Characterization of the mouse insulin-like growth factor binding protein 4 gene regulatory region and expression studies.

Insulin-like growth factor binding protein 4 (IGFBP-4) is known as a potent inhibitor of IGFs action in various cell types. In this study, the mouse IGFBP-4 gene 5' flanking region, the IGFBP-4 mRNA expression, and the IGFBP-4s intracellular transport were investigated. The regulatory region exhibits all elements typical for an eukaryotic TATA element containing promoter and was found to also contain functional elements to direct transcriptional activation of a luc reporter gene construct that gradually decreased by 5' unidirectional deletions. Responsiveness of the IGFBP-4 promoter activity was tested with thyroid hormone and found only within extended constructs but not when a potential TRalpha1-binding site had been deleted. By using exon specific probes, we observed a varying expression pattern of IGFBP-4 transcripts in three rodent cell lines. Surprisingly, mouse fibroblastic NIH/3T3 cells displayed exclusively about a 2.0-kb transcript apparently lacking the IGFBP-4 mRNA 5' region. Studies on the intracellular transport by establishment of an IGFBP4/green fluorescent protein (GFP) fusion protein clearly demonstrate that IGFBP-4 is transported continuously along the intracellular secretory pathway and is excluded from other intracellular compartments. The description of the genomic IGFBP-4 region in the mouse now opens new perspectives for further clarification of the role of IGFBP-4 in growth and development.

[1]  K. Klaushofer,et al.  Triiodothyronine, a Regulator of Osteoblastic Differentiation: Depression of Histone H4, Attenuation of c-fos/c-jun, and Induction of Osteocalcin Expression , 1997, Calcified Tissue International.

[2]  A. Ellinger,et al.  Effects of triiodothyronine on the morphology of cells and matrix, the localization of alkaline phosphatase, and the frequency of apoptosis in long-term cultures of MC3T3-E1 cells. , 1997, Bone.

[3]  P. Roschger,et al.  Effects of triiodothyronine on morphology, growth behavior, and the actin cytoskeleton in mouse osteoblastic cells (MC3T3-E1). , 1996, Bone.

[4]  L. Donahue,et al.  Insulinlike growth factors: Potential therapeutic options for osteoporosis , 1995, Trends in Endocrinology & Metabolism.

[5]  S. Mohan,et al.  Studies on the Mechanisms by Which Insulin-like Growth Factor (IGF) Binding Protein-4 (IGFBP-4) and IGFBP-5 Modulate IGF Actions in Bone Cells (*) , 1995, The Journal of Biological Chemistry.

[6]  L. Quarles,et al.  Differentiation of MC3T3-E1 osteoblasts is associated with temporal changes in the expression of IGF-I and IGFBPs. , 1995, Bone.

[7]  H. Gerdes,et al.  Visualization of protein transport along the secretory pathway using green fluorescent protein , 1995, FEBS letters.

[8]  S. Mohan,et al.  The insulin-like growth factor system and the coupling of formation to resorption. , 1995, Bone.

[9]  R. Koenig,et al.  The Interplay of Half-site Sequence and Spacing on the Activity of Direct Repeat Thyroid Hormone Response Elements (*) , 1995, The Journal of Biological Chemistry.

[10]  S. Widen,et al.  Episomal expression of sense and antisense insulin-like growth factor (IGF)-binding protein-4 complementary DNA alters the mitogenic response of a human colon cancer cell line (HT-29) by mechanisms that are independent of and dependent upon IGF-I. , 1994, Cancer research.

[11]  E. Zwarthoff,et al.  cDNA cloning and mRNA expression of the six mouse insulin-like growth factor binding proteins , 1994, Molecular and Cellular Endocrinology.

[12]  K. Klaushofer,et al.  Thyroid hormones increase insulin‐like growth factor mRNA levels in the clonal osteoblastic cell line MC3T3‐E1 , 1994, FEBS letters.

[13]  N. Jones,et al.  Different binding specificities and transactivation of variant CRE's by CREB complexes. , 1994, Nucleic acids research.

[14]  R. Evans,et al.  Isoform-specific amino-terminal domains dictate DNA-binding properties of ROR alpha, a novel family of orphan hormone nuclear receptors. , 1994, Genes & development.

[15]  N. Ling,et al.  Structure of the rat insulin-like growth factor binding protein-4 gene. , 1993, Biochemical and biophysical research communications.

[16]  S. Mohan,et al.  Autocrine regulators of MC3T3‐E1 cell proliferation , 1993, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[17]  L. Quarles,et al.  Distinct proliferative and differentiated stages of murine MC3T3‐E1 cells in culture: An in vitro model of osteoblast development , 1992, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[18]  M. Karin,et al.  The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation. , 1991, Biochimica et biophysica acta.

[19]  S. Mohan,et al.  1,25-Dihydroxyvitamin D3 differentially regulates the production of insulin-like growth factor I (IGF-I) and IGF-binding protein-4 in mouse osteoblasts. , 1991, Endocrinology.

[20]  R. Scarpulla,et al.  Transcriptional activation through ETS domain binding sites in the cytochrome c oxidase subunit IV gene , 1991, Molecular and cellular biology.

[21]  S. Mohan,et al.  Inhibitory insulin-like growth factor-binding protein: cloning, complete sequence, and physiological regulation. , 1990, Molecular endocrinology.

[22]  H. Thiesen,et al.  Target Detection Assay (TDA): a versatile procedure to determine DNA binding sites as demonstrated on SP1 protein. , 1990, Nucleic acids research.

[23]  A. Efstratiadis,et al.  A growth-deficiency phenotype in heterozygous mice carrying an insulin-like growth factor II gene disrupted by targeting , 1990, Nature.

[24]  Kojiro Takahashi,et al.  Functional modes of retinoic acid in mouse osteoblastic clone MC3T3‐E1, proved as a target cell for retinoic acid , 1990, FEBS letters.

[25]  S. Mohan,et al.  Isolation of an inhibitory insulin-like growth factor (IGF) binding protein from bone cell-conditioned medium: a potential local regulator of IGF action. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[26]  N. Ling,et al.  An insulin-like growth factor-binding protein in ovarian follicular fluid blocks follicle-stimulating hormone-stimulated steroid production by ovarian granulosa cells. , 1989, Endocrinology.

[27]  K. Kasono,et al.  Stimulation of alkaline phosphatase activity by thyroid hormone in mouse osteoblast-like cells (MC3T3-E1): a possible mechanism of hyperalkaline phosphatasia in hyperthyroidism. , 1988, Bone and mineral.

[28]  Y. Amagai,et al.  In vitro differentiation and calcification in a new clonal osteogenic cell line derived from newborn mouse calvaria , 1983, The Journal of cell biology.

[29]  F. Sanger,et al.  DNA sequencing with chain-terminating inhibitors. , 1977, Proceedings of the National Academy of Sciences of the United States of America.

[30]  T. Werner,et al.  MatInd and MatInspector: new fast and versatile tools for detection of consensus matches in nucleotide sequence data. , 1995, Nucleic acids research.

[31]  A. Bird,et al.  Effects of DNA methylation on DNA-binding proteins and gene expression. , 1993, Current opinion in genetics & development.