Disease relevance of Igfbp5

• To test the hypothesis that IGFBP-5 promotes the acquisition of bone mineral density (BMD), we generated transgenic (Tg) mice overexpressing Igfbp5 using a cytomegalovirus enhancer and beta-actin promoter (CMV/betaA) [1].
• We have expressed two N-terminal fragments of IGFBP-5 in Escherichia coli; the first encodes the N-terminal domain of the protein (residues 1-104) and the second, mini-IGFBP-5, comprises residues Ala40 to Ile92 [2].
• Androgen receptor up-regulates insulin-like growth factor binding protein-5 (IGFBP-5) expression in a human prostate cancer xenograft [3].
• IGFBP-5 immunohistochemical staining of prostate tissue specimens from patients was stronger in androgen-dependent and androgen-independent CaP than in areas of intraepithelial neoplasia (PIN) or benign prostatic hyperplasia (BPH) [3].
• Expression of IGFBP-5, both by stable transfection and adenoviral-mediated infection, was inhibitory to the growth of MDA-MB-231 and Hs578T human breast cancer cells over a 13-day period [4].

High impact information on Igfbp5

• Our findings suggest that IGFBP-5 is a direct or indirect target for Stat3 and its upregulation is essential to normal involution [5].
• IGFBP-5 has been suggested to induce apoptosis by sequestering IGF-1 to casein micelles, thereby inhibiting its survival function [5].
• Insulin-like growth factor binding protein-5 modulates muscle differentiation through an insulin-like growth factor-dependent mechanism [6].
• We have shown previously that C2 myoblasts secrete IGFBP-5 as their sole IGFBP [6].
• Compared to controls, IGFBP-5 sense myoblasts show enhanced survival in low serum medium, remaining viable for at least four weeks in culture [6].

Chemical compound and disease context of Igfbp5

• This accumulation of truncated IGFBP-5 in the conditioned medium was not dependent on osteoclastic bone resorption, since it was not blocked by calcitonin or a bisphosphonate which inhibited PTH- and PGE2-stimulated 45Ca-release [7].

Biological context of Igfbp5

• Significantly increased neonatal mortality, reduced female fertility, whole-body growth inhibition, and retarded muscle development were observed in Igfbp5-overexpressing mice [8].
• Thus, 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 [8].
• To directly examine the functional importance of segmental gene expression in the hair follicle, we have generated transgenic mice expressing Igfbp5 in differentiating keratinocytes of the medulla and inner root sheath [9].
• Igfbp5 is the most conserved and is developmentally up-regulated in key lineages and pathologies; in vitro studies suggest that IGFBP-5 functions independently of IGF interaction [8].
• Further examination of apoptotic pathways revealed that wt- and mutIGFBP-5 ameliorated the increase in caspase-9 but not the modest increase in caspase-8 during myogenesis, suggesting that IGFBP-5 increased cell survival via inhibition of intrinsic cell death pathways in an IGF-independent manner [10].

Anatomical context of Igfbp5

• We identify Igfbp5 as the first molecular marker that distinguishes among different hair follicle types [9].
• Myc-tagged wild-type (termed wtIGFBP-5) and non-IGF binding mouse Igfbp5 (termed mutIGFBP-5) cDNAs were generated and used to transfect C2 myoblasts, a cell line that undergoes differentiation to myotubes in an IGF- and IGFBP-5-regulated manner [10].
• Up-regulation of insulin-like growth factor binding protein-5 is independent of muscle cell differentiation, sensitive to rapamycin, but insensitive to wortmannin and LY294002 [11].
• Histomorphometry revealed that although the bone formation rate and mineralizing surface at the periosteum decreased in Tg mice, they increased at the endosteum, suggesting opposing effects of IGFBP-5 on periosteal and endosteal osteoblasts (by altering proliferation or survival) [1].
• In normal adult mice, IGFBP-5 messenger RNA (mRNA) was detected in all brain regions examined, and the highest levels of the mRNA were found in cerebellum, followed by brainstem, diencephalon, hippocampus, and cerebral cortex [12].

Associations of Igfbp5 with chemical compounds

• These data provide strong evidence for a functional role of IGFBP-5 expression in mediating the apoptosis induced by androgen deprivation in androgen-dependent neoplasia [13].
• Zn(2+) acts by lowering the affinity (K(a)) of IGFBP-5 for the IGFs [14].
• However, indomethacin and progesterone depressed IGFBP-5 secretion by BC3H-1 cells [15].
• Testosterone treatment of CWR22 tumor-bearing mice 6 or 12 days after castration increased IGFBP-5 mRNA 10- to 12-fold [3].
• Agents that elevate intracellular cAMP concentrations (dcAMP, forskolin, isoproterenol, and prostaglandin [PGE1]) increase secretion of IGFBP-4 and IGFBP-5 from L6 cells [15].

Physical interactions of Igfbp5

• Notable among this group were the growth factor gene Igf2 and its binding protein Igfbp5 [16].
• Both (125)I-IGF-I and (125)I-IGF-II bound to high and low affinity sites on IGFBP-5 [17].
• We have also demonstrated that IGFBP-5 interacts with alpha(s2)-casein and that this interaction implicates it in the regulation of plasminogen activation in the mammary gland [18].
• Comparison studies of IGFBP-5 binding to osteoblasts and osteoblast-derived extracellular matrix [19].

Regulatory relationships of Igfbp5

• Insulin-like growth factor I (IGF-I) regulates IGF binding protein-5 gene expression in the brain [12].
• We also showed, using a specific inhibitor, that the p38 mitogen-activated protein kinase (p38 MAPK) was not involved in the inhibition of IGFBP-5 production [20].
• Prolactin inhibits cell loss and decreases matrix metalloproteinase expression in the involuting mouse mammary gland but fails to prevent cell loss in the mammary glands of mice expressing IGFBP-5 as a mammary transgene [21].
• Interestingly Akt induced significant up-regulation of insulin-like growth factor-binding protein-5 (IGFBP-5), which could contribute to its anti-apoptotic effects in the heart [22].

Other interactions of Igfbp5

• Furthermore, as judged by in situ hybridization histochemistry, IGF-I appeared to increase both the number of IGFBP-5-expressing cells and the magnitude of their expression, an observation that was especially marked in the molecular layer and white matter of the cerebellum [12].
• In the terminal end buds (TEBs), IGFBP-3 mRNA expression was consistent with its localization in the cap cells, whereas IGFBP-5 was highly expressed in the body cells of the TEB [23].
• The refinement of the target region to four genes and the finding that the QTL affects IGFBP-5 levels suggest that PAPPA2 may be involved with normal postnatal growth [24].
• Rapamycin which indirectly prevents activation of the p70 ribosomal protein-S6 kinase (p70S6k), suppressed IGFBP-5 induction [11].
• 4. Zn(2+) is shown to depress the binding of both IGF-I and IGF-II to soluble secreted IGFBP-5; [(125)I]-IGF-I binding is affected more so than [(125)I]-IGF-II binding [14].

Analytical, diagnostic and therapeutic context of Igfbp5

• Accordingly, we found two of the six IGFBP-5 QTLs (Chrs 1 and 11) identified for serum IGFBP-5 phenotype also showed significant association with total body bone mineral density phenotype (measured by dual energy x-ray absorptiometry) in the F2 mice [25].
• IGFBP-5 mRNA was not detectable in tumors from control animals, but levels increased 120-fold in tumors 3 days after castration [13].
• In this study we purified a 23-kDa IGFBP-5 from cultures of human osteoblast-like cells using ligand affinity chromatography and reversed-phase high performance liquid chromatography and tested its bioactivity in serum-free cultures of normal mouse osteoblast-like cells [26].
• Using mammary-enriched cDNA microarrays, we identified several genes that were preferentially expressed in MK-PTEN mammary tissue, including the IGF-binding protein-5 (Igfbp5) gene, and others whose expression was reduced, including the genes for c-Jun amino-terminal kinase [27].
• Purification of membrane extracts by IGFBP-5 affinity chromatography revealed a 420-kDa band on reduced SDS-polyacrylamide gels [28].

References