Hot off the presses! Jan 08 Cell

The Jan 08 issue of the Cell is now up on Pubget (About Cell): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• In This Issue
  - Cell 140(1):1, 3 (2010)
  
• Synthetic Biology Select
  - Cell 140(1):5, 7 (2010)
  In this issue, Leading Edge highlights synthetic biology, a field that is deepening our understanding of the design principles of life and increasing our mastery of biological systems for practical applications in biotechnology and medicine. Reports from the recent literature, discussed in this Synthetic Biology Select, include the rational design of a functional enzyme, an approach for creating more stable proteins, and systems-level analyses that reveal unexpected sophistication in the regulatory networks of microorganisms.
• Stem Cell Therapies: California Dreamin'?
  - Cell 140(1):10-12 (2010)
  Ready or not, stem cells are a step closer to the clinic, thanks to $230 million awarded by CIRM to 14 California-based research groups to develop stem cell-based therapies within 4 years. But, as Kris Novak reports, some of these projects are closer to therapeutic reality than others.
• Making Cellular Memories
  - Cell 140(1):13-18 (2010)
  The induction of a protracted response to a brief stimulus is a form of cellular memory. Here we describe the role of transcriptional regulation in both natural and synthetic memory networks and discuss the potential applications of engineered memory networks in medicine and industrial biotechnology.
• Engineering Static and Dynamic Control of Synthetic Pathways
  - Cell 140(1):19-23 (2010)
  Maximizing the production of a desired small molecule is one of the primary goals in metabolic engineering. Recent advances in the nascent field of synthetic biology have increased the predictability of small-molecule production in engineered cells growing under constant conditions. The next frontier is to create synthetic pathways that adapt to changing environments.
• Chewing the Fat on Tumor Cell Metabolism
  - Cell 140(1):28-30 (2010)
  Tumor cells undergo a metabolic shift toward specific bioenergetic (glycolysis) and anabolic (protein and lipid synthesis) processes that promote rapid growth. Nomura et al. (2010) now demonstrate that an increase in monoacylglycerol lipase (MAGL) drives tumorigenesis through the lipolytic release and remodeling of free fatty acids.
• Engineering Signal Transduction Pathways
  - Cell 140(1):33-47 (2010)
  Cells respond to their environment by sensing signals and translating them into changes in gene expression. In recent years, synthetic networks have been designed in both prokaryotic and eukaryotic systems to create new functionalities and for specific applications. In this review, we discuss the challenges associated with engineering signal transduction pathways. Furthermore, we address advantages and disadvantages of engineering signaling pathways in prokaryotic and eukaryotic cells, highlighting recent examples, and discuss how progress in synthetic biology might impact biotechnology and biomedicine.
• Monoacylglycerol Lipase Regulates a Fatty Acid Network that Promotes Cancer Pathogenesis
  Nomura DK Long JZ Niessen S Hoover HS Ng SW Cravatt BF - Cell 140(1):49-61 (2010)
  Tumor cells display progressive changes in metabolism that correlate with malignancy, including development of a lipogenic phenotype. How stored fats are liberated and remodeled to support cancer pathogenesis, however, remains unknown. Here, we show that the enzyme monoacylglycerol lipase (MAGL) is highly expressed in aggressive human cancer cells and primary tumors, where it regulates a fatty acid network enriched in oncogenic signaling lipids that promotes migration, invasion, survival, and in vivo tumor growth. Overexpression of MAGL in nonaggressive cancer cells recapitulates this fatty acid network and increases their pathogenicity—phenotypes that are reversed by an MAGL inhibitor. Impairments in MAGL-dependent tumor growth are rescued by a high-fat diet, indicating that exogenous sources of fatty acids can contribute to malignancy in cancers lacking MAGL activity. Together, these findings reveal how cancer cells can co-opt a lipolytic enzyme to translate their ! lipogenic state into an array of protumorigenic signals. PaperFlick To view the video inline, enable JavaScript on your browser. However, you can download and view the video by clicking on the icon below Download this Video (23153 K)
• Biological and Molecular Heterogeneity of Breast Cancers Correlates with Their Cancer Stem Cell Content
  - Cell 140(1):62-73 (2010)
  Pathways that govern stem cell (SC) function are often subverted in cancer. Here, we report the isolation to near purity of human normal mammary SCs (hNMSCs), from cultured mammospheres, on the basis of their ability to retain the lipophilic dye PKH26 as a consequence of their quiescent nature. PKH26-positive cells possess all the characteristics of hNMSCs. The transcriptional profile of PKH26-positive cells (hNMSC signature) was able to predict biological and molecular features of breast cancers. By using markers of the hNMSC signature, we prospectively isolated SCs from the normal gland and from breast tumors. Poorly differentiated (G3) cancers displayed higher content of prospectively isolated cancer SCs (CSCs) than did well-differentiated (G1) cancers. By comparing G3 and G1 tumors in xenotransplantation experiments, we directly demonstrated that G3s are enriched in CSCs. Our data support the notion that the heterogeneous phenotypical and molecular traits of human ! breast cancers are a function of their CSC content.
• Human TUBB3 Mutations Perturb Microtubule Dynamics, Kinesin Interactions, and Axon Guidance
  - Cell 140(1):74-87 (2010)
  We report that eight heterozygous missense mutations in TUBB3, encoding the neuron-specific β-tubulin isotype III, result in a spectrum of human nervous system disorders that we now call the TUBB3 syndromes. Each mutation causes the ocular motility disorder CFEOM3, whereas some also result in intellectual and behavioral impairments, facial paralysis, and/or later-onset axonal sensorimotor polyneuropathy. Neuroimaging reveals a spectrum of abnormalities including hypoplasia of oculomotor nerves and dysgenesis of the corpus callosum, anterior commissure, and corticospinal tracts. A knock-in disease mouse model reveals axon guidance defects without evidence of cortical cell migration abnormalities. We show that the disease-associated mutations can impair tubulin heterodimer formation in vitro, although folded mutant heterodimers can still polymerize into microtubules. Modeling each mutation in yeast tubulin demonstrates that all alter dynamic instability whereas a subset! disrupts the interaction of microtubules with kinesin motors. These findings demonstrate that normal TUBB3 is required for axon guidance and maintenance in mammals.
• Mutations in Potassium Channel Kir2.6 Cause Susceptibility to Thyrotoxic Hypokalemic Periodic Paralysis
  - Cell 140(1):88-98 (2010)
  Thyrotoxic hypokalemic periodic paralysis (TPP) is characterized by acute attacks of weakness, hypokalemia, and thyrotoxicosis of various etiologies. These transient attacks resemble those of patients with familial hypokalemic periodic paralysis (hypoKPP) and resolve with treatment of the underlying hyperthyroidism. Because of the phenotypic similarity of these conditions, we hypothesized that TPP might also be a channelopathy. While sequencing candidate genes, we identified a previously unreported gene (not present in human sequence databases) that encodes an inwardly rectifying potassium (Kir) channel, Kir2.6. This channel, nearly identical to Kir2.2, is expressed in skeletal muscle and is transcriptionally regulated by thyroid hormone. Expression of Kir2.6 in mammalian cells revealed normal Kir currents in whole-cell and single-channel recordings. Kir2.6 mutations were present in up to 33% of the unrelated TPP patients in our collection. Some of these mutations clea! rly alter a variety of Kir2.6 properties, all altering muscle membrane excitability leading to paralysis.
• A Region of the Human HOXD Cluster that Confers Polycomb-Group Responsiveness
  - Cell 140(1):99-110 (2010)
  Polycomb group (PcG) proteins are essential for accurate axial body patterning during embryonic development. PcG-mediated repression is conserved in metazoans and is targeted in Drosophila by Polycomb response elements (PREs). However, targeting sequences in humans have not been described. While analyzing chromatin architecture in the context of human embryonic stem cell (hESC) differentiation, we discovered a 1.8kb region between HOXD11 and HOXD12 (D11.12) that is associated with PcG proteins, becomes nuclease hypersensitive, and then shows alteration in nuclease sensitivity as hESCs differentiate. The D11.12 element repressed luciferase expression from a reporter construct and full repression required a highly conserved region and YY1 binding sites. Furthermore, repression was dependent on the PcG proteins BMI1 and EED and a YY1-interacting partner, RYBP. We conclude that D11.12 is a Polycomb-dependent regulatory region with similarities to Drosophila PREs, indicatin! g conservation in the mechanisms that target PcG function in mammals and flies.
• H2A.Z-Containing Nucleosomes Mediate the Thermosensory Response in Arabidopsis
  Kumar SV Wigge PA - Cell 140(1):136-147 (2010)
  Plants are highly sensitive to temperature and can perceive a difference of as little as 1°C. How temperature is sensed and integrated in development is unknown. In a forward genetic screen in Arabidopsis, we have found that nucleosomes containing the alternative histone H2A.Z are essential to perceiving ambient temperature correctly. Genotypes deficient in incorporating H2A.Z into nucleosomes phenocopy warm grown plants, and show a striking constitutive warm temperature transcriptome. We show that nucleosomes containing H2A.Z display distinct responses to temperature in vivo, independently of transcription. Using purified nucleosomes, we are able to show that H2A.Z confers distinct DNA-unwrapping properties on nucleosomes, indicating a direct mechanism for the perception of temperature through DNA-nucleosome fluctuations. Our results show that H2A.Z-containing nucleosomes provide thermosensory information that is used to coordinate the ambient temperature transcripto! me. We observe the same effect in budding yeast, indicating that this is an evolutionarily conserved mechanism.
• Drosophila Genome-wide Obesity Screen Reveals Hedgehog as a Determinant of Brown versus White Adipose Cell Fate
  - Cell 140(1):148-160 (2010)
  Over 1 billion people are estimated to be overweight, placing them at risk for diabetes, cardiovascular disease, and cancer. We performed a systems-level genetic dissection of adiposity regulation using genome-wide RNAi screening in adult Drosophila. As a follow-up, the resulting 500 candidate obesity genes were functionally classified using muscle-, oenocyte-, fat-body-, and neuronal-specific knockdown in vivo and revealed hedgehog signaling as the top-scoring fat-body-specific pathway. To extrapolate these findings into mammals, we generated fat-specific hedgehog-activation mutant mice. Intriguingly, these mice displayed near total loss of white, but not brown, fat compartments. Mechanistically, activation of hedgehog signaling irreversibly blocked differentiation of white adipocytes through direct, coordinate modulation of early adipogenic factors. These findings identify a role for hedgehog signaling in white/brown adipocyte determination and link in vivo RNAi-base! d scanning of the Drosophila genome to regulation of adipocyte cell fate in mammals.
• SnapShot: Bacterial Appendages I
  - Cell 140(1):162-162.e1 (2010)