Disease relevance of IGFBP6

• Cell polarity of the insulin-like growth factor system in human intestinal epithelial cells. Unique apical sorting of insulin-like growth factor binding protein-6 in differentiated human colon cancer cells [1].
• In endometrial cancer tissues, the mean IGFBP-6 mRNA level was similar to that in cycling endometrium during the peri-ovulatory period [2].
• IGF-binding protein-6 is involved in growth inhibition in SH-SY5Y human neuroblastoma cells: its production is both IGF- and cell density-dependent [3].
• An excess of IGFBP-6 was also found in plasma of both dialysed and non-dialysed prepubertal growth retarded children with chronic renal failure (CRF) (mean SDS: 23.0 and 9.3, respectively) [4].
• Serum IGF-binding protein-6 and prostate specific antigen in breast cancer [5].

High impact information on IGFBP6

• IGFBP-2 and IGFBP-4 are secreted primarily into the basolateral side (71 and 87%, respectively), whereas IGFBP-6 is targeted to the apical surface (76%) as a possible consequence of an active sorting [1].
• This study indicates (a) that IGF-II is potentially capable of autocrine regulation on the basolateral side of HT29-D4-GAL cell, and (b) that IGFBP-6 has a unique pattern of secretory polarity [1].
• Western immunoblot analysis also demonstrated increased intact IGFBP-2 but decreased IGFBP-6 in the presence of N-myc oncogene [6].
• Our findings show that IGFBP-6 influences neuroblastoma cell growth, both in vitro and in experimental xenograft development [7].
• The N-terminal linkages of IGFBP-6 differ significantly from those of IGFBP-1 (and, by implication, the other IGFBPs), which could contribute to the distinctive IGF binding properties of IGFBP-6 [8].

Chemical compound and disease context of IGFBP6

• Infection of NSCLC cell lines in vitro with an adenovirus expressing human IGFBP-6 under the control of a CMV promoter (Ad5CMV-BP6) reduced NSCLC cell number through activation of programmed cell death, as shown by cell staining with Hoechst 33342 or DNA end-labeling with bromodeoxyuridine triphosphate [9].
• IGFBP-6 therefore might be involved in the direct effects of DES in androgen-independent prostate cancer [10].
• Insulin-like growth factor binding protein-6 inhibits prostate cancer cell proliferation: implication for anticancer effect of diethylstilbestrol in hormone refractory prostate cancer [10].

Biological context of IGFBP6

• RA enhanced IGFBP-6 gene expression by threefold in MDA-MB-231 cells, whereas IGF-1 had no effect on IGFBP-6 gene expression in either cell line.(ABSTRACT TRUNCATED AT 400 WORDS)[11]
• This study therefore shows that IGFBP-6 plays a role in neuroblastoma cell growth in vivo and in vitro and that stable overexpression of IGFBP-6 leads to alteration of the initial balance between the IGFBPs [12].
• IGFBP-6 levels were inversely correlated with glomerular filtration rate [4].
• We have characterized the genomic structure and the chromosomal location of the human IGFBP6, which is present in the human genome as a single-copy gene spanning 4.7 kb [13].
• Examples of overexpressed genes are SFRP1 that is involved in Wnt signalling and IGFBP6, which is of importance for fetal growth and inhibits cell growth through insulin-like growth factor-II [14].

Anatomical context of IGFBP6

• IGFBP-6 was expressed in greater abundance in the decidua parietalis than in decidua basalis, although the general level of expression was low [15].
• Moderate expression of the IGFBP-4 and IGFBP-5 genes was seen in all cell types, including stromal cells, but no IGFBP-6 mRNA was detected [16].
• Human fibroblast IGFBP-6 expression was stable under the different culture conditions; IGFBP-1 and -2 mRNA were not detected [17].
• The IGFBP-6 mRNA expression showed a significant cyclic variation in normal endometrium, with low levels in late-proliferative and early- to mid-secretory phases and high expression in late-secretory and early-proliferative phases [2].
• IGFBP-3, IGFBP-5 and IGFBP-6 were expressed in approximately 50% of cell lines [18].

Associations of IGFBP6 with chemical compounds

• MEASUREMENTS: The IGFBP-6 assay is competitive, utilizing a rabbit polyclonal antibody raised against a synthetic peptide comprising amino acids 90-118 of the hIGFBP-6 sequence and an additional tyrosine residue [4].
• Pretreatment serum IGFBP-2 and IGFBP-6 levels were greatly elevated, but as glucose normalized with treatment, only IGFBP-2 decreased, showing an inverse correlation with glucose (r = 0.716) [19].
• Inhibition of Caco-2 cell proliferation by all-trans retinoic acid: role of insulin-like growth factor binding protein-6 [20].
• Cycloheximide abolished the RA-stimulated increase in IGFBP-6 mRNA and reduced baseline IGFBP-5 mRNA levels, but did not affect RA-modulated mRNA levels of the other IGFBPs [21].
• The proteolytic activity against IGFBP-6 differed at least from IGFBP-5 protease activity in its sensitivity both to IGF-II and to the hydroxamic acid-based disintegrin metalloprotease inhibitor, as well as serine protease inhibitors [22].

Physical interactions of IGFBP6

• In summary, a specific antiserum and RIA were used to demonstrate elevated levels of intact IGF-II-binding IGFBP-6 in serum of CRF children [23].

Regulatory relationships of IGFBP6

• The binding proteins IGFBP-I and IGFBP-3 did not cross-react, but both IGF-I and IGF-II markedly inhibited IGFBP-6 tracer binding to antiserum [24].
• In addition, IGFBP-6 secretory level is down-regulated (approximately 60% decrease) whereas those of IGFBP-2 and IGFBP-4 remain constant during the differentiation process [25].
• Identification of IGFBP-6 as a significantly downregulated gene by beta-catenin in desmoid tumors [26].
• However, insulin-like growth factor binding protein 6 (IGFBP-6) gene expression levels were upregulated in PC-3 cells [10].
• Knockdown of p38 MAPK using short interfering RNA blocked IGFBP-6-induced migration of RD cells [27].

Other interactions of IGFBP6

• IGFBP-6 differs from other IGFBPs in having the highest affinity for IGF-II and in binding IGF-I with 20-100-fold lower affinity [8].
• The N-terminal disulfide linkages of human insulin-like growth factor-binding protein-6 (hIGFBP-6) and hIGFBP-1 are different as determined by mass spectrometry [8].
• CONCLUSION: Lower serum concentrations of IGFBP-6, -3 and -1, but higher PSA concentrations were seen in the breast cancer group, and collectively these would suggest that there is an increase in bioavailable IGF-I in breast cancer [5].
• In media treated with plasminogen, in which IGFBP-2 was proteolysed, IGFBP-6 was increased [12].
• IGFBP-6 and type 1 and 2 IGF receptor mRNA expression was detectable in all ovarian compartments only by RT-PCR [28].

Analytical, diagnostic and therapeutic context of IGFBP6

• The complete disulfide linkages of IGFBP-6 were determined using electrospray ionization mass spectrometry of purified tryptic peptide complexes digested with combinations of chymotrypsin, thermolysin, and endoproteinase Glu-C [8].
• In small IGFBP-6-expressing xenografts where tumour development had apparently been arrested, haematoxylin--eosin and TUNEL staining revealed numerous apoptotic cells [12].
• In order to obtain more insight into the clinical significance and regulation of circulating levels of IGFBP-6 we developed a specific radioimmunoassay (RIA) for this protein [4].
• In a group of CRF patients who underwent renal transplantation circulating IGFBP-6 levels were markedly lower (mean SDS: 4.6) [4].
• In situ hybridization indicated homogeneous distribution of the IGFBP-6 signal in test tumours [12].

References