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Sökning: WFRF:(Kleiner Sandra)

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  • Cramer, Alexander, et al. (författare)
  • Activation of the c-Met receptor complex in fibroblasts drives invasive cell behavior by signaling through transcription factor STAT3
  • Ingår i: Journal of Cellular Biochemistry. - : Wiley-Blackwell. - 0730-2312. ; 95:4, s. 805-816
  • Tidskriftsartikel (refereegranskat)abstract
    • c-Met is the receptor for hepatocyte growth factor/scatter factor (HGF/SF). It mediates multiple cellular responses in development and adult life, and c-Met hyperactivity is associated with malignant transformation of cells and the acquisition of metastatic properties. Signal transducer and activator of transcription 3 (STAT3) has been shown to contribute to c-Met-mediated cell motility and is, thus, potentially involved in the control of invasive cell behavior. We have functionally reconstituted c-Met-dependent signal transduction in fibroblasts with the aim of studying Met-driven cell invasiveness and the role of STAT3 in this phenomenon. Activation of the system was achieved by means of a hybrid receptor comprising the extracellular domain of the nerve growth factor (NGF) receptor TrkA, the cytoplasmic part of c-Met and a C-terminally fused blue fluorescent protein (BFP). In addition, a GFP-tagged derivative of adaptor protein Gab1 was expressed. NGF-stimulation of mouse fibroblasts expressing tagged versions of both Trk-Met and Gab1 with NGF resulted in anchorage-independent growth and enhanced invasiveness. By freeze-fracture cytochemistry and electron microscopy, we were able to visualize the ligand-induced formation of multivalent receptor complex assemblies within the cell membrane. NGF-stimulation of the heterologous receptor system evoked activation of STAT3 as evidenced by tyrosine phosphorylation and the formation of STAT3 clusters at the cell membrane. siRNA-mediated ablation of STAT3 expression resulted in a drastic reduction of c-Met-driven invasiveness, indicating an important role of STAT3 in the control of this particularly relevant property of transformed cells.
  • Dwivedi, Om Prakash, et al. (författare)
  • Loss of ZnT8 function protects against diabetes by enhanced insulin secretion
  • Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036. ; , s. 1-22
  • Tidskriftsartikel (refereegranskat)abstract
    • A rare loss-of-function allele p.Arg138* in SLC30A8 encoding the zinc transporter 8 (ZnT8), which is enriched in Western Finland, protects against type 2 diabetes (T2D). We recruited relatives of the identified carriers and showed that protection was associated with better insulin secretion due to enhanced glucose responsiveness and proinsulin conversion, particularly when compared with individuals matched for the genotype of a common T2D-risk allele in SLC30A8, p.Arg325. In genome-edited human induced pluripotent stem cell (iPSC)-derived β-like cells, we establish that the p.Arg138* allele results in reduced SLC30A8 expression due to haploinsufficiency. In human β cells, loss of SLC30A8 leads to increased glucose responsiveness and reduced KATP channel function similar to isolated islets from carriers of the T2D-protective allele p.Trp325. These data position ZnT8 as an appealing target for treatment aimed at maintaining insulin secretion capacity in T2D.
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