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In brief: August 2009Stem cells A parallel circuit of LIF signalling pathways maintains pluripotency of mouse ES cells How leukaemia inhibitory factor (LIF) signalling regulates the transcriptional circuitry that controls mouse embryonic stem cell self-renewal and pluripotency was unknown. Niwa et al. now show that LIF signals to the core pluripotency transcription factors OCT4, SOX2 and NANOG through two parallel pathways: JAK–STAT3, which activates Sox2 through the transcription factor KLF4, and PI3K–AKT, which activates Nanog through the transcription factor TBX3. These proteins maintain the expression of Oct4, which is essential for pluripotency. So, a functional hierarchy of transcription factors links extracellular signalling to embryonic stem cell pluripotency. Cytokines Suppression of interleukin-33 bioactivity through proteolysis by apoptotic caspases The interleukin-1 (IL-1) family member IL-33 is a recently described pro-inflammatory cytokine and was thought to be activated by caspase 1-mediated proteolysis. However, this study now shows that IL-33 is not a substrate for inflammatory caspases such as caspase 1. Instead, IL-33 is processed by caspases that are activated during apoptosis (caspase 3 and caspase 7). Caspase-mediated proteolysis of IL-33 was not necessary for its biological activities, such as activation of the transcription factor nuclear factor- Signalling Phosphorylation of the tumour suppressor Fat is regulated by its ligand Dachsous and the kinase discs overgrown Helen McNeill and colleagues have shown that the Drosophila melanogaster tumour suppressor gene fat is regulated by Dachsous. They found that Fat (a cadherin) is cleaved into a 110 kDa and a 450 kDa protein. Fat110 is bound and phosphorylated by the casein kinase Discs overgrown, which seemed to be regulated by Dachsous, also a cadherin. These interactions seem to be important for the regulation of planar cell polarity and the Hippo cell growth pathway, disruption of which is implicated in tumorigenesis. Metastasis Latent bone metastasis in breast cancer tied to Src-dependent survival signals Late-onset metastasis, particularly to the bone, is a common occurrence in patients with breast cancer, but the mechanism(s) by which disseminated cancer cells survive for long periods of time in the metastatic microenvironment is largely unknown. Zhang and colleagues generated a gene expression signature using samples from more than 600 patients with breast cancer, which revealed that Src activation is associated with latent bone metastasis. Both CXCL12 and TNF-related apoptosis-inducing ligand (TRAIL) are particularly expressed in the bone microenvironment, and Src promoted survival by mediating CXCL12–CXCR4–Akt pathway activation and resistance to TRAIL. Metabolism Mitochondrial STAT3 supports Ras-dependent oncogenic transformation Gough and colleagues found that signal transducer and activator of transcription 3 (STAT3) is required for HRAS-V12-mediated transformation. STAT3 is a transcription factor and when phosphorylated by tyrosine kinases it undergoes nuclear localization to activate target genes. Surprisingly, transactivation was not required for HRAS-V12-mediated transformation. Instead, mitochondrial STAT3 was sufficient and seemed to modulate metabolic pathways. Signalling Genomic antagonism between retinoic acid and estrogen signalling in breast cancer The retinoic acid receptors (RARs) are transcription factors that mediate the growth-inhibitory effects of retinoic acid and its derivatives, which are being developed as anticancer drugs. Hua and colleagues combined genome-wide chromatin immunoprecipitation and gene expression analyses in MCF7 breast cancer cells to identify RAR target genes. They found that RARs bound gene regulatory regions that overlap or are in close proximity to regions bound by oestrogen receptor- Transcriptomics Quantification of the yeast transcriptome by single-molecule sequencing Transcriptome sequencing using high-throughput short-read methods (RNA-Seq) can be used to quantify transcript levels. However, the variable number of reads per mRNA means that the whole transcriptome must be assessed to obtain a normalized quantification for each transcript. This paper reports a quantitative transcriptomics method based on single-molecule sequencing. Because no amplification is required, sequence read counts are directly proportional to transcript abundance and very high throughput can be achieved, providing an efficient and accurate method for quantitative transcriptomics. Synaptic plasticity βCaMKII controls the direction of plasticity at parallel fiber-Purkinje cell synapses Calcium/calmodulin-dependent protein kinase II (CAMKII) isoform Cancer Loss of the Alox5 gene impairs leukemia stem cells and prevents chronic myeloid leukemia Although targeting cancer stem cells is thought to be essential for curing cancers, few target genes in cancer stem cells have been identified. Chen and colleagues identified the 5-lipoxygenase gene (Alox5) as a crucial regulator of leukaemia stem cells in BCR–ABL-induced chronic myeloid leukaemia (CML). In mice lacking Alox5, BCR–ABL did not generate CML, and there was impaired function of leukaemia stem cells. Treatment of CML mice with an inhibitor of 5-lipoxygenase also impaired the function of leukaemia stem cells, and prolonged survival. Proteomics Defining RNA-binding protein preferences RNA-binding preferences for only a few RNA-binding proteins (RBPs) have been determined, in part because existing methods are costly and laborious. Ray et al. describe a rapid approach, called RNAcompete, and use it to define RNA-binding specificities for nine RBPs. In this method, a diverse RNA pool is first generated; RNAs that bind to an RBP of interest are pulled down, fluorescently labeled and then analyzed via a microarray. | |
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B, but instead attenuated the biological activity of IL-33 in vitro and in vivo and increased its susceptibility to protease degradation. The authors suggest that proteolysis of IL-33 may help to dampen the potential pro-inflammatory effects of apoptotic cell death.
, which has antagonistic effects. These data indicate that oestrogen and retinoic acid signalling exhibit extensive crosstalk.
CAMKII at these synapses is unknown. Here, whole-cell recordings revealed that paired parallel and climbing fibre stimulation induced long-term depression in Purkinje cells from wild-type mice but long-term potentiation in Purkinje cells from Camk2b-/- mice. Parallel fibre stimulation alone had the opposite result. This indicates that 