Disease relevance of INSL4

• We identified an unexpected human endogenous retrovirus (HERV) element inserted into the human INSL4 promoter with a sequence similar to that of env gene, flanked by two long terminal repeats(LTRs) [1].
• Immunohistochemistry on tissue microarrays revealed a heterogeneous expression of EPIL in breast cancer tissue and no expression in the surrounding stroma cells [2].

High impact information on INSL4

• By differential-display PCR a subclone of the SKBR3 cell line with high in vitro transendothelial invasiveness was identified to express increased levels of the INSL-4 gene [2].
• This new member of the insulin-like growth factor family encodes for a peptide, designated early placenta insulin-like (EPIL), being expressed in the so-called "invasive" phase of the placental development [2].
• Moreover, in cytotrophoblast primary culture, production of chorionic gonadotropin, a marker of trophoblast differentiation, was increased upon treatment with placentin-conditioned media, while unaffected by insulin [3].
• While these effects closely mimicked those of insulin, they were not mediated by the insulin receptor as shown by the lack of tyrosine phosphorylation of this receptor upon placentin treatment [3].
• Conditioned media produced by recombinant expression of placentin cDNA in the placental 3AsubE cell line were assayed for biological activity and found to stimulate tyrosine phosphorylation and DNA synthesis [3].

Biological context of INSL4

• Transient transfection experiments showed that the placenta-specific expression of INSL4 is mediated by the 3' LTR of the HERV element, and that the latter may have a major role in INSL4 up-regulation during human cytotrophoblast differentiation into syncytiotrophoblast [1].
• Here we have mapped INSL4 within the framework of a partial YAC contig covering the distal part of 9p to find out whether this gene lies within the critical region defined for the monosomy 9p syndrome [4].
• We used primary amniotic epithelial cells for flow cytometry to show that INSL4 caused apoptosis, which was dose-related and significant (P < 0.05) at 50 ng/ml [5].
• Expression of the INSL4 gene was doubled in the placenta of the growth-restricted twin compared to the normally grown sibling, suggesting that it may be linked to a higher level of apoptosis and loss of cell viability and, therefore, that it may contribute to fetal growth restriction [5].
• The addition of INSL4 (3-30 ng/ml) also caused a loss of cell viability, although it had no effect on the numbers of cells at different phases of the cell cycle [5].

Anatomical context of INSL4

• Expression of INSL4, of unknown function, has been recently detected in the perichondrium and ligaments of the human embryo [4].
• Although an abundance of locally acting growth factors are produced within the uterus during pregnancy, we hypothesized that INSL4 plays an important role in fetal and placental growth [5].
• In fetal tissues, INSL4 mRNA was identified in the perichondrium of all four limbs, vertebrae, and ribs [6].
• The insect developmental factor bombyxin, the relaxin-like factor from Leydig cells, and the insulin-like factor 4 (INSL4) all are made of two disulfide-linked chains and have one disulfide bond within the A-chain [7].
• Early placental insulin-like protein (INSL4 or EPIL) in placental and fetal membrane growth [5].

Associations of INSL4 with chemical compounds

• Tris/Tricine/SDS-polyacrylamide gel electrophoresis and immunoblot analyses of histidine-tagged recombinant placentin indicate that it is composed of two peptide chains of apparent molecular masses of 4 and 13 kDa [3].

Other interactions of INSL4

• The INSL4 gene maps close to WI-5527 at 9p24.1-->p23.3 clustered with two relaxin genes and outside the critical region for the monosomy 9p syndrome [4].
• These transcriptional expression profiles are in favor of a predominant role of INSL4, KiSS-1 and KiSS-1R in the control of the invasive and migratory properties of trophoblast cells [8].

Analytical, diagnostic and therapeutic context of INSL4

• The insulin like growth factor 4 (INSL4) gene belongs to the insulin gene superfamily and has been mapped by fluorescent in situ hybridization to 9p24 [4].
• By in situ hybridization, the INSL4 gene was assigned to band p24 of the short arm of chromosome 9 [9].
• Using RT-PCR, we previously found abundant INSL4 mRNA in the human placenta [6].
• Recent observations based on immunohistochemistry and RT-PCR demonstrate that early placenta insulin-like peptide (EPIL), encoded by the INSL4 gene, is present in the placenta during gestation [10].
• The recent development of a specific immunoassay based on monoclonal antibodies directed to chain C and chain A of early placenta insulin-like peptide (EPIL) encoded by the INSL4 gene, has made it possible to demonstrate pro-EPIL peptide expression during normal pregnancy [11].

References