The ubiquitin–proteasome system and signal transduction pathways regulating Epithelial Mesenchymal transition of cancer

Journal of Biomedical Science, Jul 2012

Epithelial to Mesenchymal transition (EMT) in cancer, a process permitting cancer cells to become mobile and metastatic, has a signaling hardwire forged from development. Multiple signaling pathways that regulate carcinogenesis enabling characteristics in neoplastic cells such as proliferation, resistance to apoptosis and angiogenesis are also the main players in EMT. These pathways, as almost all cellular processes, are in their turn regulated by ubiquitination and the Ubiquitin-Proteasome System (UPS). Ubiquitination is the covalent link of target proteins with the small protein ubiquitin and serves as a signal to target protein degradation by the proteasome or to other outcomes such as endocytosis, degradation by the lysosome or specification of cellular localization. This paper reviews signal transduction pathways regulating EMT and being regulated by ubiquitination.

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The ubiquitin–proteasome system and signal transduction pathways regulating Epithelial Mesenchymal transition of cancer

Journal of Biomedical Science The ubiquitin-proteasome system and signal transduction pathways regulating Epithelial Mesenchymal transition of cancer Ioannis A Voutsadakis 0 0 Centre Pluridisciplinaire d'Oncologie, BH06, Centre Hospitalier Universitaire Vaudois , Bugnon 46, Lausanne 1011 , Switzerland Epithelial to Mesenchymal transition (EMT) in cancer, a process permitting cancer cells to become mobile and metastatic, has a signaling hardwire forged from development. Multiple signaling pathways that regulate carcinogenesis enabling characteristics in neoplastic cells such as proliferation, resistance to apoptosis and angiogenesis are also the main players in EMT. These pathways, as almost all cellular processes, are in their turn regulated by ubiquitination and the Ubiquitin-Proteasome System (UPS). Ubiquitination is the covalent link of target proteins with the small protein ubiquitin and serves as a signal to target protein degradation by the proteasome or to other outcomes such as endocytosis, degradation by the lysosome or specification of cellular localization. This paper reviews signal transduction pathways regulating EMT and being regulated by ubiquitination. Epithelial to mesenchymal transition; Ubiquitination; Ubiquitin-proteasome system; Signal transduction; Carcinogenesis Introduction Epithelial to Mesenchymal transition (EMT) describes the process that allows an epithelial cell belonging in an epithelial membrane to detach from its neighbors, to transverse the dissolving basement membrane and move through the extra-cellular matrix to other sites of the tissue or even to distant organs. In order to facilitate mobility during EMT, connections joining the cell to adjacent epithelial cells are dissolved [ 1 ]. Concomitantly, the cell acquires a fibroblast-like shape, down-regulates epithelial markers and up-regulates mesenchymal markers. EMT is a process that physiologically takes place during development. Multi-cellular organisms derive their variety of specialized cells and tissues from a single cell, the fertilized ovum. This cell has to differentiate to the three layers of differentiation, the ectoderm, mesoderm and endoderm and further to different tissues and cell types in complex but ordered patterns. During development EMT takes place as an integral process of differentiation to the various cell types in a highly regulated in space and time manner. For example during embryonal gastrulation the epiblast layer produces a midline invagination, the primitive streak, from which cells are mobilized by undergoing an EMT and produce the mesoderm and endoderm. In another developmental example, dorsal neural tube-derived neural crest cells undergo an EMT and migrate to form components of the peripheral nervous system, skin melanocytes, adrenal medulla and facial bones and muscles [ 2 ]. Derived from a single cell, all cells of a multi-cellular organism possess the same DNA sequences in their whole genome and thus their various phenotypes must be the result of differences in transcriptional and posttranscriptional regulation of cellular proteins secondary to intra-cellular and external signals. Post-translational modifications can regulate function, localization and turn-over of every cell protein impacting on cell morphology, activity and interactions in the multi-cellular organism. Ubiquitination is such a post-translational modification. Ubiquitination is the covalent attachment of molecules of the small 76 amino-acids protein ubiquitin to a target protein which is then marked for proteasome destruction or endocytosis or participation in a range of processes. Ubiquitination along with other post-translational modifications of proteins such as phosphorylation, hydroxylation and acetylation is a regulated process for the execution of which a multitude of regulators exist. Many signal transducers and transcription factors involved in EMT are regulated by ubiquitination and the ubiquitin proteasome system. This review will discuss EMT signal transduction pathways and relationship with Ubiquitin-Proteasome system (UPS) while the extensive network of transcription factors regulating EMT and their relationship to UPS will not be discussed here. EMT in cancer EMT is proposed to happen in three different scenarios with different starting points and outcomes. In development EMT is used by normal fetal cells for obtaining the different specificities present in the multi-cellular organism. In adult tissue injury repair, EMT is used to heal open wounds and may lead to fibrosis. In a third scenario, EMT happens during the tissue invasion and metastatic process of malignant epithelial cells. These three EMT types have recently been labelled by convention type 1, 2 and 3 [ 3 ]. The starting point of type 1 EMT is, thus, epithelial progenitors in the embryo that lose conduct with their initial site and move to become a different structure with different morphology and function. In type 2 EMT, epithel (...truncated)


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Ioannis A Voutsadakis. The ubiquitin–proteasome system and signal transduction pathways regulating Epithelial Mesenchymal transition of cancer, Journal of Biomedical Science, 2012, pp. 67, 19, DOI: 10.1186/1423-0127-19-67