Micromanaging a large tumor suppressor

Two parallel and concordant activities characterize cell cycle progression. One is associated with preparation for and execution of DNA replication followed by mitosis (" cell cycle "). Cyclins are the motors of the cell cycle, as they activate the respective CDKs and thereby drive the cell through the sequential phases of the cycle. Their antagonists are CKis, which inhibit the CDKs stalling the cycle progression. The second type of activities involves anabolic processes that contribute to growth in cell size and mass (" cellular growth "). Constitutive signaling along the mTOR/S6K pathways is the key factor mediating these anabolic processes. 1 During unperturbed and balanced growth these two activities are flawlessly coordinated. This synchronization ensures that the cell size, as well the ratio of protein or RNA content to DNA, remains invariable for cells in particular phases of the cycle or for particular cell type. However, during arrest in cell cycle progression, for example, when induced by inhibitors of DNA replication, these activities become uncoupled. The cell growth continues, resulting in an " unbalanced growth " phenotype when the ratio of cell protein/mass to DNA content is greatly augmented. While this phenomenon was initially observed nearly five decades ago, 2 recent evidence underscores its importance and links it mechanistically with senescence and aging. Specifically, it has been postulated that cell cycle arrest when is concurrent with the ongoing or intensified mTOR/S6K signaling (growth cycle) results in induction of the unbalanced growth phenotype (cell hypertrophy), which is a characteristic feature of cell senescence as well as considered to be the primary cause of organ-ismal aging. in the currently published article, Leontieva et al. 6 describe that constitutive mTOR sig-naling during the cell cycle arrest, induced by upregulation of p21, contributed to cell senescence (geroconversion); these cells were characterized by greatly increased levels of cyclin D1 and cyclin e as well as being under replication stress, manifested by markers of DNA damage signaling. When the cycle progression was restored by downregulation of p21, the cells were able to pass through S and G 2 and decrease the level of cyclins D1 and e, but then they underwent either mitotic catastrophe or entered higher DNA ploidy by endo-reduplication. Suppression of mTOR signaling, either by rapamycin or by nutlin 3a in the cells arrested by p21, prevented geroconver-sion, lowered the level of cyclin D1 expression and, after removal of p21, restored ability to proliferate. …