While the molecular mechanisms underlying transcriptional activation have been disected to a large extent, transcriptional repression remains poorly understood. To further our knowledge about the mechanisms of transcriptional repression I have been using two molecular models: 1) the retinoblastoma protein (Rb), a key regulator of cell cycle and 2) ZEB proteins (ZEB1/deltaEF1 and ZEB2/SIP1), an emerging family of transcription factors that regulates development and cell differentiation. ZEB proteins bind to a subset of E box sequences in the promoter region of target genes to repress gene expression in several tissues.
In the present research proposal I intend to further dissect the mechanisms of transcriptional repression to gain understanding not only on the role of repression during cell differentiation in physiological conditions but, and more importantly, during pathological processes such as cancer. The lines of work proposed hereafter are: 1) study the regulation of the TGFbeta/BMP signalling pathway by ZEB proteins. 2) characterize how ZEB proteins repress gene expression through modifications of the chromatin structure and 3) further our understanding of the ZEB proteins in cell differentiation and malignant transformation.
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