title: p66Shc expression in proliferating thyroid cells is regulated by thyrotropin receptor signaling.
abstract: It is almost unanimously accepted that thyrocyte proliferation is synergistically activated by TSH and insulin/IGF-I. Moreover, it was recently suggested that p66Shc, which is an adaptor molecule of the IGF-I receptor, might play a critical role in this synergistic effect. In this study, we undertook to confirm the role and the mechanism underlying the regulation of p66Shc expression via TSH receptor in thyrocytes. We have found that p66Shc expression is elevated in proliferating human thyroid tissues, including adenomatous goiter, adenoma, Graves' disease, and thyroid cancer, but not in normal thyroid. Among growth factors, TSH increased p66Shc expression both in vivo and in vitro; however, IGF-I, epidermal growth factor, or insulin did not. TSH and Graves' Ig increased the p66Shc expression via the TSH receptor-G(s)-cAMP pathway. However, interestingly, IGF-I or epidermal growth factor increased the tyrosine phosphorylations of p66Shc, and this was enhanced by TSH pretreatment. A similar synergism was observed during the DNA synthesis. When we measured the p66Shc levels induced by individual Igs from 130 patients with Graves' disease, TSH receptor stimulating activity and goiter size showed a weak correlation. We conclude that the expression of p66Shc is regulated by signaling through the TSH receptor in proliferating thyroid cells and that p66Shc appears to be an important mediator of the synergistic effect between TSH and IGF-I with respect to thyrocyte proliferation. Moreover, we suggest that TSH potentiates the regulatory effect of IGF-I on thyrocyte growth, at least in part, by increasing the expression of p66Shc.
authors.affiliation: Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Hospital, 28 Yongon-dong Chongno-gu, Seoul 110-744, Korea. djpark@snu.ac.kr
authors.forename: Y J
authors.initials: YJ
authors.lastname: Park
authors.forename: T Y
authors.initials: TY
authors.lastname: Kim
authors.forename: S H
authors.initials: SH
authors.lastname: Lee
authors.forename: H
authors.initials: H
authors.lastname: Kim
authors.forename: S W
authors.initials: SW
authors.lastname: Kim
authors.forename: M
authors.initials: M
authors.lastname: Shong
authors.forename: Y K
authors.initials: YK
authors.lastname: Yoon
authors.forename: B Y
authors.initials: BY
authors.lastname: Cho
authors.forename: D J
authors.initials: DJ
authors.lastname: Park
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D000368:Aged; D000818:Animals; D001323:Autoantibodies / Q000097:blood; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000494:pharmacology; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006042:Goiter / Q000378:metabolism; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011989:Receptors, Thyrotropin / Q000276:immunology / Q000502:physiology*; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D013961:Thyroid Gland / Q000737:chemistry / Q000166:cytology / Q000378:metabolism*; D013972:Thyrotropin / Q000494:pharmacology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001323:Autoantibodies; D012333:RNA, Messenger; D011989:Receptors, Thyrotropin; C528024:SHC1 protein, human; D055765:Shc Signaling Adaptor Proteins; C528035:Shc1 protein, rat; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D007334:Insulin-Like Growth Factor I; D013972:Thyrotropin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D019205:GTP-Binding Protein alpha Subunits, Gs