A Carnero

..However, AKT is more than a passive bridge toward PTEN tumorigenesis, since its expression not only allows but also enforces and accelerates the tumorigenic process in combination with other oncogenes...

..Additionally, the binding of PI3K to oncogenic ras is essential for the transforming properties of ras. In summary, the data strongly support the view of the PTEN/PI3K/AKT pathway as an important target for drug discovery...

..These proteins are kinases, which are very "druggable" targets a priori, and, according to the "addiction hypothesis", cancer cells with the activated pathway will be more dependent on its activity for their survival...

..We developed U2transLUC, an assay system in which luciferase and fluorescent read-outs can be multiplexed to provide a powerful cell-based high content screening method...

..Thus, the reciprocal cooperation between myc and ras in a p21-null background during cellular immortalization lead to increased oncogenic cooperation between ras and myc...

..To that end, new developments in large-scale cell biology and compound library design in silico have evolved to obtain data with higher predictability of clinical efficacy...

..Indeed, many companies and academic laboratories have initiated a variety of approaches to inhibit the PI3K pathway at different points. In this work, we review the targeting of PI3K protein for therapeutical intervention...

..Our data suggest that the three genes identified in the genome-wide loss-of-function genetic screen are putative tumor suppressors located at 15q21.2; 7q35 and 14q32.33...

..One line of work is focussed on trans platinum complexes, some of which exhibit antitumour activity similar to or even higher than that of their cis counterparts...

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..The models introduced, though simple, help to integrate experimental information relating tumorigenesis with cellular and organism aging phenomena...

..Thus, although too early to provide a cell cycle target based new commercial drug, there is no doubt that it will be an excellent source of new anticancer compounds...

..These results facilitate the exploration of potential synergism between chemotherapeutic treatment and the search for others that can account for similar molecular mechanisms of cooperation...

..This leads to the synthesis of ETP-45658, which is a potent and selective inhibitor of phosphoinositide 3-kinases and demonstrates mechanism of action in tumor cell lines and in vivo in treated mice...

..Altogether, our results show the potential of large-scale cell-based RNAi screens to identify promising diagnostic markers and therapeutic targets...

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..It is a live debate whether these outcomes are influenced by quantitative or qualitative mechanisms. Furthermore, the relative contribution of p53 to Ras-induced senescence is also matter of controversy...

..Our data indicate that MAP17 protein activates AKT through ROS and this is determinant to confer resistance to Myc-induced apoptosis in the absence of serum...

..This review will summarise some of the key animal models which have helped us to understand this signalling network and its contribution to tumorigenesis...

..Since they define overlapping but not identical subsets of the tested tissue panel, a combination of all four markers might lead to a more accurate diagnosis of the status of the PI3K-signaling cascade in cancer patients...

..Thus, mammalian PKC zeta is most likely not directly involved in the regulation of cell proliferation in fibroblasts nor affects directly or indirectly the activation of NF kappa B...

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..However, MAP17 mRNA expression did not correlate with TNF resistance. Our data indicates that although MAP17 expression might bypass TNF-induced growth arrest, it is not the only determinant of this response...

..Our data illustrate the potential of chemical genetics when combined with robust and sensitive high-content-screening technology...

..p110 isoform-mediated protection from cell death was abrogated upon expression of a kinase-negative version of Akt...

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..The use of cell lines whose proliferative properties exclusively depend on selective targets provide a novel strategy to analyze the specificity of selective inhibitors designed against molecular targets implicated in human cancer...

..Using these models for drug testing may enable more accurate prediction of the effects that a specific drug will have on a patient...

..Our results indicate that oncogenic activation of the Ras pathway in murine fibroblasts converts p53 into a senescence inducer through a p21waf1-independent mechanism...

..Here, we review the development of HCS platforms to identify molecules influencing FOXO nuclear relocation and activation as pharmacological targets, their applicability and the future directions of the screening field...

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..Our results confirm that p21(waf1) has an essential role in TNF-induced arrest and that the deregulation of cyclin D1 may be one of the mechanisms to escape physiological signals to restrict tumoral growth...

..Interestingly, in most cases, the reduction of ribosomal protein mRNAs occurs only to 50%. Our data suggest that ribosomal protein imbalance might contribute to p53 regulation through the ribosomal biogenesis checkpoint...

..76. In summary, U2nesRELOC is a cell-based nuclear export assay suitable for high throughput screening, providing counterscreens for pathway deconvolution...

..In conclusion, a high CYP3A4 tumoral expression could be useful to predict poor response to the standard PTCL chemotherapy; in these cases alternative chemotherapy combinations or doses should be explored...

..We propose that oncogenic stress induced by ras causes ceramide accumulation, therefore, increasing PPP1CA activity, pRb dephosphorylation and onset of the p53-induced arrest, contributing to tumor suppression...

..Therefore, understanding the modulation of FOXO transcription factors will allow the design of new compounds with antitumor potential...

..Our work shows the tumorigenic capability of MAP17 through a connection between Na+-coupled co-transporters and ROS...

..These data suggest that genetically engineered tumor models involving key cell cycle regulators are a valuable tool to evaluate drugs with potential therapeutic benefit in human cancer...

..However, rational target-orientated approaches to cell based drug screens for anti-cancer agents have historically been compromised by the notorious absence of suitable control cells...

..Our observations show that BRCA1 mediates G(2)-M transition mainly through chek1 on 17-allyloamino-17-demethoxy-geldanamycin treatment...

..Mechanistically, the antitumor activity correlates with a blockade of the cell cycle in S phase and a complete abolishment of G2/M checkpoint arrest suggesting physical interaction of compound with DNA inhibiting S phase transition...

..The transcriptional signature described here may lead to the identification of ET-743 downstream mediators and transcription regulators and the proposal of strategies by which ET-743-sensitive tumors may be identified...

..Manipulation of these control mechanisms provides new avenues for the design of advanced therapeutic strategies against tumor development...

..Because wild-type p53 down-regulates PGM, mutation of p53 can facilitate immortalization via effects on PGM levels and glycolysis...

..These results could help in interpreting the cellular actions of (R)-roscovitine but also in guiding the synthesis of more selective roscovitine analogs...

..These results give a partial explanation for the physiologic role of c-Myc overexpression in prostate cancer...

..Together, these data suggest that CBX7 represses p16Ink4a and p14Arf expression in normal and tumor-derived prostate cells, affecting their growth depending on the status of the p16Ink4a/Rb and the p14Arf/p53 pathways...

..Our data indicate that our compounds are not cross-resistant with cisplatin and might be promising agents in the treatment of tumors unresponsive to cisplatin...