Insulin-regulated periovulatory gene expression in superovulated mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE129222 | GEO | 2021/01/11
REPOSITORIES: GEO
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Project description:Commonalities and dissimilarities between the IGF1R and INSR pathways Insulin and insulin-like growth factor-1 (IGF1), acting respectively via the insulin (INSR) and IGF1 (IGF1R) receptors, play key developmental and metabolic roles throughout life. In addition, both signaling pathways fulfill important roles in cancer initiation and progression. The inherent complexity of the INSR/IGF1R pathways, along with the well documented cross-talk between insulin-like ligands and receptors, translated into a disappointingly slow pace in the development of INSR/IGF1R-directed therapies in oncology. The present study was aimed at identifying mechanistic differences between INSR and IGF1R using a recently developed bioinformatics tool, the Biological Network Simulator (BioNSi). This application allows to import and merge multiple pathways and interaction information from the KEGG database into a single network representation. The BioNsi network simulation tool allowed us to exploit the availability of gene expression data derived from breast cancer cell lines with specific disruptions of the INSR or IGF1R genes in order to investigate potential differences in protein expression that might be linked to biological attributes of the specific receptor networks. Modeling-generated information was corroborated by experimental and biological assays. Our simulation analysis identified a number of commonalities and, most importantly, dissimilarities between the IGF1R and INSR pathways that were experimentally validated and that might help explain the basis for the biological differences between these networks.
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Project description:Insulin analogues are designed to improve the pharmacokinetic parameters compared to regular human insulin. This provides a sustained control of blood glucose levels in diabetic patients. All novel insulin analogues are tested for their mitogenic side effects, however these assays do not take into account the molecular mode-of-action of different insulin analogues. Insulin analogues can bind the insulin receptor (INSR) and the insulin-like growth factor-1 receptor (IGF1R) with different affinities and consequently will activate different downstream signaling pathways. Here we used a panel of MCF7 human breast cancer cell lines that selectively express either one of the isoforms of the INSR (IRA or IRB) or the IGF1R. We sought to study the role of the different receptors (IRA, IRB and IGF1R) in the mitogenic signaling of insulin-like molecules (including insulin, glargine, X10 (or AspB10) and IGF1). MCF7 IRA, MCF7 IRB or MCF7 IGF1R cells (as described in Arch Toxicol. 2014 Apr;88(4):953-66. doi: 10.1007/s00204-014-1201-2. Epub 2014 Jan 25.) were cultured in RPMI supplemented with 5% (v/v) CDFBS (Hyclone) and used for experiments. Cells have been exposed for 1 or 6 hours to 10 nM of the indicated insulin-like molecule. As a control sample a vehicle stimulation was performed that contained everything except the active compound.
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Project description:The insulin inhibitory receptor (inceptor) was recently identified as a key terminator of insulin and insulin-like growth factor 1 receptor (INSR/IGF1R) signaling in pancreatic ?-cells12. Yet, the relevance of ?-cell inceptor for glucose regulation through the INS1R/IGF1R axis has only been demonstrated for normoglycemic and insulin sensitive lean mice, questioning whether inceptor regulation of INS1R/IGF1R action also plays a role in glucose metabolism under conditions of diet-induced obesity and insulin resistance. Here we demonstrate that whole-body germline loss of inceptor improves glucose metabolism in diet-induced obese mice with only minimal effects on weight and body composition. To assess the effect in different tissues we performed proteomics in the global, neuronal and beta cell specific mouse knock-outs.
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Project description:The goal of this study was to test the hypothesis that sodium selenite (ISe) vs. a 1:1 blend (MIX) of ISe and SEL-PLEX in a basal vitamin-mineral (VM) mix would differentially alter corpora lutea transcriptome profiles in non-lactating beef cows. Predominately-Angus cows were randomly selected from herds of fall-calving cows consuming VM mixes that contained 35 ppm Se as ISe and MIX forms. Cows were depleted of Se for 45 d followed by a 45 d repletion period with ISe to bring all cows to Se adequate status. Cows were then randomly assigned to treatment (ISe, n=5; or MIX, n=5) with treatments administered for at least 90 days using in-pasture Calan gates. Corpora lutea samples were then collected on Day 7 post-estrus and examined for changes in global expression patterns by microarray analysis.
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Project description:The LH surge triggers dramatic transcriptional changes in genes associated with ovulation and luteinization. The present study investigated the spatiotemporal expression of nuclear factor interleukin-3 (NFIL3), a transcriptional regulator of the bZIP transcription factor superfamily, and its potential role in the ovary during the periovulatory period. NFIL3, also known as E4-binding protein 4 or NFIL3/E4BP4, was originally identified as a transcriptional repressor based on its DNA-binding activity at the promoter of the gene encoding the adenovirus E4 protein. Immature female rats were injected with PMSG, treated with hCG, and ovaries or granulosa cells were collected at various times after hCG. Nfil3 mRNA was highly induced both in intact ovaries and granulosa cells after hCG treatment. In situ hybridization demonstrated that Nfil3 mRNA was highly induced in theca-interstitial cells at 4-8 h after hCG, localized to granulosa cells at 12 h, and decreased at 24 h. Over-expression of NFIL3 in granulosa cells inhibited the induction of prostaglandin-endoperoxide synthase 2 (Ptgs2), progesterone receptor (Pgr), epiregulin (Ereg), and amphiregulin (Areg) and down regulated levels of prostaglandin E2. The inhibitory effect on Ptgs2 induction was reversed by NFIL3 siRNA treatment. In theca-interstitial cells the expression of hydroxyprostaglandin dehydrogenase 15-(NAD) (Hpgd) was also inhibited by NFIL3 over-expression. Data from luciferase assays demonstrated that NFIL3 over-expression decreased the induction of the Ptgs2 and Areg promoter activity. EMSA and ChIP analyses indicated that NFIL3 binds to the promoter region containing the DNA binding sites of CREB and C/EBP?. In summary, hCG induction of NFIL3 expression may modulate the process of ovulation and theca-interstitial and granulosa cell differentiation by regulating expression of PTGS2, PGR, AREG, EREG, and HPGD, potentially through interactions with CREB and C/EBP? on their target gene promoters.
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