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Mechanism of action and transcriptional regulation of the spleen tyrosine kinase Syk, a new candidate tumour suppressor gene in breast cancer


The role of the cytoplasm tyrosine kinas Sky (spleen tyrosine lamas) was, until recently, uniquely studied in haematopoietic cells. In these cells, Sky is involved in coupling activated immunoreceptors to downstream signalling events that mediate diverse cellular responses including proliferation and differentiation. We focus on the Sky expression in epithelial cells and its role as a tumour suppressor hi breast cancer cells. Breast cancer remains the most common malignancy in women. Loss of Sky expression is associated with the acquisition of a malignant (invasive/metastasis) breast tumour phenotype. Its role as a potential tumour suppressor gene has been strengthened not only in breast cancer but also in acute lymphoblastic leukemia.Our observations strongly indicates that Sky might directly affect mitosis and cytokines is. For the first time, we demonstrated that Sky is localised at the coatrooms, a key organelle for cell division. In order to evaluate the role of Skin the control of mitosis, variations in its expression and activity during the cell cycle will be quantified and its subcellularlocalisation will be analysed by time-lapse video microscopy. To unravel its tumour suppressor mechanism, the identification of the downstream signalling effectors of Sky in non-haematopoietic cells is essential and will be investigated using a phosphoproteomic approach. The absence of the Sky protein in breast cancer cells is reflected by the loss of its mina expression and suggests regulation at the transcriptional level. Analysis of the promoter activity by co-transfixion and reporter assays will indicate the important regulatory elements for putative activating and repressing transcription factors. Furthermore, the analysis of differential gene expression associated with the loss of Sky expression, can point out other genes involved in the acquisition of a malignant breast tumour phenotype. This innovating study on the #

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