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In brief: November 2008Cell polarity Actin-driven chromosomal motility leads to symmetry breaking in mammalian meiotic oocytes Oocyte meiotic divisions are highly asymmetric, and symmetry breaking initiates when chromosomes move from the oocyte centre towards the cortex. Rong Li and colleagues used four-dimensional (4D) tracking, and genetic and pharmacological manipulations to determine the force-generating mechanism that underlies this chromosome movement. They found that chromosomes move towards the cortex in a pulsatile manner along a meandering path. Rather than being propelled by myosin-II-driven cortical flow, this movement was associated with a cloud of dynamic filaments trailing behind the chromosomes. Formation of these filaments depends on the actin nucleation activity of the formin protein FMN2, which concentrates around the chromosomes. These findings do not favour the model that chromosomes are moved as cargo along a pre-existing actin track or through an actin–myosin-II-based contractile network. Instead, they are consistent with a model in which chromosome movement is driven by actin polymerization. Protein degradation Ubiquitin-like protein involved in the proteasome pathway of Mycobacterium tuberculosis The protein modifier ubiquitin is a signal for proteasome-mediated degradation in eukaryotes. By contrast, proteasome-bearing prokaryotes have been thought to degrade proteins through a ubiquitin-independent pathway. Pearce et al. have now identified a prokaryotic ubiquitin-like protein, Pup (also known as Rv2111c), which was specifically conjugated to proteasome substrates in the pathogen Mycobacterium tuberculosis. Similar to ubiquitylation, pupylation occurs on Lys residues and requires proteasome accessory factor A (PafA). In a pafA mutant, pupylated proteins were absent and substrates accumulated, thereby connecting pupylation with protein degradation. So, like eukaryotes, bacteria might use a small protein modifier to control protein stability. Tumour immunology Modulation of the antitumor immune response by complement Contrary to expectations, this study shows that key by-products of complement activation — the anaphylatoxins C3a and C5a — promote tumour growth by suppressing the antitumour immune response. In a mouse model involving subcutaneous injection of TC-1 malignant cells, deficiency of the complement components C3 or C4 or the C5a receptor (C5aR) was shown to inhibit tumour growth. Moreover, pharmacological inhibition of C5aR was as efficient as the antitumour drug paclitaxel at limiting tumour growth. The suggested role of C5a in promoting tumour growth was explained by the finding that C5a induced the recruitment of myeloid-derived suppressor cells (MDSCs) to tumours and increased their suppressive capacity. MDSCs inhibit local antitumour responses by producing reactive oxygen and nitrogen species, an activity that was enhanced by C5a and was consistent with an observed increase in antitumour T-cell responses following C5aR blockade. Cell cycle AP4 encodes a c-MYC-inducible repressor of p21 This study reports a novel mechanism of p21 downregulation by the oncoprotein MYC. p21 is a central regulator of cell cycle inhibition and its loss allows cells to continue replication of their DNA in the presence of DNA damage. The authors found that expression of p21 could be altered by MYC binding to AP4 regulatory motifs, thus altering AP4 expression. AP4 is a transcriptional activator and repressor, and regulates expression of CDKN1A, the gene that encodes p21, by binding sites in the CDKN1A promoter. AP4 sensitizes cells to DNA-damaging agents, which are commonly used in cancer therapy. Therefore, modulation of processes that are regulated by AP4 may have therapeutic value. Signalling Defective Notch activation in microenvironment leads to myeloproliferative disease Inactivation of mind bomb 1 (Mib1), an essential component of Notch ligand endocytosis, in non-haematopoietic cells led to the development of myeloproliferative disease in conditional knockout mice. The introduction of a constitutively active form of Notch into the Mib1-null background significantly suppressed disease progression, which suggested that myeloproliferative disease development is caused by defective activation of Notch in non-haematopoietic cells. Therefore, Notch ligand–receptor interactions between the non-haematopoietic cells that constitute the cellular microenvironment are absolutely required for normal haematopoiesis. Functional genomics A genomewide functional network for the laboratory mouse The authors have generated a global functional network for the mouse by integrating various genetic and functional genome-wide data sets using a probabilistic model. This community resource (which is freely available at http://mouseNET.princeton.edu) predicts the probability that two proteins are involved in the same biological process. It encompasses linkages between over 20,000 protein-coding genes and can be used to discover protein functions and novel pathway components as well as for exploring the general features of cellular interactomes. Gene expression A quantitative model of transcription factor-activated gene expression A new quantitative framework for modelling the relationship between transcription factor (TF) input and gene expression in eukaryotes (the gene–regulation function, GRF) is described in this report. The model was constructed by relating mutations in the PHO5 promoter of Saccharomyces cerevisiae to gene expression profiles and chromatin remodelling; it concludes that variation in gene expression depends on the nucleosome-regulated availability of TF binding sites. The new framework could be adapted to describe the GRF of other eukaryotic genes. Feeding behaviour Hypothalamic IKK Insulin and leptin are central regulators of feeding behaviour. This study shows that overnutrition leads to IKK Development Temporal progression of hypothalamic patterning by a dual action of BMP Bone morphogenetic protein (BMP) and Sonic hedgehog (SHH) establish opposing spatial gradients that are crucial for the patterning of the developing nervous system. This study showed that in the developing chick hypothalamus BMP antagonizes the action of SHH in a temporal manner, first by upregulating the transcription factor that SHH represses, GLI3, and second by activating the BMP signal transducer SMAD5. This temporal integration of antagonistic ligands is required for the specification of precursor cells of the ventrolateral hypothalamus and represents a new mechanism by which to achieve cellular diversity. Neuroimmunology Innate immunity in Caenorhabditis elegans is regulated by neurons expressing NPR-1/GPCR Precisely how the nervous system regulates the innate immune system is unclear. The authors show that the G-protein-coupled receptor NPR1 is required for innate immune responses in Caenorhabditis elegans. Activity in a neural circuit that includes the NPR1-expressing neurons AQR, PQR and URX suppresses innate immune responses through the modification of immunity-related genes. This study reveals a mechanism by which neurons can control innate immunity. Cancer Glycogen synthase kinase 3 in MLL leukaemia maintenance and targeted therapy Glycogen synthase kinase 3 (GSK3) inhibition has attracted interest as a therapeutic strategy but there has been some concern that GSK3 inhibitors might be oncogenic. This paper demonstrates an unexpected oncogenic requirement for GSK3 in the maintenance of a human leukaemia that has poor prognosis (defined by mutations in MLL). GSK3 paradoxically supported MLL leukaemia cell proliferation and transformation by a mechanism involving destabilization of the cyclin-dependent kinase inhibitor p27Kip1. In a mouse model of MLL leukaemia, inhibition of GSK3 prolonged survival, highlighting the potential of GSK3 as a cancer drug target. Chemical biology Chemical control of proteins in mice Banaszynski et al. expanded a previously developed method to control protein function in cells. They express a protein of interest as a fusion to an unstable domain. The unstable fusion protein is targeted for degradation, but the presence of a stabilizing ligand protects the fusion protein from degradation, in a dose-dependent manner. By using a viral vector to deliver the fusion protein, they now show they can control protein function in living mice. | |
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B and ER stress link overnutrition to energy imbalance and obesity