title: Correlation between suppression of c-myc and antiproliferative effect of transforming growth factor-beta 1 in thyroid carcinoma cell growth.
abstract: The growth regulatory activity of transforming growth factor-beta 1 (TGF beta 1) was studied in a clonal strain of thyroid papillary carcinoma cell (NPA). Despite the presence of TGF beta 1 and its receptor messenger RNA in thyroid carcinoma, the molecular mechanism of TGF beta 1 action on cell growth of thyroid carcinoma has not yet been elucidated. Exogenously added TGF beta 1 inhibited DNA synthesis and cell growth in a dose- and time-dependent manner at concentrations of 0.1-10 ng/ml. TGF beta 1 inhibited not only basal but also fetal bovine serum-stimulated cell proliferation. Steady state levels of c-myc messenger RNA transcripts were inhibited by TGF beta 1 after 0.5-h treatment. Antisense, but not sense, c-myc oligodeoxynucleotides also caused suppression of NPA cell growth in a dose-responsive manner. Transfection studies of the 5'-up-stream flanking region (UFR) of c-myc/chloramphenicol acetyltransferase chimera genes suggest the presence of a TGF beta 1-responsive DNA element in the 2.3-kilobase c-myc 5'-UFR. Deletion mutant studies indicate the element lies between -106 to 70 relative to the P1 transcription start site. Studies with the gel mobility shift assay using 23-basepair double strand DNA showed the presence of at least two nuclear factors in NPA cell. TGF beta 1 treatment did not cause any alteration in TGF beta 1-induced mobility; however, the reduction of a positive band was selectively observed during 30 min to 2 h after treatment with TGF beta 1. In contrast, the position and intensity of another band were not altered by TGF beta 1 treatment. These results demonstrate that the inhibition of a nuclear factor binding to the c-myc 5'-UFR and subsequent suppression of c-myc gene expression are directly involved in the antiproliferative action of TGF beta 1 in NPA cell growth.
authors.affiliation: Department of Cell Physiology, Nagasaki University School of Medicine, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Usa
authors.forename: T
authors.initials: T
authors.lastname: Tsukazaki
authors.forename: H
authors.initials: H
authors.lastname: Namba
authors.forename: A
authors.initials: A
authors.lastname: Ohtsuru
authors.forename: H
authors.initials: H
authors.lastname: Kimura
authors.forename: M C
authors.initials: MC
authors.lastname: Villadolid
authors.forename: S
authors.initials: S
authors.lastname: Nagataki
authors.forename: S
authors.initials: S
authors.lastname: Yamashita
mesh_terms: D001483:Base Sequence; D015152:Blotting, Northern; D002291:Carcinoma, Papillary / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D002452:Cell Count; D002455:Cell Division / Q000187:drug effects; D015500:Chloramphenicol O-Acetyltransferase / Q000378:metabolism; D016207:Cytokines / Q000502:physiology; D004273:DNA, Neoplasm / Q000032:analysis / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D016259:Genes, myc / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D013489:Suppression, Genetic / Q000187:drug effects* / Q000502:physiology; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D013972:Thyrotropin / Q000502:physiology; D013997:Time Factors; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D016207:Cytokines; D004273:DNA, Neoplasm; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D013972:Thyrotropin; D015500:Chloramphenicol O-Acetyltransferase