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Insulin-Like growth factor I (IGF-I) and cyclic adenosine 3',5'-monophosphate regulate IGF-binding protein-3 gene expression by transcriptional and posttranscriptional mechanisms in mammary epithelial cells. 2000

W S Cohick, and B Wang, and P Verma, and Y R Boisclair
Department of Animal Sciences, Rutgers, State University of New Jersey, New Brunswick 08901, USA. cohick@aesop.rutgers.edu

Insulin-like growth factor I (IGF-I) is a potent mitogen for both normal and transformed mammary epithelial cells (MEC), and IGF-binding protein-3 (IGFBP-3) potentiates IGF-I action in these cells. The synthesis of IGFBP-3 is stimulated by both IGF-I and agents that increase intracellular cAMP (e.g. forskolin) in the bovine MEC line MAC-T. In addition, the combination of IGF-I and cAMP increases IGFBP-3 messenger RNA to a greater extent than does either treatment alone. The molecular mechanisms responsible for this regulation are not known and therefore represent the focus of this study. The half-life of IGFBP-3 messenger RNA in untreated MAC-T cells was determined to be 11 h. Exposure to IGF-I or forskolin increased the half-life to 27 and 101 h, respectively. Nuclear run-on assays indicated that IGFBP-3 transcription rates were increased 3.5 +/- 0.83-fold (n = 4) in cells treated with a combination of IGF-I and forskolin. To further study this regulation, 1.1 kb of the 5'-flanking region of the IGFBP-3 promoter were fused to a promoterless reporter plasmid encoding luciferase. Transient transfection assays indicated that both IGF-I and forskolin alone produced small, but significant, increases in IGFBP-3 promoter activity of 1.57 +/- 0.12 and 1.59 +/- 0.08-fold (P < 0.01), respectively (mean +/- SE; n = 7). However, the combination of IGF-I and forskolin increased IGFBP-3 promoter activity 2.25 +/- 0.14-fold above control values (P < 0.01), suggesting that these factors activate discrete signaling pathways that act in concert to stimulate IGFBP-3 gene transcription. Deletion analysis indicated that promoter fragments containing as little as 267 bp upstream of the TATA box retained responsiveness to IGF-I and forskolin. This region contains a 200-bp sequence that is approximately 80% homologous between the murine and bovine promoters. It contains several conserved AP-2 and Sp1 consensus binding sequences that may be important for the effects of IGF-I and forskolin on IGFBP-3 promoter activity. In summary, these data indicate that IGF-I and cAMP, working through separate signaling pathways, activate both transcriptional and post-transcriptional mechanisms to stimulate IGFBP-3 synthesis in MEC.

UI MeSH Term Description Entries
D007334 Insulin-Like Growth Factor I A well-characterized basic peptide believed to be secreted by the liver and to circulate in the blood. It has growth-regulating, insulin-like, and mitogenic activities. This growth factor has a major, but not absolute, dependence on GROWTH HORMONE. It is believed to be mainly active in adults in contrast to INSULIN-LIKE GROWTH FACTOR II, which is a major fetal growth factor. IGF-I,Somatomedin C,IGF-1,IGF-I-SmC,Insulin Like Growth Factor I,Insulin-Like Somatomedin Peptide I,Insulin Like Somatomedin Peptide I
D008321 Mammary Glands, Animal MAMMARY GLANDS in the non-human MAMMALS. Mammae,Udder,Animal Mammary Glands,Animal Mammary Gland,Mammary Gland, Animal,Udders
D008969 Molecular Sequence Data Descriptions of specific amino acid, carbohydrate, or nucleotide sequences which have appeared in the published literature and/or are deposited in and maintained by databanks such as GENBANK, European Molecular Biology Laboratory (EMBL), National Biomedical Research Foundation (NBRF), or other sequence repositories. Sequence Data, Molecular,Molecular Sequencing Data,Data, Molecular Sequence,Data, Molecular Sequencing,Sequencing Data, Molecular
D011401 Promoter Regions, Genetic DNA sequences which are recognized (directly or indirectly) and bound by a DNA-dependent RNA polymerase during the initiation of transcription. Highly conserved sequences within the promoter include the Pribnow box in bacteria and the TATA BOX in eukaryotes. rRNA Promoter,Early Promoters, Genetic,Late Promoters, Genetic,Middle Promoters, Genetic,Promoter Regions,Promoter, Genetic,Promotor Regions,Promotor, Genetic,Pseudopromoter, Genetic,Early Promoter, Genetic,Genetic Late Promoter,Genetic Middle Promoters,Genetic Promoter,Genetic Promoter Region,Genetic Promoter Regions,Genetic Promoters,Genetic Promotor,Genetic Promotors,Genetic Pseudopromoter,Genetic Pseudopromoters,Late Promoter, Genetic,Middle Promoter, Genetic,Promoter Region,Promoter Region, Genetic,Promoter, Genetic Early,Promoter, rRNA,Promoters, Genetic,Promoters, Genetic Middle,Promoters, rRNA,Promotor Region,Promotors, Genetic,Pseudopromoters, Genetic,Region, Genetic Promoter,Region, Promoter,Region, Promotor,Regions, Genetic Promoter,Regions, Promoter,Regions, Promotor,rRNA Promoters
D002417 Cattle Domesticated bovine animals of the genus Bos, usually kept on a farm or ranch and used for the production of meat or dairy products or for heavy labor. Beef Cow,Bos grunniens,Bos indicus,Bos indicus Cattle,Bos taurus,Cow,Cow, Domestic,Dairy Cow,Holstein Cow,Indicine Cattle,Taurine Cattle,Taurus Cattle,Yak,Zebu,Beef Cows,Bos indicus Cattles,Cattle, Bos indicus,Cattle, Indicine,Cattle, Taurine,Cattle, Taurus,Cattles, Bos indicus,Cattles, Indicine,Cattles, Taurine,Cattles, Taurus,Cow, Beef,Cow, Dairy,Cow, Holstein,Cows,Dairy Cows,Domestic Cow,Domestic Cows,Indicine Cattles,Taurine Cattles,Taurus Cattles,Yaks,Zebus
D002460 Cell Line Established cell cultures that have the potential to propagate indefinitely. Cell Lines,Line, Cell,Lines, Cell
D004847 Epithelial Cells Cells that line the inner and outer surfaces of the body by forming cellular layers (EPITHELIUM) or masses. Epithelial cells lining the SKIN; the MOUTH; the NOSE; and the ANAL CANAL derive from ectoderm; those lining the RESPIRATORY SYSTEM and the DIGESTIVE SYSTEM derive from endoderm; others (CARDIOVASCULAR SYSTEM and LYMPHATIC SYSTEM) derive from mesoderm. Epithelial cells can be classified mainly by cell shape and function into squamous, glandular and transitional epithelial cells. Adenomatous Epithelial Cells,Columnar Glandular Epithelial Cells,Cuboidal Glandular Epithelial Cells,Glandular Epithelial Cells,Squamous Cells,Squamous Epithelial Cells,Transitional Epithelial Cells,Adenomatous Epithelial Cell,Cell, Adenomatous Epithelial,Cell, Epithelial,Cell, Glandular Epithelial,Cell, Squamous,Cell, Squamous Epithelial,Cell, Transitional Epithelial,Cells, Adenomatous Epithelial,Cells, Epithelial,Cells, Glandular Epithelial,Cells, Squamous,Cells, Squamous Epithelial,Cells, Transitional Epithelial,Epithelial Cell,Epithelial Cell, Adenomatous,Epithelial Cell, Glandular,Epithelial Cell, Squamous,Epithelial Cell, Transitional,Epithelial Cells, Adenomatous,Epithelial Cells, Glandular,Epithelial Cells, Squamous,Epithelial Cells, Transitional,Glandular Epithelial Cell,Squamous Cell,Squamous Epithelial Cell,Transitional Epithelial Cell
D005260 Female Females
D005576 Colforsin Potent activator of the adenylate cyclase system and the biosynthesis of cyclic AMP. From the plant COLEUS FORSKOHLII. Has antihypertensive, positive inotropic, platelet aggregation inhibitory, and smooth muscle relaxant activities; also lowers intraocular pressure and promotes release of hormones from the pituitary gland. Coleonol,Forskolin,N,N-Dimethyl-beta-alanine-5-(acetyloxy)-3-ethenyldodecahydro-10,10b-dihydroxy-3,4a,7,7,10a-pentamethyl-1-oxo-1H-naphtho(2,1-b)pyran-6-yl Ester HCl,NKH 477,NKH-477,NKH477
D005786 Gene Expression Regulation Any of the processes by which nuclear, cytoplasmic, or intercellular factors influence the differential control (induction or repression) of gene action at the level of transcription or translation. Gene Action Regulation,Regulation of Gene Expression,Expression Regulation, Gene,Regulation, Gene Action,Regulation, Gene Expression

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