 1-37-1 Kami-ikebukuro, Toshima-ku, Tokyo 170-8455, Japan; Department of Clinical Radiology, Faculty of Health Sciences, Hiroshima International University, Kurose-cho, Hiroshima 724-0695, Japan; and Department of Molecular Genetics, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Osamu","family":"Minowa","sequence":"additional","affiliation":[{"name":"Departments of Experimental Pathology and Cell Biology, Cancer Institute, Japanese Foundation for Cancer Research, 1-37-1 Kami-ikebukuro, Toshima-ku, Tokyo 170-8455, Japan; Department of Clinical Radiology, Faculty of Health Sciences, Hiroshima International University, Kurose-cho, Hiroshima 724-0695, Japan; and Department of Molecular Genetics, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshinobu","family":"Sugitani","sequence":"additional","affiliation":[{"name":"Departments of Experimental Pathology and Cell Biology, Cancer Institute, Japanese Foundation for Cancer Research, 1-37-1 Kami-ikebukuro, Toshima-ku, Tokyo 170-8455, Japan; Department of Clinical Radiology, Faculty of Health Sciences, Hiroshima International University, Kurose-cho, Hiroshima 724-0695, Japan; and Department of Molecular Genetics, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Setsuo","family":"Takai","sequence":"additional","affiliation":[{"name":"Departments of Experimental Pathology and Cell Biology, Cancer Institute, Japanese Foundation for Cancer Research, 1-37-1 Kami-ikebukuro, Toshima-ku, Tokyo 170-8455, Japan; Department of Clinical Radiology, Faculty of Health Sciences, Hiroshima International University, Kurose-cho, Hiroshima 724-0695, Japan; and Department of Molecular Genetics, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroaki","family":"Mitani","sequence":"additional","affiliation":[{"name":"Departments of Experimental Pathology and Cell Biology, Cancer Institute, Japanese Foundation for Cancer Research, 1-37-1 Kami-ikebukuro, Toshima-ku, Tokyo 170-8455, Japan; Department of Clinical Radiology, Faculty of Health Sciences, Hiroshima International University, Kurose-cho, Hiroshima 724-0695, Japan; and Department of Molecular Genetics, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Etsuko","family":"Kobayashi","sequence":"additional","affiliation":[{"name":"Departments of Experimental Pathology and Cell Biology, Cancer Institute, Japanese Foundation for Cancer Research, 1-37-1 Kami-ikebukuro, Toshima-ku, Tokyo 170-8455, Japan; Department of Clinical Radiology, Faculty of Health Sciences, Hiroshima International University, Kurose-cho, Hiroshima 724-0695, Japan; and Department of Molecular Genetics, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetsuo","family":"Noda","sequence":"additional","affiliation":[{"name":"Departments of Experimental Pathology and Cell Biology, Cancer Institute, Japanese Foundation for Cancer Research, 1-37-1 Kami-ikebukuro, Toshima-ku, Tokyo 170-8455, Japan; Department of Clinical Radiology, Faculty of Health Sciences, Hiroshima International University, Kurose-cho, Hiroshima 724-0695, Japan; and Department of Molecular Genetics, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Okio","family":"Hino","sequence":"additional","affiliation":[{"name":"Departments of Experimental Pathology and Cell Biology, Cancer Institute, Japanese Foundation for Cancer Research, 1-37-1 Kami-ikebukuro, Toshima-ku, Tokyo 170-8455, Japan; Department of Clinical Radiology, Faculty of Health Sciences, Hiroshima International University, Kurose-cho, Hiroshima 724-0695, Japan; and Department of Molecular Genetics, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2001,7,3]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1007\/s004390000348","volume":"107","author":"Cheadle J P","year":"2000","unstructured":"J P Cheadle, M P Reeve, J R Sampson, D J Kwiatkowski Hum Genet 107, 97\u2013114 (2000).","journal-title":"Hum Genet"},{"key":"e_1_3_4_2_2","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.1016\/0092-8674(93)90618-Z","volume":"75","year":"1993","unstructured":"Cell 75, 1305\u20131315 (1993).","journal-title":"Cell"},{"key":"e_1_3_4_3_2","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1126\/science.277.5327.805","volume":"277","author":"van Slegtenhorst M","year":"1997","unstructured":"M van Slegtenhorst, R de Hoogt, C Hermans, M Nellist, B Janssen, S Verhoef, D Lindhout, A van den Ouweland, D Halley, J Young, et al. 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