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Cold Spring Harbor Perspectives in Biology

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https://www.readbyqxmd.com/read/27920040/regulation-of-tgf-%C3%AE-family-signaling-by-inhibitory-smads
#1
Keiji Miyazawa, Kohei Miyazono
Inhibitory Smads (I-Smads) have conserved carboxy-terminal MH2 domains but highly divergent amino-terminal regions when compared with receptor-regulated Smads (R-Smads) and common-partner Smads (co-Smads). Smad6 preferentially inhibits Smad signaling initiated by the bone morphogenetic protein (BMP) type I receptors ALK-3 and ALK-6, whereas Smad7 inhibits both transforming growth factor β (TGF-β)- and BMP-induced Smad signaling. I-Smads also regulate some non-Smad signaling pathways. Here, we discuss the vertebrate I-Smads, their roles as inhibitors of Smad activation and regulators of receptor stability, as scaffolds for non-Smad signaling, and their possible roles in the nucleus...
December 5, 2016: Cold Spring Harbor Perspectives in Biology
https://www.readbyqxmd.com/read/27920039/systems-chronobiology-global-analysis-of-gene-regulation-in-a-24-hour-periodic-world
#2
Jérôme Mermet, Jake Yeung, Felix Naef
Mammals have evolved an internal timing system, the circadian clock, which synchronizes physiology and behavior to the daily light and dark cycles of the Earth. The master clock, located in the suprachiasmatic nucleus (SCN) of the brain, takes fluctuating light input from the retina and synchronizes other tissues to the same internal rhythm. The molecular clocks that drive these circadian rhythms are ticking in nearly all cells in the body. Efforts in systems chronobiology are now being directed at understanding, on a comprehensive scale, how the circadian clock controls different layers of gene regulation to provide robust timing cues at the cellular and tissue level...
December 5, 2016: Cold Spring Harbor Perspectives in Biology
https://www.readbyqxmd.com/read/27920038/tgf-%C3%AE-family-signaling-in-the-control-of-cell-proliferation-and-survival
#3
Yun Zhang, Peter B Alexander, Xiao-Fan Wang
The transforming growth factor β (TGF-β) family controls many fundamental aspects of cellular behavior. With advances in the molecular details of the TGF-β signaling cascade and its cross talk with other signaling pathways, we now have a more coherent understanding of the cytostatic program induced by TGF-β. However, the molecular mechanisms are still largely elusive for other cellular processes that are regulated by TGF-β and determine a cell's proliferation and survival, apoptosis, dormancy, autophagy, and senescence...
December 5, 2016: Cold Spring Harbor Perspectives in Biology
https://www.readbyqxmd.com/read/27881449/primary-cilia-and-mammalian-hedgehog-signaling
#4
Fiona Bangs, Kathryn V Anderson
It has been a decade since it was discovered that primary cilia have an essential role in Hedgehog (Hh) signaling in mammals. This discovery came from screens in the mouse that identified a set of genes that are required for both normal Hh signaling and for the formation of primary cilia. Since then, dozens of mouse mutations have been identified that disrupt cilia in a variety of ways and have complex effects on Hedgehog signaling. Here, we summarize the genetic and developmental studies used to deduce how Hedgehog signal transduction is linked to cilia and the complex effects that perturbation of cilia structure can have on Hh signaling...
November 23, 2016: Cold Spring Harbor Perspectives in Biology
https://www.readbyqxmd.com/read/27881448/prion-like-polymerization-in-immunity-and-inflammation
#5
Xin Cai, Hui Xu, Zhijian J Chen
The innate immune system relies on receptors that sense common signs of infection to trigger a robust host-defense response. Receptors such as RIG-I and NLRP3 activate downstream adaptors mitochondrial antiviral signaling (MAVS) and apoptosis-associated speck-like protein (ASC), respectively, to propagate immune and inflammatory signaling. Recent studies have indicated that both MAVS and ASC form functional prion-like polymers to propagate immune signaling. Here, we summarize the biochemical, genetic, and structural studies that characterize the prion-like behavior of MAVS and ASC in their respective signaling pathways...
November 23, 2016: Cold Spring Harbor Perspectives in Biology
https://www.readbyqxmd.com/read/27864315/protein-quality-control-in-health-and-disease
#6
Tatyana Dubnikov, Tziona Ben-Gedalya, Ehud Cohen
Maintaining functional protein homeostasis (proteostasis) is a constant challenge in the face of limited protein-folding capacity, environmental threats, and aging. Cells have developed several quality-control mechanisms that assist nascent polypeptides to fold properly, clear misfolded molecules, respond to the accumulation of protein aggregates, and deposit potentially toxic conformers in designated sites. Proteostasis collapse can lead to the development of diseases known as proteinopathies. Here we delineate the current knowledge on the different layers of protein quality-control mechanisms at the organelle and cellular levels with an emphasis on the prion protein (PrP)...
November 18, 2016: Cold Spring Harbor Perspectives in Biology
https://www.readbyqxmd.com/read/27864314/cilia-and-mucociliary-clearance
#7
Ximena M Bustamante-Marin, Lawrence E Ostrowski
Mucociliary clearance (MCC) is the primary innate defense mechanism of the lung. The functional components are the protective mucous layer, the airway surface liquid layer, and the cilia on the surface of ciliated cells. The cilia are specialized organelles that beat in metachronal waves to propel pathogens and inhaled particles trapped in the mucous layer out of the airways. In health this clearance mechanism is effective, but in patients with primary cilia dyskinesia (PCD) the cilia are abnormal, resulting in deficient MCC and chronic lung disease...
November 18, 2016: Cold Spring Harbor Perspectives in Biology
https://www.readbyqxmd.com/read/27864313/non-smad-signaling-pathways-of-the-tgf-%C3%AE-family
#8
Ying E Zhang
Transforming growth factor β (TGF-β) and structurally related factors use several intracellular signaling pathways in addition to Smad signaling to regulate a wide array of cellular functions. These non-Smad signaling pathways are activated directly by ligand-occupied receptors to reinforce, attenuate, or otherwise modulate downstream cellular responses. This review summarizes the current knowledge of the mechanisms by which non-Smad signaling pathways are directly activated in response to ligand binding, how activation of these pathways impinges on Smads and non-Smad targets, and how final cellular responses are affected in response to these noncanonical signaling modes...
November 18, 2016: Cold Spring Harbor Perspectives in Biology
https://www.readbyqxmd.com/read/27836835/cross-%C3%AE-polymerization-of-low-complexity-sequence-domains
#9
Masato Kato, Steven L McKnight
Most transcription factors and RNA regulatory proteins encoded by eukaryotic genomes ranging from yeast to humans contain polypeptide domains variously described as intrinsically disordered, prion-like, or of low complexity (LC). These LC domains exist in an unfolded state when DNA and RNA regulatory proteins are studied in biochemical isolation from cells. Upon incubation in the purified state, many of these LC domains polymerize into homogeneous, labile amyloid-like fibers. Here, we consider several lines of evidence that may favor biologic utility for LC domain polymers...
November 11, 2016: Cold Spring Harbor Perspectives in Biology
https://www.readbyqxmd.com/read/27836834/signaling-cross-talk-between-tgf-%C3%AE-smad-and-other-signaling-pathways
#10
Kunxin Luo
Cytokines of the transforming growth factor β (TGF-β) family, including TGF-βs, bone morphogenic proteins (BMPs), activins, and Nodal, play crucial roles in embryonic development and adult tissue homeostasis by regulating cell proliferation, survival, and differentiation, as well as stem-cell self-renewal and lineage-specific differentiation. Smad proteins are critical downstream mediators of these signaling activities. In addition to regulating the transcription of direct target genes of TGF-β, BMP, activin, or Nodal, Smad proteins also participate in extensive cross talk with other signaling pathways, often in a cell-type- or developmental stage-specific manner...
November 11, 2016: Cold Spring Harbor Perspectives in Biology
https://www.readbyqxmd.com/read/27815300/prions-chaperones-and-proteostasis-in-yeast
#11
Tatiana A Chernova, Keith D Wilkinson, Yury O Chernoff
Prions are alternatively folded, self-perpetuating protein isoforms involved in a variety of biological and pathological processes. Yeast prions are protein-based heritable elements that serve as an excellent experimental system for studying prion biology. The propagation of yeast prions is controlled by the same Hsp104/70/40 chaperone machinery that is involved in the protection of yeast cells against proteotoxic stress. Ribosome-associated chaperones, proteolytic pathways, cellular quality-control compartments, and cytoskeletal networks influence prion formation, maintenance, and toxicity...
November 4, 2016: Cold Spring Harbor Perspectives in Biology
https://www.readbyqxmd.com/read/27793968/ciliopathies
#12
Daniela A Braun, Friedhelm Hildebrandt
Nephronophthisis-related ciliopathies (NPHP-RC) are a group of inherited diseases that affect genes encoding proteins that localize to primary cilia or centrosomes. With few exceptions, ciliopathies are inherited in an autosomal recessive manner, and affected individuals manifest early during childhood or adolescence. NPHP-RC are genetically very heterogeneous, and, currently, mutations in more than 90 genes have been described as single-gene causes. The phenotypes of NPHP-RC are very diverse, and include cystic-fibrotic kidney disease, brain developmental defects, retinal degeneration, skeletal deformities, facial dimorphism, and, in some cases, laterality defects, and congenital heart disease...
October 28, 2016: Cold Spring Harbor Perspectives in Biology
https://www.readbyqxmd.com/read/27793967/the-three-dimensional-structures-of-amyloids
#13
Roland Riek
Amyloids are highly ordered protein aggregates that are associated with both disease (including PrP prion, Alzheimer's, and Parkinson's) and biological function. The amyloid structure is composed of the cross-β-sheet entity, which is an almost indefinitely repeating two-layered intermolecular β-sheet motif. The three-dimensional (3D) structure is unique among protein folds because it folds only upon intermolecular contacts (for a folding to occur, only short sequences of amino acid residues are required), and the structure repeats itself at the atomic level (i...
October 28, 2016: Cold Spring Harbor Perspectives in Biology
https://www.readbyqxmd.com/read/27770015/open-sesame-how-transition-fibers-and-the-transition-zone-control-ciliary-composition
#14
Francesc R Garcia-Gonzalo, Jeremy F Reiter
Cilia are plasma membrane protrusions that act as cellular propellers or antennae. To perform these functions, cilia must maintain a composition distinct from those of the contiguous cytosol and plasma membrane. The specialized composition of the cilium depends on the ciliary gate, the region at the ciliary base separating the cilium from the rest of the cell. The ciliary gate's main structural features are electron dense struts connecting microtubules to the adjacent membrane. These structures include the transition fibers, which connect the distal basal body to the base of the ciliary membrane, and the Y-links, which connect the proximal axoneme and ciliary membrane within the transition zone...
October 21, 2016: Cold Spring Harbor Perspectives in Biology
https://www.readbyqxmd.com/read/27770014/the-central-apparatus-of-cilia-and-eukaryotic-flagella
#15
Thomas D Loreng, Elizabeth F Smith
The motile cilium is a complex organelle that is typically comprised of a 9+2 microtubule skeleton; nine doublet microtubules surrounding a pair of central singlet microtubules. Like the doublet microtubules, the central microtubules form a scaffold for the assembly of protein complexes forming an intricate network of interconnected projections. The central microtubules and associated structures are collectively referred to as the central apparatus (CA). Studies using a variety of experimental approaches and model organisms have led to the discovery of a number of highly conserved protein complexes, unprecedented high-resolution views of projection structure, and new insights into regulation of dynein-driven microtubule sliding...
October 21, 2016: Cold Spring Harbor Perspectives in Biology
https://www.readbyqxmd.com/read/27663774/alternative-watson-crick-synthetic-genetic-systems
#16
Steven A Benner, Nilesh B Karalkar, Shuichi Hoshika, Roberto Laos, Ryan W Shaw, Mariko Matsuura, Diego Fajardo, Patricia Moussatche
In its "grand challenge" format in chemistry, "synthesis" as an activity sets out a goal that is substantially beyond current theoretical and technological capabilities. In pursuit of this goal, scientists are forced across uncharted territory, where they must answer unscripted questions and solve unscripted problems, creating new theories and new technologies in ways that would not be created by hypothesis-directed research. Thus, synthesis drives discovery and paradigm changes in ways that analysis cannot...
September 23, 2016: Cold Spring Harbor Perspectives in Biology
https://www.readbyqxmd.com/read/27663773/evolution-of-cilia
#17
David R Mitchell
Anton van Leeuwenhoek's startling microscopic observations in the 1600s first stimulated fascination with the way that cells use cilia to generate currents and to swim in a fluid environment. Research in recent decades has yielded deep knowledge about the mechanical and biochemical nature of these organelles but only opened a greater fascination about how such beautifully intricate and multifunctional structures arose during evolution. Answers to this evolutionary puzzle are not only sought to satisfy basic curiosity, but also, as stated so eloquently by Dobzhansky (Am Zool 4: 443 [1964]), because "nothing in biology makes sense except in the light of evolution...
September 23, 2016: Cold Spring Harbor Perspectives in Biology
https://www.readbyqxmd.com/read/27638178/primary-cilia-and-coordination-of-receptor-tyrosine-kinase-rtk-and-transforming-growth-factor-%C3%AE-tgf-%C3%AE-signaling
#18
Søren T Christensen, Stine K Morthorst, Johanne B Mogensen, Lotte B Pedersen
Since the beginning of the millennium, research in primary cilia has revolutionized our way of understanding how cells integrate and organize diverse signaling pathways during vertebrate development and in tissue homeostasis. Primary cilia are unique sensory organelles that detect changes in their extracellular environment and integrate and transmit signaling information to the cell to regulate various cellular, developmental, and physiological processes. Many different signaling pathways have now been shown to rely on primary cilia to function properly, and mutations that lead to ciliary dysfunction are at the root of a pleiotropic group of diseases and syndromic disorders called ciliopathies...
September 16, 2016: Cold Spring Harbor Perspectives in Biology
https://www.readbyqxmd.com/read/27908937/the-centrosome-a-multitalented-renaissance-organelle
#19
REVIEW
Anastassiia Vertii, Heidi Hehnly, Stephen Doxsey
The centrosome acts as a microtubule-organizing center (MTOC) from the G1 to G2 phases of the cell cycle; it can mature into a spindle pole during mitosis and/or transition into a cilium by elongating microtubules (MTs) from the basal body on cell differentiation or cell cycle arrest. New studies hint that the centrosome functions in more than MT organization. For instance, it has recently been shown that a specific substructure of the centrosome-the mother centriole appendages-are required for the recycling of endosomes back to the plasma membrane...
December 1, 2016: Cold Spring Harbor Perspectives in Biology
https://www.readbyqxmd.com/read/27908936/genome-editing-technologies-principles-and-applications
#20
REVIEW
Thomas Gaj, Shannon J Sirk, Sai-Lan Shui, Jia Liu
Targeted nucleases have provided researchers with the ability to manipulate virtually any genomic sequence, enabling the facile creation of isogenic cell lines and animal models for the study of human disease, and promoting exciting new possibilities for human gene therapy. Here we review three foundational technologies-clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9), transcription activator-like effector nucleases (TALENs), and zinc-finger nucleases (ZFNs)...
December 1, 2016: Cold Spring Harbor Perspectives in Biology
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