TORCing to secretory senescence

Cellular senescence is often accompanied by the production of secreted proteins that mediate the diverse effects of senescence on the tissue microenvironment. The mammalian target of rapamycin (mTOR), a master regulator of protein synthesis, is now shown to control the senescence-associated secretory phenotype by modulating gene transcription and mRNA translation and stabilization.This is the author accepted manuscript. The final version is available from NPG via http://dx.doi.org/10.1038/ncb324

The expanding territories of condensin II.

This is the author accepted manuscript. The final version is available from Taylor & Francis via http://dx.doi.org/10.1080/15384101.2015.106335

CELL BIOLOGY. GATA get a hold on senescence.

A transcription factor's abundance connects autophagy to cellular senescence and a secretory phenotype [Also see Research Article by Kang et al. ] This is the author accepted manuscript. The final version is available from AAAS via http://dx.doi.org/10.1126/science.aad250

Dynamic modulation of autophagy: implications for aging and cancer.

Reduced autophagy has been implicated in aging, yet whether its loss can promote aging phenotypes and pathologies in mammals, and how reversible this process is, has never been fully explored. Using inducible short hairpin RNA (shRNA) mouse models, we have recently shown that autophagy inhibition accelerates aging, and that even a temporary block in autophagy can create irreversible damage that increases a cancer risk

Effect of crowning radius on rolling contact fatigue strength for traction drive elements

A simulation of the rolling contact fatigue strength of a traction drive element was developed. This simulation accounts for both the distribution of sizes of inclusions in the element material and the influence of traction forces at the element surface. The shear strength of the matrix structure surrounding an inclusion was estimated with an equation. The hardness distribution and the Weibull distribution of inclusion dimensions, which are necessary parameters to calculate the rolling contact fatigue strength, were determined by observation of an actual test specimen. The purpose of this report is simulations to evaluate the effect of the crowning radius on the rolling contact fatigue strength and the torque capacity. The simulations were carried out by varying the crowning radius of the virtual roller. To consider the effect of the crowning radius, a simulated two-dimensional virtual roller, which has actual material properties, was modified to a roller multilayered toward the axial direction. The simulation assuming the actual roller led to a difference of 1.0% from the experimental rolling contact fatigue strength. This difference was 2.4 points smaller than the result for the two-dimensional virtual roller. The rolling contact fatigue strength decreased with increasing crowning radius for two reasons. One was the increase in the number of inclusions under the high stress due to the increasing crowning radius. The other was the expansion of the portion of the roller subject to high stresses down to a depth having small hardness. However, the torque capacity calculated from the contact force resulting in failure increased with the increasing crowning radius

Short-term gain, long-term pain: the senescence life cycle and cancer.

Originally thought of as a stress response end point, the view of cellular senescence has since evolved into one encompassing a wide range of physiological and pathological functions, including both protumorignic and antitumorigenic features. It has also become evident that senescence is a highly dynamic and heterogenous process. Efforts to reconcile the beneficial and detrimental features of senescence suggest that physiological functions require the transient presence of senescent cells in the tissue microenvironment. Here, we propose the concept of a physiological "senescence life cycle," which has pathological consequences if not executed in its entirety.The Narita laboratory is funded by a Cancer Research UK Cambridge Institute Core Grant (C14303/A17197). Masashi Narita is also supported by Cancer Research UK Early Detection Pump Priming award (C20/A20976), Medical Research Council (MR/R010013/1) and the Tokyo Tech World Research Hub Initiative (WRHI)

p53 in senescence - it's a marathon, not a sprint.

The tumour suppressor p53, a stress-responsive transcription factor, plays a central role in cellular senescence. The role of p53 in senescence-associated stable proliferative arrest has been extensively studied. However, increasing evidence indicates that p53 also modulates the ability of senescent cells to produce and secrete diverse bioactive factors (collectively called the senescence-associated secretory phenotype, SASP). Senescence has been linked with both physiological and pathological conditions, the latter including ageing, cancer and other age-related disorders, in part through the SASP. Cellular functions are generally dictated by the expression profile of lineage-specific genes. Indeed, expression of SASP factors and their regulators are often biased by cell type. In addition, emerging evidence suggests that p53 contributes to deregulation of more stringent lineage-specific genes during senescence. P53 itself is also tightly regulated at the protein level. In contrast to the rapid and transient activity of p53 upon stress ('acute-p53'), during senescence and other prolonged pathological conditions, p53 activities are sustained and fine-tuned through a combination of different inputs and outputs ('chronic-p53')

The power behind the throne; senescence and the hallmarks of cancer

The hallmarks of cancer was an attempt to describe the underlying principles of carcinogenesis. In their latest iteration, there is a particular focus on the role that the microenvironment and signalling between cancer cells and their neighbors play in the pathology of tumors. Since the original description of the hallmarks there has been a huge leap forward in our understanding of the biology of cellular senescence promoting it from an autonomous tumor suppressor to a complex, dynamic phenotype that can sometimes be tumor suppressive, but sometimes oncogenic. In particular, our understanding of the diverse non-autonomous effects that senescent cells can have upon both cancer cells and the tumor microenvironment suggests that senescent cells could play a major role in many human cancer types. Here we suggest that cellular senescence could underpin the biology of many of the hallmarks of cancer, making it the true power behind the throne.We thank members of the Narita lab for comments on this review. M.H. is supported by a Cancer Research UK clinician scientist fellowship (C52489/A19924). M.N. is supported by a Cancer Research UK Cambridge Institute core grant (C14303/A17197)

Metabolomic changes during cellular transformation monitored by metabolite-metabolite correlation analysis and correlated with gene expression.

To investigate metabolic changes during cellular transformation, we used a 1H NMR based metabolite-metabolite correlation analysis (MMCA) method, which permits analysis of homeostatic mechanisms in cells at the steady state, in an inducible cell transformation model. Transcriptomic data were used to further explain the results. Transformed cells showed many more metabolite-metabolite correlations than control cells. Some had intuitively plausible explanations: a shift from glycolysis to amino acid oxidation after transformation was accompanied by a strongly positive correlation between glucose and glutamine and a strongly negative one between lactate and glutamate; there were also many correlations between the branched chain amino acids and the aromatic amino acids. Others remain puzzling: after transformation strong positive correlations developed between choline and a group of five amino acids, whereas the same amino acids showed negative correlations with phosphocholine, a membrane phospholipid precursor. MMCA in conjunction with transcriptome analysis has opened a new window into the metabolome.We acknowledge the support of The University of Cambridge, Cancer Research UK (C14303/A17197) and Hutchison Whampoa Limited.This is the final version of the article. It first appeared from Springer via http://dx.doi.org/10.1007/s11306-015-0838-