Human insulin-like growth factor binding protein-4 and -6 : gene structure and transcription regulation
Author: Zazzi, Henric
Date: 2000-02-04
Location: Hudklinikens föreläsningssal, hus B3, plan 1, Karolinska Sjukhuset
Time: 10.00
Department: Institutionen för molekylär medicin / Department of Molecular Medicine
Abstract
Insulin-like growth factors (IGF-I and IGF-II) are among the more
abundant growth factors isolated from bone tissue and are synthesized by
various bone cells including osteoblasts. The activity of IGFs is
controlled by a family of binding proteins (IGFBPs) divided into
subfamilies depending on their individual affinity for IGFs. IGFBP-4 to
-6 have been found in bone, and suggested to participate in regulation of
bone matrix. This thesis is based on findings concerning structure,
regulation, and chromosomal localization of the genes for human IGFBP-4
and -6. The human IGFBP-4 gene had been located previously to chromosome
l7q 12-2 1. 1, but a new microsatellite within the IGFBP-4 gene enabled
high-resolution genetic mapping to the vicinity of BRCA1. The human
IGFBP-6 gene was mapped to chromosome 12q 13 and characterized: IGFBP6 is
spanning 4.7 kb and consist of four exons separated by three introns with
sizes 2661, 182, and 884. Three mRNA CAP sites were located to 10 1, 100,
and 96 bp upstream of the translation initiation site, but no TATA or
CAAT consensus sequences were found 5' of these sites. The IGFBP-4 gene
is contained within 15.3 kb, with its transcription initiation site
located 28 bp downstream of a TATA box sequence and 286 bp 5' of the
translation initiation codon. The gene is composed of four exons
separated by three introns with sizes 8903, 787, and 2386 bp. Basal
promoter activity of IGFBP4 decreased 60% between - 135 to - 103, and was
completely repressed by deletions from -60 to -41. A 3-hour treatment
with prostaglandin E2 augmented IGFBP4 transcription two-fold, whereas a
24-hours treatment with interferon-[gamma] decreased IGFBP4 transcription
to 40%. EMSA showed that prostaglandin E2 activated Sp I, which was
capable to bind to a GC-box located from -46 to -43, whereas
interferon-[gamma] stimulated an inhibitory nuclear protein with an
affinity for the NF-[kappa]B recognition sequence located from -47 to
-44. The IGFBP4 promoter had a CpG/GpC ratio of 1.08 and was shown to be
influenced by its methylation status. A partially methylated promoter,
constructed by HpaII in vitro methylation, had 50% activity after 24
hours, and this activity decreased to 34% after this time point. Complete
methylation of the promoter by the Sssl-methylase abolished
transcription. Treatment with a deacetylase inhibitor increased IGFBP4
transcription activity to 750% in cells transfected with non-methylated
and partially methylated constructs, but was not able to affect IGFBP4
transcription activity in cells transfected with the completely
methylated promoter.
List of papers:
I. Zazzi H, Nikoshkov A, Hall K, Luthman H (1998). "Structure and transcription regulation of the human insulin-like growth factor binding protein 4 gene (IGFBP4). " Genomics 49(3): 401-410
Pubmed
II. Tonin P, Ehrenborg E, Lenoir G, Feunteun J, Lynch H, Morgan K, Zazzi H, Vivier A, Pollak M, Huynh H, et al (1993). " The human insulin-like growth factor-binding protein 4 gene maps to chromosome region 17q12-q21.1 and is close to the gene for hereditary breast-ovarian cancer." Genomics 18(2): 414-417
Pubmed
III. Zazzi H, Skoog T, Eriksson P, Luthman H (1970). "Prostaglandin E2 and Interferon-gamma regulate the transcription of the human insulin-like growth factor binding protein 4 gene." (Manuscript)
IV. Zazzi H, Sandberg G, Luthman H (1970). "Methylation of the human insulin-like growth fator binding protein 4 gene." (Manuscript)
V. Ehrenborg E, Zazzi H, Lagercrantz S, Granqvist M, Hillerbrand U, Allander SV, Larsson C, Luthman H (1999). "Characterization and chromosomal localization of the human insulin-like growth factor-binding protein 6 gene." Mamm Genome 10(4): 376-380
Pubmed
I. Zazzi H, Nikoshkov A, Hall K, Luthman H (1998). "Structure and transcription regulation of the human insulin-like growth factor binding protein 4 gene (IGFBP4). " Genomics 49(3): 401-410
Pubmed
II. Tonin P, Ehrenborg E, Lenoir G, Feunteun J, Lynch H, Morgan K, Zazzi H, Vivier A, Pollak M, Huynh H, et al (1993). " The human insulin-like growth factor-binding protein 4 gene maps to chromosome region 17q12-q21.1 and is close to the gene for hereditary breast-ovarian cancer." Genomics 18(2): 414-417
Pubmed
III. Zazzi H, Skoog T, Eriksson P, Luthman H (1970). "Prostaglandin E2 and Interferon-gamma regulate the transcription of the human insulin-like growth factor binding protein 4 gene." (Manuscript)
IV. Zazzi H, Sandberg G, Luthman H (1970). "Methylation of the human insulin-like growth fator binding protein 4 gene." (Manuscript)
V. Ehrenborg E, Zazzi H, Lagercrantz S, Granqvist M, Hillerbrand U, Allander SV, Larsson C, Luthman H (1999). "Characterization and chromosomal localization of the human insulin-like growth factor-binding protein 6 gene." Mamm Genome 10(4): 376-380
Pubmed
Issue date: 2000-01-14
Publication year: 2000
ISBN: 91-628-3873-3
Statistics
Total Visits
Views | |
---|---|
Human ...(legacy) | 283 |
Human ... | 106 |
Total Visits Per Month
July 2020 | August 2020 | September 2020 | October 2020 | November 2020 | December 2020 | January 2021 | |
---|---|---|---|---|---|---|---|
Human ... | 2 | 1 | 1 | 3 | 0 | 4 | 2 |
Top country views
Views | |
---|---|
Sweden | 77 |
United States | 39 |
Germany | 37 |
China | 27 |
Russia | 11 |
Turkey | 8 |
Finland | 3 |
Japan | 3 |
Denmark | 2 |
Greece | 2 |
Top cities views
Views | |
---|---|
Kiez | 15 |
Sunnyvale | 8 |
Woodbridge | 6 |
Beijing | 5 |
Easton | 3 |
Moscow | 3 |
Shenzhen | 3 |
Tokyo | 3 |
University Park | 3 |
Athens | 2 |