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MicroRNAs (miRNAs) are a class of regulatory RNAs of ;21 nucleotides that posttranscriptionally regulate gene expression by directing mRNA cleavage or translational inhibition. Increasing evidence points to a potential role of miRNAs in diverse physiological processes. miR398 targets two closely related Cu/Zn superoxide dismutases (cytosolic CSD1 and chloroplastic CSD2) that can detoxify superoxide radicals. CSD1 and CSD2 transcripts are induced in response to oxidative stress, but the regulatory mechanism of the induction is unknown. Here, we show that miR398 expression is downregulated transcriptionally by oxidative stresses, and this downregulation is important for posttranscriptional CSD1 and CSD2 mRNA accumulation and oxidative stress tolerance. We also provide evidence for an important role of miR398 in specifying the spatial and temporal expression patterns of CSD1 and CSD2 mRNAs. Our results suggest that CSD1 and CSD2 expression is fine-tuned by miR398-directed mRNA cleavage. Additionally, we show that transgenic Arabidopsis thaliana plants overexpressing a miR398-resistant form of CSD2 accumulate more CSD2 mRNA than plants overexpressing a regular CSD2 and are consequently much more tolerant to high light, heavy metals, and other oxidative stresses. Thus, relieving miR398-guided suppression of CSD2 in transgenic plants is an effective new approach to improving plant productivity under oxidative stress conditions.

Elucidation of the mutational landscape of human cancer has progressed rapidly and been accompanied by the development of therapeutics targeting mutant oncogenes. However, a comprehensive mapping of cancer dependencies has lagged behind and the discovery of therapeutic targets for counteracting tumor suppressor gene loss is needed. To identify vulnerabilities relevant to specific cancer subtypes, we conducted a large-scale RNAi screen in which viability effects of mRNA knockdown were assessed for 7,837 genes using an average of 20 shRNAs per gene in 398 cancer cell lines. We describe findings of this screen, outlining the classes of cancer dependency genes and their relationships to genetic, expression, and lineage features. In addition, we describe robust gene-interaction networks recapitulating both protein complexes and functional cooperation among complexes and pathways. This dataset along with a web portal is provided to the community to assist in the discovery and translation of new therapeutic approaches for cancer.

Cold temperatures trigger the expression of the CBF family of transcription factors, which in turn activate many downstream genes that confer freezing tolerance to plants. It has been shown previously that the cold regulation of CBF3 involves an upstream bHLH-type transcription factor, ICE1. ICE1 binds to the Myc recognition sequences in the CBF3 promoter. Apart from Myc recognition sequences, CBF promoters also have Myb recognition sequences. We report here that the Arabidopsis MYB15 is involved in cold-regulation of CBF genes and in the development of freezing tolerance. The MYB15 gene transcript is up-regulated by cold stress. The MYB15 protein interacts with ICE1 and binds to Myb recognition sequences in the promoters of CBF genes. Overexpression of MYB15 results in reduced expression of CBF genes whereas its loss-of-function leads to increased expression of CBF genes in the cold. The myb15 mutant plants show increased tolerance to freezing stress whereas its overexpression reduces freezing tolerance. Our results suggest that MYB15 is part of a complex network of transcription factors controlling the expression of CBFs and other genes in response to cold stress.Cold temperatures have a huge impact on the survivability and distribution of living organisms. Plants, being sessile, have evolved efficient mechanisms to sense and adapt to low temperature stress. Plant responses to adverse low temperature are manifested at physiological, molecular and biochemical levels. Many temperate plants have the potential to increase their freezing tolerance after a prior exposure to nonfreezing temperatures, a process known as cold acclimation (1-3). At the molecular level, a specific set of proteins is induced in response to low temperature, which helps plants cope with chilling and freezing stress (4 -8). Proteins induced during cold acclimation include enzymes involved in respiration and metabolism of carbohydrates, lipids, phenylpropanoids, and antioxidants, molecular chaperones, antifreeze proteins, and many others with a presumed function in tolerance to cellular dehydration caused by apoplastic freezing (1, 4, 9).Promoters of many of the cold-responsive genes have the DRE/CRT/LTRE (dehydration responsive element/C-repeat/ low temperature responsive element) sequence, a cis element necessary and sufficient for gene transcription under cold stress (10 -12). The CBF/DREB family of transcription factors binds to this sequence and activates cold-responsive genes (11, 13). The CBF transcription factor genes are also induced by cold, and their induction is regulated by components upstream in the cold response pathways (14 -17). In addition, it has been shown that a loss-of-function mutation in CBF2 results in increased expression of CBF1 and CBF3, implying that CBF2 negatively regulates the expression of CBF1 and CBF3 (18).In addition to the CBF pathway, recent studies have revealed the presence of parallel pathways associated with cold acclimation (19 -21). Some important components mediating cold tolerance through CBF-inde...

SUMMARY Activating mutations in KRAS are among the most frequent events in diverse human carcinomas and are particularly prominent in human pancreatic ductal adenocarcinoma (PDAC). An inducible KrasG12D-driven mouse model of PDAC has established a critical role for sustained KrasG12D expression in tumor maintenance, providing a model to determine the potential for, and the underlying mechanisms of, KrasG12D–independent PDAC recurrence. Here we show that some tumors undergo spontaneous relapse and are devoid of KrasG12D expression and downstream canonical MAPK signaling and instead acquire amplification and overexpression of the transcriptional co-activator Yap1. Functional studies established the role of Yap1 and the transcriptional factor Tead2 in driving KrasG12D–independent tumor maintenance. The Yap1/Tead2 complex acts cooperatively with E2F transcription factors to activate a cell cycle and DNA replication program. Our studies, along with corroborating evidence from human PDAC models, portend a novel mechanism of escape from oncogenic Kras addiction in PDAC.