Genistein prevents thyroid hormone-dependent tail regression of Rana catesbeiana tadpoles by targetting protein kinase C and thyroid hormone receptor alpha.
Thyroid hormone (TH)-regulated gene expression is mainly mediated by TH binding to nuclear thyroid hormone receptors (TRs). Despite extensive studies in mammalian cell lines that show that phosphorylation signaling pathways are important in TH action, little is known about their roles on TH signaling in vivo during development. Anuran metamorphosis is a postembryonic process that is absolutely dependent upon TH and tadpole tail resorption can be precociously induced by exogenous administration of 3,5,3'-triiodothyronine (T(3)). We demonstrate that genistein (a major isoflavone in soy products and tyrosine kinase inhibitor) and the PKC inhibitor (H7) prevent T(3)-induced regression of the Rana catesbeiana tadpole tail. T(3)-induced protein kinase C tyrosine phosphorylation and kinase activity are inhibited by genistein while T(3)-induced up-regulation of TRbeta mRNA, but not TRalpha mRNA, is significantly attenuated, most likely through inhibition of T(3)-dependent phosphorylation of the TRalpha protein. This phosphorylation may be modulated through PKC. These data demonstrate that T(3) signaling in the context of normal cells in vivo includes phosphorylation as an important factor in establishing T(3)-dependent tail regression during development.
Ji
L
L
Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia, Canada.
Domanski
D
D
Skirrow
R C
RC
Helbing
C C
CC
D000818:Animals; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D015180:Electrophoresis, Gel, Two-Dimensional; D005419:Flavonoids / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D019833:Genistein / Q000494:pharmacology; D015151:Immunoblotting; D047468:Immunoprecipitation; D007814:Larva / Q000187:drug effects / Q000235:genetics / Q000254:growth & development; D009924:Organ Culture Techniques; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011892:Rana catesbeiana / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D013623:Tail / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism*; D037021:Thyroid Hormone Receptors alpha / Q000235:genetics / Q000378:metabolism*; D013963:Thyroid Hormones / Q000378:metabolism*; D014284:Triiodothyronine / Q000494:pharmacology
D005419:Flavonoids; D012333:RNA, Messenger; D037021:Thyroid Hormone Receptors alpha; D013963:Thyroid Hormones; D014284:Triiodothyronine; D019833:Genistein; D011493:Protein Kinase C; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D004121:Dimethyl Sulfoxide