Feb 03, 2012

Leading Edge

In This Issue

In This Issue
PAGE 473

Select

Cancer Metabolism
Cancer cells are now revealing their metabolic secrets with a combination of biochemical approaches and omic-level analyses. This issue's Select highlights articles that begin to clarify how cells are metabolically rewired during oncogenesis, reporting new functions for metabolic enzymes, delineating unexpected biosynthetic processes, and identifying potential therapeutic targets.

Previews

Finding a Target for Resveratrol
• Ruth I. Tennen,
• Eriko Michishita-Kioi,
• Katrin F. Chua
Despite resveratrol's well-documented health benefits, its mechanism of action remains controversial. In particular, the direct molecular target of resveratrol has been elusive. Park et al. now show that resveratrol directly inhibits cAMP-dependent phosphodiesterases, triggering a cascade of events that converge on the important energy-sensing metabolic regulators AMPK, SIRT1, and PGC-1α.

Innate Immunity to TB: A Druggable Balancing Act
• Ajit Lalvani,
• Marcel A. Behr,
• Saranya Sridhar
Tobin and colleagues show that both inhibition and excessive production of the inflammatory mediator TNFα impact the pathogenesis of tuberculosis (TB) and the response to therapy. Identifying a critical role for the genetically determined balance between pro- and anti-inflammatory eicosanoids in regulating TNFα levels provides a roadmap to tailored TB treatment based on host genotype.

Immune Cells Exploit a Neural Circuit to Enter the CNS
• Kevin J. Tracey
Multiple sclerosis (MS) is associated with the appearance of autoreactive T cells in the central nervous system. Using a mouse model of MS, Arima et al. now show that this attack begins at a specific spinal cord location. T cell entry into the CNS is regulated by a reflex neural circuit originating from leg muscle contractions.

A New Histone at the Centromere?
• Daniel R. Foltz,
• P. Todd Stukenberg
The centromere is a classic system to study epigenetic specification, and most research has focused on a specialized histone variant, CENP-A, that is required for kinetochore assembly. Now Nishino et al. reveal a new level of complexity for centromeric chromatin, by showing that the kinetochore complex CENP-T-W-S-X shares structural and functional properties with canonical histones.

FGF21 and the Second Coming of PPARγ
• Li Qiang,
• Domenico Accili
Peptide hormone fibroblast growth factor-21 (FGF21) has insulin-mimetic properties. Dutchak et al. now suggest that FGF21 also acts in an autocrine fashion in adipocytes and is required to mediate effects of the PPARγ agonist class of antidiabetic drugs. Does this new property improve FGF21's fledgling clinical prospects or endorse a clinical resuscitation of PPARγ agonists?

Reviews

Hypoxia-Inducible Factors in Physiology and Medicine
• Gregg L. Semenza
Oxygen homeostasis represents an organizing principle for understanding metazoan evolution, development, physiology, and pathobiology. The hypoxia-inducible factors (HIFs) are transcriptional activators that function as master regulators of oxygen homeostasis in all metazoan species. Rapid progress is being made in elucidating homeostatic roles of HIFs in many physiological systems, determining pathological consequences of HIF dysregulation in chronic diseases, and investigating potential targeting of HIFs for therapeutic purposes.

The Genetic Basis for Cancer Treatment Decisions
• Janet E. Dancey,
• Philippe L. Bedard,
• Nicole Onetto,
• Thomas J. Hudson
Personalized cancer medicine is based on increased knowledge of the cancer mutation repertoire and availability of agents that target altered genes or pathways. Given advances in cancer genetics, technology, and therapeutics development, the timing is right to develop a clinical trial and research framework to move future clinical decisions from heuristic to evidence-based decisions. Although the challenges of integrating genomic testing into cancer treatment decision making are wide-ranging and complex, there is a scientific and ethical imperative to realize the benefits of personalized cancer medicine, given the overwhelming burden of cancer and the unprecedented opportunities for advancements in outcomes for patients.

Articles

Resveratrol Ameliorates Aging-Related Metabolic Phenotypes by Inhibiting cAMP Phosphodiesterases
• Sung-Jun Park,
• Faiyaz Ahmad,
• Andrew Philp,
• Keith Baar,
• Tishan Williams,
• Haibin Luo,
• Hengming Ke,
• Holger Rehmann,
• Ronald Taussig,
• Alexandra L. Brown,
• Myung K. Kim,
• Michael A. Beaven,
• Alex B. Burgin,
• Vincent Manganiello,
• Jay H. Chung
The antiaging, antidiabetic polyphenol in red wine indirectly activates Sirt1 via competitive inhibition of cAMP-phosphodiesterases to ultimately increase NAD⁺ levels. This suggests that PDEs are potential therapeutic targets for aging-related metabolic disorders.

Host Genotype-Specific Therapies Can Optimize the Inflammatory Response to Mycobacterial Infections
• David M. Tobin,
• Francisco J. Roca,
• Sungwhan F. Oh,
• Ross McFarland,
• Thad W. Vickery,
• John P. Ray,
• Dennis C. Ko,
• Yuxia Zou,
• Nguyen D. Bang,
• Tran T.H. Chau,
• Jay C. Vary,
• Thomas R. Hawn,
• Sarah J. Dunstan,
• Jeremy J. Farrar,
• Guy E. Thwaites,
• Mary-Claire King,
• Charles N. Serhan,
• Lalita Ramakrishnan
A polymorphism in a locus that controls the balance between pro- and anti-inflammatory mediators is predictive of response to anti-inflammatory therapy in tuberculous meningitis.

Regional Neural Activation Defines a Gateway for Autoreactive T Cells to Cross the Blood-Brain Barrier
• Yasunobu Arima,
• Masaya Harada,
• Daisuke Kamimura,
• Jin-Haeng Park,
• Fuminori Kawano,
• Fiona E. Yull,
• Tadafumi Kawamoto,
• Yoichiro Iwakura,
• Ulrich A.K. Betz,
• Gabriel Márquez,
• Timothy S. Blackwell,
• Yoshinobu Ohira,
• Toshio Hirano,
• Masaaki Murakami
In a mouse model of multiple sclerosis, activation of peripheral sensory neurons by leg muscles creates a chemokine rich zone in the spinal column, establishing a localized gateway through which pathogenic T cells can attack the central nervous system.

Three-Dimensional Folding and Functional Organization Principles of the Drosophila Genome
• Tom Sexton,
• Eitan Yaffe,
• Ephraim Kenigsberg,
• Frédéric Bantignies,
• Benjamin Leblanc,
• Michael Hoichman,
• Hugues Parrinello,
• Amos Tanay,
• Giacomo Cavalli
A genome-wide chromosomal contact map of the Drosophila genome at kilobase resolution shows that the genome is partitioned into physical domains and that contact between domains is dependent upon their epigenetic profile.

A Transcription Factor Collective Defines Cardiac Cell Fate and Reflects Lineage History
• Guillaume Junion,
• Mikhail Spivakov,
• Charles Girardot,
• Martina Braun,
• E. Hilary Gustafson,
• Ewan Birney,
• Eileen E.M. Furlong
The five transcription factors that specify cardiac fate in Drosophila bind cooperatively to cardiac enhancers. Surprisingly, the arrangement of binding sites along the enhancer is flexible, but all five must be present for maximal enhancer activity.

CENP-T-W-S-X Forms a Unique Centromeric Chromatin Structure with a Histone-like Fold
• Tatsuya Nishino,
• Kozo Takeuchi,
• Karen E. Gascoigne,
• Aussie Suzuki,
• Tetsuya Hori,
• Takuji Oyama,
• Kosuke Morikawa,
• Iain M. Cheeseman,
• Tatsuo Fukagawa
The CENP-T-W-S-X heterotetramer is essential for kinetochore assembly and wraps DNA like nucleosomes, suggesting an extension of the “histone code” beyond canonical nucleosome proteins.

Cortical Dynein Controls Microtubule Dynamics to Generate Pulling Forces that Position Microtubule Asters
• Liedewij Laan,
• Nenad Pavin,
• Julien Husson,
• Guillaume Romet-Lemonne,
• Martijn van Duijn,
• Magdalena Preciado López,
• Ronald D. Vale,
• Frank Jülicher,
• Samara L. Reck-Peterson,
• Marileen Dogterom
Surface-attached dynein captures microtubules and modulates their shrinkage to produce pulling forces that ensure microtubule organizing centers are positioned for cell division.

Critical Role of Amyloid-like Oligomers of Drosophila Orb2 in the Persistence of Memory
• Amitabha Majumdar,
• Wanda Colón Cesario,
• Erica White-Grindley,
• Huoqing Jiang,
• Fengzhen Ren,
• Mohammed “Repon” Khan,
• Liying Li,
• Edward Man-Lik Choi,
• Kasthuri Kannan,
• Fengli Guo,
• Jay Unruh,
• Brian Slaughter,
• Kausik Si
The amyloid-like oligomerization of the neuronal regulator of translation Orb2/CPEB is required for the formation of stable, long-term memories. The self-sustaining prion properties of this protein may underlie memory persistence.

A Structure-Based Mechanism for Arf1-Dependent Recruitment of Coatomer to Membranes
• Xinchao Yu,
• Marianna Breitman,
• Jonathan Goldberg
Coatomer recruitment to the Golgi membrane depends on interaction with two membrane-bound Arf1-GTP molecules, suggesting that a bivalent interaction initiates vesicle budding.

PKCε Promotes Oncogenic Functions of ATF2 in the Nucleus while Blocking Its Apoptotic Function at Mitochondria
• Eric Lau,
• Harriet Kluger,
• Tal Varsano,
• KiYoung Lee,
• Immo Scheffler,
• David L. Rimm,
• Trey Ideker,
• Ze'ev A. Ronai
In contrast to its role as a proto-oncogenic nuclear transcription factor, ATF2 promotes apoptosis by impairing mitochondrial membrane permeability. In melanoma, PKCε blocks ATF-2 nuclear export, preventing its association with mitochondria and shifting the balance from tumor suppression to progression.

Fibroblast Growth Factor-21 Regulates PPARγ Activity and the Antidiabetic Actions of Thiazolidinediones
• Paul A. Dutchak,
• Takeshi Katafuchi,
• Angie L. Bookout,
• Jang Hyun Choi,
• Ruth T. Yu,
• David J. Mangelsdorf,
• Steven A. Kliewer
FGF21 functions in a feed-forward loop to regulate PPARγ, the major target of antidiabetic drugs. FGF21 is required for normal fat cell function and the effects of antidiabetic drugs.

Ret Is a Multifunctional Coreceptor that Integrates Diffusible- and Contact-Axon Guidance Signals
• Dario Bonanomi,
• Onanong Chivatakarn,
• Ge Bai,
• Houari Abdesselem,
• Karen Lettieri,
• Till Marquardt,
• Brian A. Pierchala,
• Samuel L. Pfaff
The axon guidance molecules GNDF and ephrin-A are both detected by the RTK Ret, which turns out to be the long-sought coreceptor that acts with EphA to transmit reverse signals from ephrin-A back to the nerve growth cone. Ret's dual role in detecting guidance cues sets up a coincidence detection mechanism that fine-tunes axon growth and navigation.

Visualizing Neuromodulation In Vivo: TANGO-Mapping of Dopamine Signaling Reveals Appetite Control of Sugar Sensing
• Hidehiko K. Inagaki,
• Shlomo Ben-Tabou de-Leon,
• Allan M. Wong,
• Smitha Jagadish,
• Hiroshi Ishimoto,
• Gilad Barnea,
• Toshihiro Kitamoto,
• Richard Axel,
• David J. Anderson
Visualizing levels of dopamine signaling across the whole brain reveals how starved flies become more keenly receptive to sugar. Hunger promotes dopamine release onto sugar-sensing neurons, enhancing calcium influx upon encountering food.

Modular Genetic Control of Sexually Dimorphic Behaviors
• Xiaohong Xu,
• Jennifer K. Coats,
• Cindy F. Yang,
• Amy Wang,
• Osama M. Ahmed,
• Maricruz Alvarado,
• Tetsuro Izumi,
• Nirao M. Shah
An unbiased screen identifies numerous genes with sexually dimorphic expression patterns in the hypothalamus of mice. Disrupting individual genes produces extremely specific deficits in sexually dimorphic behaviors, such as the time to retrieve pups or to intromit after chemoinvestigation.

Theory

Optimality in the Development of Intestinal Crypts
• Shalev Itzkovitz,
• Irene C. Blat,
• Tyler Jacks,
• Hans Clevers,
• Alexander van Oudenaarden
To minimize the time it takes to build a mature intestinal crypt, stem cells employ a “bang-bang” control strategy. They undergo rapid symmetric divisions to first establish the adult pool of stem cells before abruptly switching to asymmetric divisions, which give rise to nonstem cells.

Erratum

Global Identification of Modular Cullin-RING Ligase Substrates
• Michael J. Emanuele,
• Andrew E.H. Elia,
• Qikai Xu,
• Claudio R. Thoma,
• Lior Izhar,
• Yumei Leng,
• Ailan Guo,
• Yi-Ning Chen,
• John Rush,
• Paul Wei-Che Hsu,
• Hsueh-Chi Sherry Yen,
• Stephen J. Elledge
(Cell 147, 459–475; October 14, 2011)

Snapshot

SnapShot: Insulin Signaling Pathways
• Takashi Kadowaki,
• Kohjiro Ueki,
• Toshimasa Yamauchi,
• Naoto Kubota