4512 CellPrime®r Insulin Recombinant human insulin
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- Brochure
CellPrime r Insulin
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Tyrosine 302 in RACK1 is essential for insulin-like growth factor-I-mediated competitive binding of PP2A and beta1 integrin and for tumor cell proliferation and migration ...
- Insulin-like growth factor (IGF)-I regulates a mutually exclusive interaction of PP2A and beta1 integrin with the WD repeat scaffolding protein RACK1. This interaction is required for the integration of IGF-I receptor (IGF-IR) and adhesion signaling. Here we investigated the nature of the binding site for PP2A and beta1 integrin in RACK1. A WD7 deletion mutant of RACK1 did not associate with PP2A but retained some interaction with beta1 integrin, whereas a WD6/WD7 mutant lost the ability to bind to both PP2A and beta1 integrin. Using immobilized peptide arrays representing the entire RACK1 protein, we identified a common cluster of amino acids (FAGY) at positions 299-302 within WD7 of RACK1 which were essential for binding of both PP2A and beta1 integrin to RACK1. PP2A showed a higher level of association with a peptide in which Tyr-302 was phosphorylated compared with an unphosphorylated peptide, whereas beta1 integrin binding was not affected by phosphorylation. RACK1 mutants in which either the FAGY cluster or Tyr-302 were mutated to AAAF, or Phe, respectively, did not interact with either PP2A or beta1 integrin. These mutants were unable to rescue the decrease in PP2A activity caused by suppression of RACK1 in MCF-7 cells with small interfering RNA. MCF-7 cells and R+ (IGF-IR-overexpressing fibroblasts) expressing these mutants exhibited decreased proliferation and migration, whereas R- cells (IGF-IR null fibroblasts) were unaffected. Taken together, the data demonstrate that Tyr-302 in RACK1 is required for interaction with PP2A and beta1 integrin, for regulation of PP2A activity, and for IGF-I-mediated cell migration and proliferation.
- Dokumentumtípus:
- Reference
- Katalógusszám:
- AB1952
- Katalógusszám:
- Anti-Integrin beta1 Antibody, Cytosolic
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Reduction of insulin signalling pathway IRS-1/IRS-2/AKT/mTOR and decrease of epithelial cell proliferation in the prostate of glucocorticoid-treated rats.
- Previous studies by our research group using a model of insulin resistance induced by dexamethasone (DEX) showed that in the rat ventral prostate there was epithelial and smooth muscle cell atrophy and there were also alterations in fibroblasts. Proteins of the insulin signalling pathway are known to be very important for cell proliferation and development. Thus, we investigated the insulin signalling pathway and epithelial proliferation in the rat ventral prostate in this model and correlated the findings with expression of glucocorticoid (GR) and androgen (AR) receptors. Insulin resistance was induced in adult male Wistar rats by injection of DEX (1 mg/kg, ip for 5 consecutive days), whereas control (CTL) rats received saline. DEX treatment resulted in a significant decrease in body weight, but not in prostate weight. Reductions in insulin receptor 1 (IRS-1) (CTL 1.11 ± 0.06; DEX 0.85 ± 0.03), IRS-2 (CTL 0.95 ± 0.05; DEX 0.49 ± 0.04), AKT (CTL 0.98 ± 0.03; DEX 0.78 ± 0.02), mammalian target of rapamycin (mTOR; CTL 0.65 ± 0.08; DEX 0.22 ± 0.05), GR (CTL 1.30 ± 0.09; DEX 0.57 ± 0.10) and AR (CTL 1.83 ± 0.16; DEX 0.55 ± 0.08) protein levels were observed in the prostate of DEX-treated rats. The expression of the IRα-subunit, phosphoinositide 3-kinase, p-AKT, p70(S6K) , extracellular signal-regulated kinase (ERK) and p-ERK was not altered. The frequency of AR-positive cells in the epithelium of the prostate decreased in the glucocorticoid-treated group, and the intensity of the reaction for this receptor in the cell nuclei was lower in this group. Furthermore, the treatment with DEX reduced the frequency of proliferating cell nuclear antigen-positive (PCNA) cells 30-fold. This study suggests that the reduction in the insulin signalling pathway proteins IRS-1/IRS-2/AKT/mTOR in the prostate of DEX-treated rats may be associated with the morphological alterations observed previously.
- Dokumentumtípus:
- Reference
- Katalógusszám:
- 06-195
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Impaired glucose tolerance is accompanied by decreased insulin sensitivity in tissues of mice implanted with cells that overexpress resistin.
- Resistin, the expression of which is suppressed by thiazolidinedione treatment in adipocytes, is one of the key molecules for the tight link between adiposity and insulin resistance. Here, we show the in vivo effects of resistin on insulin sensitivity in mature mice using a cell implantation method.Resistin cDNA was transfected into 3T3-L1 pre-adipocytes, which were then implanted into subcutaneous areas of nude mice. Metabolic analyses were performed 4 or 6 weeks after implantation.The mice implanted with 3T3-L1 cells overexpressing resistin (R-mice) showed significantly (pless than 0.05) increased plasma resistin levels. After a glucose load plasma insulin levels were significantly greater in R-mice than in mice implanted with mock-transfected cells (M-mice). The AUC of insulin after glucose loading was positively correlated with circulating resistin levels. Significantly decreased glucose responses after insulin injection were observed in R-mice, compared to M-mice. The insulin-induced phosphorylation level of IRS-1 was significantly lower in muscles of R-mice than M-mice. The expression of TNF-alpha mRNA in intra-peritoneal fat tissues was significantly greater in R-mice than in M-mice, but there was no difference between the two groups with regard to subcutaneous fat tissues. The concentration of TNF-alpha in plasma was positively correlated with resistin levels in R-mice.Resistin, when actually secreted from cells in mature mice, causes disturbed glucose metabolism, possibly based on decreased insulin sensitivity in muscle. The in vivo effects of resistin on insulin sensitivity might be in part mediated by increased TNF-alpha expression in visceral fat tissues.
- Dokumentumtípus:
- Reference
- Katalógusszám:
- AB3708
- Katalógusszám:
- Anti-Resistin Antibody
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Estrogen upregulates the IGF-1 signaling pathway in lung cancer through estrogen receptor-β.
- The estrogen receptor (ER) signaling and the insulin-like growth factor-1 receptor (IGF-1R) signaling are implicated in lung cancer progression. Here, we sought to investigate whether estrogen regulated the IGF-1R signaling in non-small cell lung cancer (NSCLC) and the underlying mechanisms. We examined and analyzed the correlation of the expression of aromatase (Arom), ERβ, ERα, insulin-like growth factor-1 (IGF-1), and IGF-1R in NSCLC. Tissue-microarray and immunohistochemistry analysis of tissue specimens from 162 NSCLC patients and 38 patients with benign pulmonary lesions showed that Arom, ERβ, IGF-1, and IGF-1R were overexpressed while ERα was not expressed in NSCLC. Furthermore, ERβ expression was positively correlated with that of Arom, IGF-1, and IGF-1R (r = 0.554, 0.649, 0.496, respectively, P values are equal to 0.000), while Arom expression was positively associated with that of IGF-1 and IGF-1R (r = 0.657, 0.714, respectively, P values are equal to 0.000). Additionally, ERβ, IGF-1, and phospho-IGF-1R, but not ERα, were expressed in A549 cells. Immunoblotting assays showed that A549 cells treated with E2 showed significantly higher IGF-1 and p-IGF-1R levels than those receiving the combination treatment of 17β-estradiol (E2) and fulvestrant (Ful, ER antagonist) (P = 0.042, 0.002, respectively) or controls (P values are equal to 0.000). The MTT assays further revealed that E2 and IGF-1 synergistically promoted A549 cell proliferation. Together, our study provides the first direct evidence for an interaction between ER and IGF-1R in lung cancer. We showed that estrogen upregulated the IGF-1R signaling through ERβ in lung cancer tissues and A549 cells. These findings shed further light on the mechanisms whereby estrogen promotes lung cancer and highlight the ER and IGF-1R signaling pathways as promising targets for combinational therapy for lung cancer.
- Dokumentumtípus:
- Reference
- Katalógusszám:
- AB1410