Beta-catenin/Tcf-1-mediated transactivation of cyclin D1 promoter is negatively regulated by thyroid hormone.
Cyclin D1 is an oncogenic cyclin frequently over-expressed in cancer. To examine the effect of thyroid hormone (T3) and its receptor (TR) on the transcription of cyclin D1 gene, we co-transfected the chloramphenicol acetyl-transferase (CAT) reporter plasmid containing cyclin D1 promoter together with the expression plasmids for TRbeta1 and wild-type or mutant beta-catenin (SA) into 293T cells. In the presence of T3, beta-catenin-dependent transactivation of cyclin D1 promoter was suppressed by co-transfection of TRbeta1. The suppression by T3/TRbeta1 was in a dose-dependent manner. The CAT reporter gene in which Tcf/Lef-1 sites were fused to heterologous promoter was also suppressed by T3/TRbeta1. Furthermore, inhibition of endogenous wild-type beta-catenin by T3/TRbeta1 was observed in SW480 colon carcinoma cells with mutation of the adenomatous polyposis coli gene. These results indicate that the T3-bound TR inhibits the transcription of cyclin D1 through the Tcf/Lef-1 site, which is positively regulated by the Wnt-signaling pathway.
Natsume
Hiroko
H
Second Division of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan.
Sasaki
Shigekazu
S
Kitagawa
Masatoshi
M
Kashiwabara
Yumiko
Y
Matsushita
Akio
A
Nakano
Keiko
K
Nishiyama
Kozo
K
Nagayama
Koji
K
Misawa
Hiroko
H
Masuda
Hiroko
H
Nakamura
Hirotoshi
H
D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism*; D019938:Cyclin D1 / Q000235:genetics* / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D019940:Genes, bcl-1 / Q000187:drug effects; D006801:Humans; D007668:Kidney / Q000196:embryology / Q000378:metabolism*; D051821:Lymphoid Enhancer-Binding Factor 1; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011988:Receptors, Thyroid Hormone / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects*; D014162:Transfection; D014284:Triiodothyronine / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D051176:beta Catenin
C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D051821:Lymphoid Enhancer-Binding Factor 1; D011988:Receptors, Thyroid Hormone; D015534:Trans-Activators; D014157:Transcription Factors; D051176:beta Catenin; D014284:Triiodothyronine; D019938:Cyclin D1