ABSTRACT
All multicellular organisms require a life-long regulation of the number and the size of cells, which build up their organs. mTOR acts as a signaling nodule for the regulation of protein synthesis and growth. To activate the translational cascade, mTOR phosphorylates S6 kinase (S6K1), which is liberated from the eIF3-complex and mobilized for activation of its downstream targets. How S6K1 regulates cell size remains unclear. Here, we challenged cell size control through S6K1 by specifically depleting its binding partner eIF3 in normal and transformed cell lines. We show that loss of eIF3 leads to a massive reduction of cell size and cell number accompanied with an unexpected increase in S6K1-activity. The hyperactive S6K1-signaling was rapamycin-sensitive, suggesting an upstream mTOR-regulation. A selective S6K1 inhibitor (PF-4708671) was unable to interfere with the reduced size, despite efficiently inhibiting S6K1-activity. Restoration of eIF3 expression recovered size defects, without affecting the p-S6 levels. We further show that two, yet uncharacterized, cancer-associated mutations in the eIF3-complex, have the capacity to recover from reduced size phenotype, suggesting a possible role for eIF3 in regulating cancer cell size. Collectively, our results uncover a role for eIF3-complex in maintenance of normal and neoplastic cell size - independent of S6K1-signaling.
Subject(s)
Cell Size , Eukaryotic Initiation Factor-3/metabolism , Gene Expression Regulation, Neoplastic , Ribosomal Protein S6 Kinases, 70-kDa/metabolism , Cell Proliferation , Cell Transformation, Neoplastic , Enzyme Inhibitors/chemistry , Fibroblasts/metabolism , HEK293 Cells , Humans , Imidazoles/chemistry , Mutation , Phenotype , Phosphorylation , Piperazines/chemistry , RNA, Small Interfering/metabolism , Ribosomal Protein S6 Kinases, 70-kDa/antagonists & inhibitors , Signal Transduction , TOR Serine-Threonine Kinases/metabolismABSTRACT
BACKGROUND: The ability of cells to travel long distances in order to form tissues and organs is inherently connected to embryogenesis. The process in which epithelial-like embryonic cells become motile and invasive is termed 'epithelial-to-mesenchymal transition' (EMT), while the reversion of this programme--yielding differentiated cells and organs--is called 'mesenchymal-to-epithelial transition' (MET). DESIGN: Here, we review the processes of EMT and MET in development and cancer and combine them with knowledge from pluripotent stem cell research. RESULTS: Research has shown that these processes are activated in many cancers leading to dissemination of cancer cells throughout the body and formation of metastasis. While the regulation of EMT during cancer progression has been extensively studied for decades, many fundamental processes that govern normal development are only poorly understood. Recent discoveries, such as reprogramming to pluripotent stem cells and identification of ground and primed states of pluripotent stem cells, have redirected much attention to EMT and MET. CONCLUSION: Findings from pluripotent stem cell research and EMT/MET should be combined in order to design future strategies aimed to improve our understanding of cancer progression and to help develop novel anticancer strategies.
