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Aging is characterized by the progressive decline of physiology at the cell, tissue and organism level, leading to an increased risk of mortality. Proteotoxic stress, mitochondrial dysfunction and genomic instability are considered major universal drivers of cell aging, and accumulating evidence establishes clear biunivocal relationships among these key hallmarks. In this regard, the finite lifespan of the budding yeast, together with the extensive armamentarium of available analytical tools, has made this single cell eukaryote a key model to study aging at molecular and cellular levels. Here we review the current data that link proteostasis to cell cycle progression in the budding yeast, focusing on senescence as an inherent phenotype displayed by aged cells. Recent advances in high-throughput systems to study yeast mother cells while they replicate are providing crucial information on aging-related processes and their temporal interdependencies at a systems level. In our view, the available data point to the existence of multiple feedback mechanisms among the major causal factors of aging, which would converge into the loss of proteostasis as a nodal driver of cell senescence and death., This work was funded by grants from the Ministry of Economy and Competitiveness of Spain and the European Union (FEDER) to M.A. D.F.M. received a FI fellowship of Generalitat de Catalunya.

Objective To investigate the effect of dienogest on the proliferation of endometriotic stromal cells. Design Comparative and laboratory study. Setting University of Tokyo Hospital. Patient(s) Endometriotic stromal cells were isolated and cultured from ovarian endometriomas of patients undergoing surgery. Intervention(s) Dienogest was added to the cultured endometriotic stromal cells. Main Outcome Measure(s) 5-Bromo-2′-deoxyuridine (BrdU) incorporation into DNA of the endometriotic stromal cells was measured by ELISA. Cell cycle analysis of the cultured endometriotic stromal cells was performed by flow cytometry. Result(s) Dienogest at concentration of 10 -7 M and 10 -6 M significantly inhibited BrdU incorporation into DNA at 24 and 48 hours. Dienogest significantly increased the cells in G 0 /G 1 phase and reduced the cells in S phase and G 2 /M phase in 24 and 48 hours. Conclusion(s) The present study indicates that dienogest can inhibit the proliferation of the endometriotic stromal cells with G 0 /G 1 arrest, suggesting a possible direct effect of dienogest in the treatment of endometriosis.

DNA damage such as chemical carcinogen or gamma-rays induces aberrant crypts in the rat colorectum. We demonstrated that formation of aberrant crypts is different among inbred rat strains (WKAH, DA and F344/N). DA had less preneoplastic lesions in the colorectum than the others regardless of the way of DNA damage. We analyzed changes in in vivo number of colonic epithelial cells undergo mitosis, DNA synthesis and apoptosis following DNA damage histochemically. It is indicated that rapid onset of G1 arrest and termination of G2/M arrest and apoptosis in damaged epithelial cells is important to reduce subsequent formation of the preneoplastic lesions.

The MDM2 protein, through its interaction with p53, plays an important role in the regulation of the G(1) checkpoint of the cell cycle. In addition to binding to and inhibiting the transcriptional activation function of the p53 protein, MDM2 binds, inter alia, to RB and the E2F-1.DP-1 complex and in so doing may promote progression of cells into S phase. Mice transgenic for Mdm2 possess cells that have cell cycle regulation defects and develop an altered tumor profile independent of their p53 status. MDM2 also blocks the growth inhibitory effects of transforming growth factor-beta1 in a p53-independent manner. We show here that a novel growth regulatory molecule is also the target of MDM2-mediated inhibition. Using a yeast two-hybrid screen, we have identified a gene that encodes a novel cellular protein (MTBP) that binds to MDM2. MTBP can induce G(1) arrest, which in turn can be blocked by MDM2. Our results suggest the existence of another growth control pathway that may be regulated, at least in part, by MDM2.

Summary We report here a new and easy method to induce highly synchronous cell division in Tetrahymena thermophila by using cells that have arrested their cell cycle. When cells in the stationary phase of growth were suspended in a fresh nutrient medium at a cell density of 2 × 10 5 cells/ml, about 80% of the cells divided at 2 h after the suspension. Synchronous cell division was also induced if the cells were suspended in Tris-saline buffer, pH 7.4. The division index was less than 40%, but the density of the cells doubled after 3 h. These results show that cells in the stationary phase still have an ability to divide even without any nutrients present, and that their cell cycle was arrested at a specific point. We examined the effects of various factors on the cell cycle arrest. Results showed that the cell cycle arrest was induced by substances that were released from the cells. These substances were heat stable and had a molecular weight of less than 5,000 daltons.

Summary The majority of Tetrahymena thermophila cells in the stationary phase of growth was arrested in their cell cycle at G1 phase by low molecular weight substances released by the cells themselves and accumulated in the culture medium. The experiments for understanding the mechanism of G1 arrest in the stationary phase showed that the substances could arrest the cell cycle if the cells were in G1 and S phases.

cells showed G1 phase pile-up at 48 hr after 2.0 or 2.5 Gy s (32.5 3.9% for nonirradiated compared to 47.0 3.6% and 45.1 4.4% (p Z 0.0253 or 0.0275, respectively). In contrast cells from neural rosettes or parent fibroblasts showed no significant G1 arrest at 24 or 48 hr after either irradiation dose. Conclusions: Human iPSCs are more radiosensitive than either parent fibroblasts or differentiated neural rosettes. These three cell populations are potentially of value to identify the molecular signaling pathways controlling induction and release from radiosensitivity. Author Disclosure: M. Epperly: None. F. Houghton: None. L. D’Aiuto: None. X. Zhang: None. V. Nimgaonkar: None. J. Greenberger: None.

which, however, is mostly transient. When combined with X-irradiation, EGFR inhibition may lead to an enhanced permanent radiation-induced G1 arrest. This effect, however, only occurs in p53 wt cells with erlotinib being slightly more effective than BIBX. Increase in permanent G1 arrest is abolished when p21 is absent or knocked down. After EGFR inhibition increase in cellular radiosensitivity is also only found for cells which are p53 wt (A549) and not those, which are negative (FaDu, H1299). For A549 cells no radiosensitization after EGFR inhibition was seen, when increase in radiation-induced permanent G1 arrest was abolished. Conclusions: For tumor cells with wt p53, EGFR inhibition prior to irradiation increases permanent G1 arrest which contributes to an enhanced cellular radiosensitivity.

a Genomic Research Center for Lung and Breast/Ovarian Cancer, Korea University College of Medicine, Seoul, Republic of Korea b Department of Internal Medicine and Division of Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Anam Hospital, 126-1, 5-Ga Anam-Dong, Sungbuk-Gu, Seoul 136-705, Republic of Korea c Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea

The effects of isoleucine deprivation on DNA synthesis were compared with leucine deprivation. Omission of either amino acid prevented entry of G1 cells into S. Cells deprived of isoleucine were able to complete S although the rate of DNA synthesis decreased steadily after deprivation. The effects of leucine deprivation were more drastic and not all cells were able to complete S. It is proposed that isoleucine deprivation results in G1 arrest because S phase cells are less sensitive to its omission than to the omission of other amino acids.