title: Transgenic expression of the N525S-tuberin variant in Tsc2 mutant (Eker) rats causes dominant embryonic lethality.
abstract: The Tsc2 product, tuberin, negatively regulates the mTOR pathway. We have exploited the Eker (Tsc2-mutant) rat system to analyse various Tsc2 mutations. Here, we focus on the N525S-Tsc2 variant (NSM), which is known to cause distinct symptoms in patients even though normal suppression of mTOR is observed. Unexpectedly, we were repeatedly unable to generate viable rats carrying the NSM transgene. Genotypic analysis revealed that most of the embryos carrying the transgene died around embryonic day after 14.5-similar to the stage of lethality observed for Eker homozygotes. Thus, the NSM transgene appeared to have a dominant lethal effect in our rat model. Further, no significant differences were observed for various signal transduction molecules in transiently expressed NSM cells compared to WT. These results indicate that a non-mTOR pathway, critical for embryogenesis, is being regulated by tuberin, providing a link between tuberin expression and the severity of Tsc2 mutation-related pathogenesis.
authors.affiliation: 1] Department of Clinical Oncology, Tohoku University Hospital, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan [2] Department of Pathology and Oncology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Shiono
authors.affiliation: Department of Pathology and Oncology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Kobayashi
authors.affiliation: 1] PhoenixBio Co., Ltd., 1198-4 Iwazo-machi, Utsunomiya, Tochigi 321-0973, Japan [2] Animal Resources Center, Central Institute for Experimental Animals, 3-25-12 Tonomachi, Kawasaki, Kangawa 210-0821, Japan.
authors.forename: Riichi
authors.initials: R
authors.lastname: Takahashi
authors.affiliation: 1] PhoenixBio Co., Ltd., 1198-4 Iwazo-machi, Utsunomiya, Tochigi 321-0973, Japan [2] Transgenic Animal Division, Utsunomiya Institute, Institute of Immunology Co., Ltd., 1198-4 Iwazo-machi, Utsunomiya, Tochigi 321-0973, Japan.
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Ueda
authors.affiliation: 1] Department of Clinical Oncology, Tohoku University Hospital, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan [2] Department of Clinical Oncology, Institute of Development, Aging, and Cancer, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan.
authors.forename: Chikashi
authors.initials: C
authors.lastname: Ishioka
authors.affiliation: Department of Pathology and Oncology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: Okio
authors.initials: O
authors.lastname: Hino
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001483:Base Sequence; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D047108:Embryonic Development / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D005799:Genes, Dominant; D005804:Genes, Lethal; D057809:HEK293 Cells; D006720:Homozygote; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D051381:Rats; D055647:Rats, Transgenic; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D014402:Tuberous Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics*
chemical_list: C000624653:TSC2 protein, human; C000624655:Tsc2 protein, rat; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases
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