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The flow of information through the epidermal growth factor receptor (EGFR) is shaped by molecular interactions in the plasma membrane. The EGFR is associated with lipid rafts, but their role in modulating receptor mobility and subsequent interactions is unclear. To investigate the role of nanoscale rafts in EGFR dynamics, we used single-molecule fluorescence imaging to track individual receptors and their dimerization partner, human epidermal growth factor receptor 2 (HER2), in the membrane of human mammary epithelial cells. We found that the motion of both receptors was interrupted by dwellings within nanodomains. EGFR was significantly less mobile than HER2. This difference was likely due to F-actin because its depolymerization led to similar diffusion patterns between the EGFR and HER2. Manipulations of membrane cholesterol content dramatically altered the diffusion pattern of both receptors. Cholesterol depletion led to almost complete confinement of the receptors, whereas cholesterol enrichment extended the boundaries of the restricted areas. Interestingly, F-actin depolymerization partially restored receptor mobility in cholesterol-depleted membranes. Our observations suggest that membrane cholesterol provides a dynamic environment that facilitates the free motion of EGFR and HER2, possibly by modulating the dynamic state of F-actin. The association of the receptors with lipid rafts could therefore promote their rapid interactions only upon ligand stimulation. 相似文献
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Alessio Innocenti Serdar Durdagi Nadjmeh Doostdar T. Amanda Strom Andrew R. Barron Claudiu T. Supuran 《Bioorganic & medicinal chemistry》2010,18(8):2822-2828
We investigated a series of derivatized fullerenes possessing alcohol, amine, and amino acid pendant groups as inhibitors of the zinc enzymes carbonic anhydrases (CAs, EC 4.2.1.1). We discovered that fullerenes bind CAs with submicromolar—low micromolar affinity, despite the fact that these compounds do not possess moieties normally associated with CA inhibitors such as the sulfonamides and their isosteres, or the coumarins. The 13 different mammalian CA isoforms showed a diverse inhibition profile with these compounds. By means of computational methods we assessed the inhibition mechanism as being due to occlusion of the active site entrance by means of the fullerene cage (possessing dimension of the same order of magnitude as the opening of the enzyme cavity, of 1 nm). The pendant moieties to the fullerene cage make interactions with amino acid residues from the active site, among which His64, His94, His96, Val121, and Thr200. Fullerenes thus represent a totally new class of nanoscale CA inhibitors which may show applications for targeting physiologically relevant isoforms, such as the dominant CA II and the tumor-associated CA IX. 相似文献
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Effects of ovariectomy and tamoxifen on rat bone tissue: histomorphometric and histopathologic study
Aktug H Uslu S Terek MC Terzi H Turgut M Ozşener S Bilgin O 《Analytical and quantitative cytology and histology / the International Academy of Cytology [and] American Society of Cytology》2006,28(4):207-212
OBJECTIVE: To investigate possible detrimental effects on bone tissue induced by ovariectomy and tamoxifen (TMX) using bone densitometry and histomorphologic analysis. STUDY DESIGN: Twenty-four rats were allocated into 4 groups: group 1, intact normal rats (n = 6); group 2, ovariectomized rats (n = 6); group 3, normal female rats that received 1 mg/kg/day TMX dissolved in dimethyl sulfoxide (DMSO) for 2 months (n = 6); group 4, normal female rats that received DMSO for the same duration and with a volume equal to that of TMX (n = 6). Results of histomorphometric analysis for trabecular thickness, number of osteoblasts and osteoclasts, trabecular number, and area and cortical thickness were compared. RESULTS: No significant effects of ovariectomy on femoral or lumbar bone mineral density (BMD) were found. In the TMX group, the value of femoral BMD increased significantly compared to control group cellular and pathologic changes. TMX caused significant decrease in osteoblasts compared to the control group. CONCLUSION: TMX has a positive effect on inorganic bone tissue, but a negative effect on number of osteoblasts and osteoclasts. Future studies investigating estrogenic and antiestrogenic effects of TMX should include cellular parameters related to proliferation using histopathologic and histomorphometric analyses. 相似文献
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Deb S Zhou J Jianfeng Z Amin SA Imir AG Gonca IA Yilmaz MB Bertan YM Lin Z Zihong L Bulun SE 《The Journal of biological chemistry》2006,281(5):2585-2597
The aromatase gene encodes the key enzyme for estrogen formation. Aromatase enzyme inhibitors eliminate total body estrogen production and are highly effective therapeutics for postmenopausal breast cancer. A distal promoter (I.4) regulates low levels of aromatase expression in tumor-free breast adipose tissue. Two proximal promoters (I.3/II) strikingly induce in vivo aromatase expression in breast fibroblasts surrounding malignant cells. Treatment of breast fibroblasts with medium conditioned with malignant breast epithelial cells (MCM) or a surrogate hormonal mixture (dibutyryl (Bt2)cAMP plus phorbol diacetate (PDA)) induces promoters I.3/II. The mechanism of promoter-selective expression, however, is not clear. Here we reported that sodium butyrate profoundly decreased MCM- or Bt2cAMP + PDA-induced promoter I.3/II-specific aromatase mRNA. MCM, Bt2cAMP + PDA, or sodium butyrate regulated aromatase mRNA or activity only via promoters I.3/II but not promoters I.1 or I.4 in breast, ovarian, placental, and hepatic cells. Mechanistically, recruitment of phosphorylated ATF-2 by a CRE (-211/-199, promoter I.3/II) conferred inductions by MCM or Bt2cAMP + PDA. Chromatin immunoprecipitation-PCR and immunoprecipitation-immunoblotting assays indicated that MCM or Bt2cAMP + PDA stabilized a complex composed of phosphorylated ATF-2, C/EBPbeta, and cAMP-response element-binding protein (CREB)-binding protein in the common regulatory region of promoters I.3/II. Overall, histone acetylation patterns of promoters I.3/II did not correlate with sodium butyrate-dependent silencing of promoters I.3/II. Sodium butyrate, however, consistently disrupted the activating complex composed of phosphorylated ATF-2, C/EBPbeta, and CREB-binding protein. This was mediated, in part, by decreased ATF-2 phosphorylation. Together, these findings represent a novel mechanism of sodium butyrate action and provide evidence that aromatase activity can be ablated in a signaling pathway- and cell-specific fashion. 相似文献