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.
Highlights
Regulation and maintenance of cell number and cell size represent the most fundamental homeostatic mechanisms to preserve the consistency and the continuity of life in all living beings
In case that eukaryotic initiation factor 3 (eIF3)-complex represents a platform for activation of S6K1 by mTOR, we expected to see a reduction of S6K1-signaling
In case that eIF3-complex is essential for retention of S6K1, we expected to observe an increase in S6K1-activity
Summary
Regulation and maintenance of cell number and cell size represent the most fundamental homeostatic mechanisms to preserve the consistency and the continuity of life in all living beings. While the regulation of cell proliferation has been extensively studied for decades, the regulation of cell size has so far received much less attention. Cell growth and proliferation are separable processes [1, 2] – cells may grow without dividing (for example, postmitotic neurons) and may proliferate without growing (for example, the divisions in a fertilized egg). Differences in animal size or organ size seem to be genetically determined and primarily reflect differences in cell number, rather than differences in cell size [3]. There is a general agreement that nondividing adult cells that maintain a constant size are not biosynthetically inactive or lacking growth signals, but in a balanced state of protein synthesis and degradation resulting in no net change in mass and volume
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