Peter S Linsley

..Simultaneous silencing of these genes was more effective at blocking cell cycle progression than disruption of the individual genes. Thus, miR-16 coordinately regulates targets that may act in concert to control cell cycle progression...

..Our results showing a role for miR-192/215 in cell proliferation combined with recent observations that these miRNAs are underexpressed in primary cancers support the idea that miR-192 and miR-215 function as tumor suppressors...

..Thus, our integrated genomic approach has led to the identification of a novel mediator of p53 network biology...

..These findings establish a link between synthetic lethality of PARPi in BRCA-network disrupted cells and interferon pathway activation triggered by genetic instability...

..Thus, miR-210 influences the hypoxia response in tumor cells through targeting a key transcriptional repressor of the MYC-MAX network...

..Therefore, siRNA therapeutics may trigger microRNA-like silencing of many unintended targets in vivo, and the potential toxicities caused by these off-target gene regulations cannot be accurately assessed in rodent models...

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..When combined with phenotypic evaluation, our approach should help to unleash the full potential of siRNAs in systematically unveiling the molecular mechanism of biological events...

..We also show that miR-106b overrides a doxorubicin-induced DNA damage checkpoint. Thus, miR-106b family members contribute to tumor cell proliferation in part by regulating cell cycle progression and by modulating checkpoint functions...

..Four of these ESTs were extended to novel full-length clones encoding T-cell-regulated proteins with predicted functions in GTP metabolism, cell organization, and signal transduction...

..In summary, through a functional genomics approach, pathways essential in the context of oncogenic MYC but not to normal cells were identified, thus revealing a rich therapeutic space linked to a previously "undruggable" oncogene...

..Moreover, miR-1 and miR-124, and presumably other tissue-specific miRNAs, seem to downregulate a far greater number of targets than previously appreciated, thereby helping to define tissue-specific gene expression in humans...

..These results demonstrate the feasibility of screening with large collections of lentiviral vectors to identify drug enhancers and suppressors...

..Thus, tumor cells having disruptions in BRCA1/2 network genes and TP53 together are more sensitive to cisplatin than cells with either disruption alone...

..In contrast, knockdown of the endogenous miRNAs accelerate differentiation. Our data show that in ES cells c-Myc acts, in part, through a subset of miRNAs to attenuate differentiation...

..Thus, short stretches of sequence complementarity to the siRNA or shRNA seed region are key to the silencing of unintended transcripts...

..These studies demonstrate the feasibility of using DNA microarrays to measure the variations in gene expression of PBL from different individuals in response to environmental and genetic factors...

..Together, these data validate the utility of the RNAi approach and suggest that siRNA can be used as a complement to classical knockout technology in gene function studies...

..We discuss emerging evidence that support the idea that some microRNA activity may be cell cycle dependent, and we outline how the coordinate regulation of microRNA targets may influence cell cycle progression...

..Supporting this view, the number of applications of DNA microarray technology has since expanded exponentially. Here, we review recent advances in microarray technology and selected new applications of the technology...

..These results demonstrate that siRNAs may cross-react with targets of limited sequence similarity...

..Furthermore, the link we observed between siRNA efficacy and phenotypic outcome indicates that distinct stages during cell cycle progression are disrupted by the differential modulation of KIF14 expression...

..These studies point to specific gene pathways that might be exploited for both prognostic indicators as well as new targets for therapy...

..These findings suggest that expression patterns can be used to identify a complex environmental exposure in humans...

..We identify a gene expression pattern strongly associated with obesity in a murine cross, and observe two distinct obesity subtypes. Furthermore, we find that these obesity subtypes are under the control of different loci...

..In the meantime, caution is warranted in interpreting gene function and phenotypes resulting from RNAi experiments...

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..Transfection efficiency, performances of control siRNAs, and other quality metrics were monitored and demonstrated that the new, optimized transfection protocol produced high-quality results throughout the screen...

..The p53 network suppresses tumour formation through the coordinated activation of multiple transcriptional targets, and miR-34 may act in concert with other effectors to inhibit inappropriate cell proliferation...

..Hence, the presented esiRNA libraries offer an efficient, cost-effective and specific alternative to presently available mammalian RNAi resources...

..This gene expression profile will outperform all currently used clinical parameters in predicting disease outcome. Our findings provide a strategy to select patients who would benefit from adjuvant therapy...

..Our data suggest that siRNAs can be designed to discriminate between the wild-type and mutant alleles of many genes that differ by just a single nucleotide...

..Cytotoxic T lymphocyte antigen 4 (CTLA-4) engagement selectively blocked augmentation of gene regulations by CD28-mediated costimulation, but did not ablate gene regulation induced by TCR triggering alone...

..Maximal inhibition of target genes was achieved at lower concentrations and silencing at 24 h was often greater. These studies provide the basis for an improved approach to triggering experimental silencing via the RNAi pathway...

..Furthermore, we describe siRNA bar-code screens to rapidly identify individual siRNA vectors associated with a specific phenotype. These new tools will greatly facilitate large-scale loss-of-function genetic screens in mammalian cells...

..Together, these data suggest that CTLA-4 and PD-1 inhibit T-cell activation through distinct and potentially synergistic mechanisms...

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