Alternative titles; symbols
HGNC Approved Gene Symbol: IGFBP5
Cytogenetic location: 2q35 Genomic coordinates (GRCh38): 2:216,672,105-216,695,549 (from NCBI)
For background information on the IGFBP gene family, see IGFBP4 (146733).
Allander et al. (1994) cloned the IGFBP5 gene from a human genomic library.
Sato et al. (2002) overexpressed a constitutively active form of Six5 (600963) in murine P19 embryonal carcinoma cells. Using expression profiling in cDNA arrays, they identified 21 potential target genes whose expression level increased by the treatment. One of these genes was Igfbp5, which was also decreased in Six5-deficient mouse fibroblasts. The response of human IGFBP5 to MyoD (159970)-induced muscle conversion was altered in cells of myotonic dystrophy-1 (DM1; 160900) patients. The authors concluded that Six5 is an activator that directs Igfbp5 expression, and hypothesized that reduced SIX5 expression in DM1 may contribute to the DM1 phenotype.
Using a yeast 2-hybrid screen, Amaar et al. (2002) found strong and specific interaction between IGFBP5 and FHL2 (602633). Western blot analysis of nuclear extracts from calvaria and rib osteoblasts and immunofluorescence microscopy of osteosarcoma cell lines indicated interaction between FHL2 and IGFBP5 in vivo. Purified FHL2 did not interact with any other IGFBP tested.
Butt et al. (2003) found that expression of IGFBP5 by stable transfection and adenovirus-mediated infection was inhibitory to growth in 2 human breast cancer cell lines. IGFBP5 expression led to G2/M cell cycle arrest and apoptosis. Apoptosis was associated with increased expression of the proapoptotic regulator BAX (600040) and a decrease in the antiapoptotic BCL2 (151430), and it was abrogated by a broad-spectrum caspase inhibitor. Stable expression of IGFBP5 in the breast cancer cell lines also inhibited the formation and growth of tumors following injection in athymic mice. The authors concluded that IGFBP5 is a growth inhibitor and proapoptotic agent in breast cancer cells.
Chivukula et al. (2014) observed defects in epithelial regeneration after injury of mice lacking both Mir143 (612117) and Mir145 (611795) that resulted from dysfunction of smooth muscle and myofibroblasts. Treatment with dextran sulfate sodium (DSS), which was tolerated in wildtype mice, resulted in lethal intestinal injury in Mir143/Mir145-deficient mice. Mir143/Mir145-deficient mice had upregulated expression of Igfbp5, an Mir143 target gene, which resulted in impaired IGF signaling that likely contributed to regenerative failure after DSS-mediated injury.
Allander et al. (1994) showed that the IGFBP5 gene is divided into 4 exons and spans about 33 kb, primarily due to a first intron of approximately 25 kb. Primer extension studies identified the IGFBP5 mRNA cap site 772 bp 5-prime to the first nucleotide of the translation start codon. A potential TATA element beginning 33 bp 5-prime to the mRNA cap site was identified. When a DNA fragment containing this cap site and 461 bp of upstream sequence was placed 5-prime to the chloramphenicol acetyltransferase (CAT) reporter gene and transfected into human breast cancer cells, it directed CAT expression in an orientation-specific manner, suggesting that this region contains elements essential for IGFBP5 promoter activity.
By PCR amplification of DNA from somatic human/rodent cell hybrids, by fluorescence in situ hybridization, and by hybridization to pulsed field gel electrophoresis fragments, Allander et al. (1994) mapped the IGFBP5 gene to chromosome 2q33-q34. Southern analysis identified a single copy of the IGFBP5 gene in the haploid human genome. The IGFBP2 gene (146731) and the IGFBP5 gene are transcribed convergently and are separated by approximately 20 to 40 kb of DNA.
Kou et al. (1994) demonstrated that, in the mouse, Igfbp2 and Igfbp5 colocalize to a proximal region of chromosome 1 that is syntenic with human chromosome 2q33-q36 and that the 2 genes are 5 kb apart in a tail-to-tail orientation. This suggests that the human IGFBP5 gene is located on 2q33-q36. Kou et al. (1994) also used interspecific backcross mapping and gene cloning to demonstrate that the Igfbp1 and Igfbp3 are located in the proximal part of chromosome 11. In the human genome, these 2 loci map within 20 kb of one another on 7p14-p12, and the genes are organized in a tail-to-tail configuration. The results suggested to Kou et al. (1994) an evolutionary scheme in which a primordial IGFBP gene duplicated to form a cluster that was later replicated to create a second linkage group.
The insulin-like growth factors IGF1 (147440) and IGF2 (147470) are essential for development; bioavailable IGF is tightly regulated by 6 related IGFBPs. IGFBP5 is the most conserved and is developmentally upregulated in key lineages and pathologies; in vitro studies suggest that it functions independently of IGF interaction (Butt et al., 2003). Genetic ablation of individual Igfbps yields limited phenotypes because of substantial compensation by remaining family members. Therefore, to reveal Igfbp5 actions in vivo, Salih et al. (2004) generated lines of transgenic mice that ubiquitously overexpressed Igfbp5 from early development. Significantly increased neonatal mortality, reduced female fertility, whole-body growth inhibition, and retarded muscle development were observed in Igfbp5-overexpressing mice. Despite only modest changes in Igf and Igfbp concentrations, the Igfbp5-overexpressing mice displayed a phenotype more extreme than that observed for other Igfbp genetic models. Although growth retardation was obvious prenatally, maximal inhibition occurred postnatally before the onset of growth hormone-dependent growth, regardless of Igfbp5 expression level, revealing a period of sensitivity to Igfbp5 during this important stage of tissue programming.
Allander, S. V., Larsson, C., Ehrenborg, E., Suwanichkul, A., Weber, G., Morris, S. L., Bajalica, S., Kiefer, M. C., Luthman, H., Powell, D. R. Characterization of the chromosomal gene and promoter for human insulin-like growth factor binding protein-5. J. Biol. Chem. 269: 10891-10898, 1994. [PubMed: 7511611]
Amaar, Y. G., Thompson, G. R., Linkhart, T. A., Chen, S.-T., Baylink, D. J., Mohan, S. Insulin-like growth factor-binding protein 5 (IGFBP-5) interacts with a four and a half LIM protein 2 (FHL2). J. Biol. Chem. 277: 12053-12060, 2002. [PubMed: 11821401] [Full Text: https://doi.org/10.1074/jbc.M110872200]
Butt, A. J., Dickson, K. A., McDougall, F., Baxter, R. C. Insulin-like growth factor-binding protein-5 inhibits the growth of human breast cancer cells in vitro and in vivo. J. Biol. Chem. 278: 29676-29685, 2003. [PubMed: 12777377] [Full Text: https://doi.org/10.1074/jbc.M301965200]
Chivukula, R. R., Shi, G., Acharya, A., Mills, E. W., Zeitels, L. R., Anandam, J. L., Abdelnaby, A. A., Balch, G. C., Mansour, J. C., Yopp, A. C., Maitra, A., Mendell, J. T. An essential mesenchymal function for miR-143/145 in intestinal epithelial regeneration. Cell 157: 1104-1116, 2014. [PubMed: 24855947] [Full Text: https://doi.org/10.1016/j.cell.2014.03.055]
Kou, K., James, P. L., Clemmons, D. R., Copeland, N. G., Gilbert, D. J., Jenkins, N. A., Rotwein, P. Identification of two clusters of mouse insulin-like growth factor binding protein genes on chromosomes 1 and 11. Genomics 21: 653-655, 1994. [PubMed: 7525452] [Full Text: https://doi.org/10.1006/geno.1994.1329]
Salih, D. A. M., Tripathi, G., Holding, C., Szestak, T. A. M., Ivelisse Gonzalez, M., Carter, E. J., Cobb, L. J., Eisemann, J. E., Pell, J. M. Insulin-like growth factor-binding protein 5 (Igfbp5) compromises survival, growth, muscle development, and fertility in mice. Proc. Nat. Acad. Sci. 101: 4314-4319, 2004. [PubMed: 15010534] [Full Text: https://doi.org/10.1073/pnas.0400230101]
Sato, S., Nakamura, M., Cho, D. H., Tapscott, S. J., Ozaki, H., Kawakami, K. Identification of transcriptional targets for Six5: implication for the pathogenesis of myotonic dystrophy type 1. Hum. Molec. Genet. 11: 1045-1058, 2002. [PubMed: 11978764] [Full Text: https://doi.org/10.1093/hmg/11.9.1045]