An expanding role for mTOR in cancer

Rapamycin, a valuable drug with diverse clinical applications, inhibits mTOR (mammalian target of rapamycin), which is a protein kinase that controls cell growth by regulating many cellular processes, including protein synthesis and autophagy. The sensitivity of select tumor cells to rapamycin has ignited considerable excitement over its potential as an anti-cancer therapeutic. Recent findings identified a rapamycin-insensitive function of mTOR in regulating a cell-survival pathway that is hyperactive in many cancers, particularly those with elevated PtdIns3K signaling or harboring mutations in the tumor suppressor PTEN (phosphatase and tensin homolog deleted on chromosome 10). These new findings suggest that targeting this function of mTOR might have broader applications in cancer therapy. In this article, we re-evaluate mTOR signaling, suggesting a more central role for mTOR in cancers with defective PtdIns3K-PTEN signaling and conceptually discuss these implications in the context of drug discovery.     

The expanding cosmos of nuclear receptor coactivators

About 200 coactivators play a central role in promoting gene expression mediated by nuclear receptors. This diverse group of proteins are key integrators of signals from steroid hormones and have been implicated in cancer and other diseases.     

Towards expanding relevance vector machines to large scale datasets

In this paper we develop and analyze methods for expanding automated learning of Relevance Vector Machines (RVM) to large scale text sets. RVM rely on Bayesian inference learning and while maintaining state-of-the-art performance, offer sparse and probabilistic solutions. However, efforts towards applying RVM to large scale sets have met with limited success in the past, due to computational constraints. We propose a diversified set of divide-and-conquer approaches where decomposition techniques promote the definition of smaller working sets that permit the use of all training examples. The rationale is that by exploring incremental, ensemble and boosting strategies, it is possible to improve classification performance, taking advantage of the large training set available. Results on Reuters-21578 and RCV1 are presented, showing performance gains and maintaining sparse solutions that can be deployed in distributed environments.     

The relevance of the nuclear division cycle to radiosensitivity in yeast

Summary To investigate whether the nuclear division cycle could be related to cycle-specific changes in repair of ionizing radiation damage, we have determined the survival curves after -irradiation of samples taken frequently from synchronously dividing cultures of Saccharomyces cerevisiae cells. Survival was low in G1 and increased during S, reaching a maximum around the end of the S phase, which was maintained in G2. The shape of the survival curves for samples taken from later stages revealed a rapid cycle-specific drop in the radioresistance of individual cells. A simple model was formulated on the assumption that survival is greatly enhanced by the action of an enzymatic repair mechanism which requires duplicated but unsegregated DNA as a substrate. By taking into account the measurable age heterogeneity of samples taken from the synchronous cultures, this model was shown to fit the survival data closely. For an individual cell, the increasing survival during the S phase is thus attributable to a rising fraction of duplicated genome, whereas the rapid decrease in radioresistance at a later stage in the cell cycle may be interpreted as due to the final physical separation of sister chromatids. The start of the latter event was timed to the stage in mitosis when the nucleus begins to move towards the neck of the bud. The data are consistent with the hypothesis that the high radioresistance of cells in late S and G2 is due to the repair of double-stranded DNA breaks by a process involving recombination between sister chromatids.     

Unraveling the multifaceted nature of the nuclear function of mTOR

Positioned at the axis between the cell and its environment, mTOR directs a wide range of cellular activity in response to nutrients, growth factors, and stress. Our understanding of the role of mTOR is evolving beyond the spatial confines of the cytosol, and its role in the nucleus becoming ever more apparent. In this review, we will address various studies that explore the role of nuclear mTOR (nmTOR) in specific cellular programs and how these pathways influence one another. To understand the emerging roles of nuclear mTOR, we discuss data and propose plausible mechanisms to offer novel ideas, hypotheses, and future research directions.     

The influence of chromosome density variations on the increase in nuclear disorder strength in carcinogenesis

Microscopic structural changes have long been observed in cancer cells and used as a marker in cancer diagnosis. Recent development of an optical technique, partial-wave spectroscopy (PWS), enabled more sensitive detection of nanoscale structural changes in early carcinogenesis in terms of the disorder strength related to density variations. These nanoscale alterations precede the well-known microscopic morphological changes. We investigate the influence of nuclear density variations due to chromosome condensation on changes of disorder strength by computer simulations of model chromosomes. Nuclear configurations with different degrees of chromosome condensation are realized from simulations of decondensing chromosomes and the disorder strength is calculated for these nuclear configurations. We found that the disorder strength increases significantly for configurations with slightly more condensed chromosomes. Coupled with PWS measurements, the simulation results suggest that the chromosome condensation and the resulting spatial density inhomogeneity may represent one of the earliest events in carcinogenesis.     

The expanding cell

The final size of a plant depends far less on the number ofcells produced by division than on the massive expansion ofthose cells once they have stopped dividing. Even in the tallestplant the apical meristems that ride this wave of cell expansiononly measure millimetres and, in more modest plants, micrometres.It is the swelling produced by the entry of water into the vacuoleof the non-dividing cells just behind the apex that drives thegrowing point further into its surroundings. This separationbetween division and expansion has been known since the     

The functions of mTOR in ischemic diseases

Mammalian Target of Rapamycin (mTOR) is a serine/threonine kinase and that forms two multiprotein complexes known as the mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). mTOR regulates cell growth, proliferation and survival. mTORC1 is composed of the mTOR catalytic subunit and three associated proteins: raptor, mLST8/GβL and PRAS40. mTORC2 contains mTOR, rictor, mLST8/GβL, mSin1, and protor. Here, we discuss mTOR as a promising anti-ischemic agent. It is believed that mTORC2 lies down-stream of Akt and acts as a direct activator of Akt. The different functions of mTOR can be explained by the existence of two distinct mTOR complexes containing unique interacting proteins. The loss of TSC2, which is upstream of mTOR, activates S6K1, promotes cell growth and survival, activates mTOR kinase activities, inhibits mTORC1 and mTORC2 via mTOR inhibitors, and suppresses S6K1 and Akt. Although mTOR signaling pathways are often activated in human diseases, such as cancer, mTOR signaling pathways are deactivated in ischemic diseases. From Drosophila to humans, mTOR is necessary for Ser473 phosphorylation of Akt, and the regulation of Akt-mTOR signaling pathways may have a potential role in ischemic disease. This review evaluates the potential functions of mTOR in ischemic diseases. A novel mTOR-interacting protein deregulates over-expression in ischemic disease, representing a new mechanism for controlling mTOR signaling pathways and potential therapeutic strategies for ischemic diseases.     

The expanding snoRNA world

In eukaryotes, the site-specific formation of the two prevalent types of rRNA modified nucleotides, 2'-O-methylated nucleotides and pseudouridines, is directed by two large families of snoRNAs. These are termed box C/D and H/ACA snoRNAs, respectively, and exert their function through the formation of a canonical guide RNA duplex at the modification site. In each family, one snoRNA acts as a guide for one, or at most two modifications, through a single, or a pair of appropriate antisense elements. The two guide families now appear much larger than anticipated and their role not restricted to ribosome synthesis only. This is reflected by the recent detection of guides that can target other cellular RNAs, including snRNAs, tRNAs and possibly even mRNAs, and by the identification of scores of tissue-specific specimens in mammals. Recent characterization of homologs of eukaryotic modification guide snoRNAs in Archaea reveals the ancient origin of these non-coding RNA families and offers new perspectives as to their range of function.     

The expanding polymerase universe

Over the past year, the number of known prokaryotic and eukaryotic DNA polymerases has exploded. Many of these newly discovered enzymes copy aberrant bases in the DNA template over which 'respectable' polymerases fear to tread. The next step is to unravel their functions, which are thought to range from error-prone copying of DNA lesions, somatic hypermutation and avoidance of skin cancer, to restarting stalled replication forks and repairing double-stranded DNA breaks.     

The role of carboxypeptidases in carcinogenesis

The literature and own experimental data on the role of metallocarboxypeptidases in carcinogenesis have been reviewed. The development of various tumors is accompanied by the increase in activity of all groups of these. It is suggested that in some cases carboxypeptidases play a protective role attributed to inhibition of tumor development.     

The integral role of mTOR in lipid metabolism

Comment on: Soliman GA, et al. Lipids 2010; 45:1089-100.