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Publisher: Elsevier   (Total: 3043 journals)

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Showing 1 - 200 of 3043 Journals sorted alphabetically
AASRI Procedia     Open Access   (Followers: 15)
Academic Pediatrics     Hybrid Journal   (Followers: 22, SJR: 1.402, h-index: 51)
Academic Radiology     Hybrid Journal   (Followers: 21, SJR: 1.008, h-index: 75)
Accident Analysis & Prevention     Partially Free   (Followers: 84, SJR: 1.109, h-index: 94)
Accounting Forum     Hybrid Journal   (Followers: 25, SJR: 0.612, h-index: 27)
Accounting, Organizations and Society     Hybrid Journal   (Followers: 30, SJR: 2.515, h-index: 90)
Achievements in the Life Sciences     Open Access   (Followers: 4)
Acta Anaesthesiologica Taiwanica     Open Access   (Followers: 5, SJR: 0.338, h-index: 19)
Acta Astronautica     Hybrid Journal   (Followers: 356, SJR: 0.726, h-index: 43)
Acta Automatica Sinica     Full-text available via subscription   (Followers: 3)
Acta Biomaterialia     Hybrid Journal   (Followers: 25, SJR: 2.02, h-index: 104)
Acta Colombiana de Cuidado Intensivo     Full-text available via subscription   (Followers: 1)
Acta de Investigación Psicológica     Open Access   (Followers: 2)
Acta Ecologica Sinica     Open Access   (Followers: 8, SJR: 0.172, h-index: 29)
Acta Haematologica Polonica     Free   (SJR: 0.123, h-index: 8)
Acta Histochemica     Hybrid Journal   (Followers: 3, SJR: 0.604, h-index: 38)
Acta Materialia     Hybrid Journal   (Followers: 234, SJR: 3.683, h-index: 202)
Acta Mathematica Scientia     Full-text available via subscription   (Followers: 5, SJR: 0.615, h-index: 21)
Acta Mechanica Solida Sinica     Full-text available via subscription   (Followers: 9, SJR: 0.442, h-index: 21)
Acta Oecologica     Hybrid Journal   (Followers: 10, SJR: 0.915, h-index: 53)
Acta Otorrinolaringologica (English Edition)     Full-text available via subscription   (Followers: 1)
Acta Otorrinolaringológica Española     Full-text available via subscription   (Followers: 3, SJR: 0.311, h-index: 16)
Acta Pharmaceutica Sinica B     Open Access   (Followers: 2)
Acta Poética     Open Access   (Followers: 4)
Acta Psychologica     Hybrid Journal   (Followers: 23, SJR: 1.365, h-index: 73)
Acta Sociológica     Open Access  
Acta Tropica     Hybrid Journal   (Followers: 6, SJR: 1.059, h-index: 77)
Acta Urológica Portuguesa     Open Access  
Actas Dermo-Sifiliograficas     Full-text available via subscription   (Followers: 4)
Actas Dermo-Sifiliográficas (English Edition)     Full-text available via subscription   (Followers: 3)
Actas Urológicas Españolas     Full-text available via subscription   (Followers: 4, SJR: 0.383, h-index: 19)
Actas Urológicas Españolas (English Edition)     Full-text available via subscription   (Followers: 2)
Actualites Pharmaceutiques     Full-text available via subscription   (Followers: 5, SJR: 0.141, h-index: 3)
Actualites Pharmaceutiques Hospitalieres     Full-text available via subscription   (Followers: 4, SJR: 0.112, h-index: 2)
Acupuncture and Related Therapies     Hybrid Journal   (Followers: 4)
Acute Pain     Full-text available via subscription   (Followers: 13)
Ad Hoc Networks     Hybrid Journal   (Followers: 11, SJR: 0.967, h-index: 57)
Addictive Behaviors     Hybrid Journal   (Followers: 15, SJR: 1.514, h-index: 92)
Addictive Behaviors Reports     Open Access   (Followers: 5)
Additive Manufacturing     Hybrid Journal   (Followers: 7, SJR: 1.039, h-index: 5)
Additives for Polymers     Full-text available via subscription   (Followers: 21)
Advanced Drug Delivery Reviews     Hybrid Journal   (Followers: 135, SJR: 5.2, h-index: 222)
Advanced Engineering Informatics     Hybrid Journal   (Followers: 11, SJR: 1.265, h-index: 53)
Advanced Powder Technology     Hybrid Journal   (Followers: 17, SJR: 0.739, h-index: 33)
Advances in Accounting     Hybrid Journal   (Followers: 9, SJR: 0.299, h-index: 15)
Advances in Agronomy     Full-text available via subscription   (Followers: 15, SJR: 2.071, h-index: 82)
Advances in Anesthesia     Full-text available via subscription   (Followers: 25, SJR: 0.169, h-index: 4)
Advances in Antiviral Drug Design     Full-text available via subscription   (Followers: 3)
Advances in Applied Mathematics     Full-text available via subscription   (Followers: 6, SJR: 1.054, h-index: 35)
Advances in Applied Mechanics     Full-text available via subscription   (Followers: 11, SJR: 0.801, h-index: 26)
Advances in Applied Microbiology     Full-text available via subscription   (Followers: 22, SJR: 1.286, h-index: 49)
Advances In Atomic, Molecular, and Optical Physics     Full-text available via subscription   (Followers: 16, SJR: 3.31, h-index: 42)
Advances in Biological Regulation     Hybrid Journal   (Followers: 4, SJR: 2.277, h-index: 43)
Advances in Botanical Research     Full-text available via subscription   (Followers: 3, SJR: 0.619, h-index: 48)
Advances in Cancer Research     Full-text available via subscription   (Followers: 25, SJR: 2.215, h-index: 78)
Advances in Carbohydrate Chemistry and Biochemistry     Full-text available via subscription   (Followers: 9, SJR: 0.9, h-index: 30)
Advances in Catalysis     Full-text available via subscription   (Followers: 5, SJR: 2.139, h-index: 42)
Advances in Cellular and Molecular Biology of Membranes and Organelles     Full-text available via subscription   (Followers: 12)
Advances in Chemical Engineering     Full-text available via subscription   (Followers: 26, SJR: 0.183, h-index: 23)
Advances in Child Development and Behavior     Full-text available via subscription   (Followers: 10, SJR: 0.665, h-index: 29)
Advances in Chronic Kidney Disease     Full-text available via subscription   (Followers: 9, SJR: 1.268, h-index: 45)
Advances in Clinical Chemistry     Full-text available via subscription   (Followers: 29, SJR: 0.938, h-index: 33)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 18, SJR: 2.314, h-index: 130)
Advances in Computers     Full-text available via subscription   (Followers: 16, SJR: 0.223, h-index: 22)
Advances in Dermatology     Full-text available via subscription   (Followers: 12)
Advances in Developmental Biology     Full-text available via subscription   (Followers: 11)
Advances in Digestive Medicine     Open Access   (Followers: 6)
Advances in DNA Sequence-Specific Agents     Full-text available via subscription   (Followers: 5)
Advances in Drug Research     Full-text available via subscription   (Followers: 22)
Advances in Ecological Research     Full-text available via subscription   (Followers: 41, SJR: 3.25, h-index: 43)
Advances in Engineering Software     Hybrid Journal   (Followers: 25, SJR: 0.486, h-index: 10)
Advances in Experimental Biology     Full-text available via subscription   (Followers: 7)
Advances in Experimental Social Psychology     Full-text available via subscription   (Followers: 41, SJR: 5.465, h-index: 64)
Advances in Exploration Geophysics     Full-text available via subscription   (Followers: 3)
Advances in Food and Nutrition Research     Full-text available via subscription   (Followers: 50, SJR: 0.674, h-index: 38)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 16)
Advances in Genetics     Full-text available via subscription   (Followers: 15, SJR: 2.558, h-index: 54)
Advances in Genome Biology     Full-text available via subscription   (Followers: 11)
Advances in Geophysics     Full-text available via subscription   (Followers: 6, SJR: 2.325, h-index: 20)
Advances in Heat Transfer     Full-text available via subscription   (Followers: 22, SJR: 0.906, h-index: 24)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 9, SJR: 0.497, h-index: 31)
Advances in Imaging and Electron Physics     Full-text available via subscription   (Followers: 2, SJR: 0.396, h-index: 27)
Advances in Immunology     Full-text available via subscription   (Followers: 35, SJR: 4.152, h-index: 85)
Advances in Inorganic Chemistry     Full-text available via subscription   (Followers: 9, SJR: 1.132, h-index: 42)
Advances in Insect Physiology     Full-text available via subscription   (Followers: 3, SJR: 1.274, h-index: 27)
Advances in Integrative Medicine     Hybrid Journal   (Followers: 6)
Advances in Life Course Research     Hybrid Journal   (Followers: 8, SJR: 0.764, h-index: 15)
Advances in Lipobiology     Full-text available via subscription   (Followers: 2)
Advances in Magnetic and Optical Resonance     Full-text available via subscription   (Followers: 9)
Advances in Marine Biology     Full-text available via subscription   (Followers: 16, SJR: 1.645, h-index: 45)
Advances in Mathematics     Full-text available via subscription   (Followers: 10, SJR: 3.261, h-index: 65)
Advances in Medical Sciences     Hybrid Journal   (Followers: 6, SJR: 0.489, h-index: 25)
Advances in Medicinal Chemistry     Full-text available via subscription   (Followers: 5)
Advances in Microbial Physiology     Full-text available via subscription   (Followers: 4, SJR: 1.44, h-index: 51)
Advances in Molecular and Cell Biology     Full-text available via subscription   (Followers: 22)
Advances in Molecular and Cellular Endocrinology     Full-text available via subscription   (Followers: 10)
Advances in Molecular Toxicology     Full-text available via subscription   (Followers: 7, SJR: 0.324, h-index: 8)
Advances in Nanoporous Materials     Full-text available via subscription   (Followers: 4)
Advances in Oncobiology     Full-text available via subscription   (Followers: 3)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 15, SJR: 2.885, h-index: 45)
Advances in Parallel Computing     Full-text available via subscription   (Followers: 7, SJR: 0.148, h-index: 11)
Advances in Parasitology     Full-text available via subscription   (Followers: 7, SJR: 2.37, h-index: 73)
Advances in Pediatrics     Full-text available via subscription   (Followers: 24, SJR: 0.4, h-index: 28)
Advances in Pharmaceutical Sciences     Full-text available via subscription   (Followers: 13)
Advances in Pharmacology     Full-text available via subscription   (Followers: 15, SJR: 1.718, h-index: 58)
Advances in Physical Organic Chemistry     Full-text available via subscription   (Followers: 8, SJR: 0.384, h-index: 26)
Advances in Phytomedicine     Full-text available via subscription  
Advances in Planar Lipid Bilayers and Liposomes     Full-text available via subscription   (Followers: 3, SJR: 0.248, h-index: 11)
Advances in Plant Biochemistry and Molecular Biology     Full-text available via subscription   (Followers: 8)
Advances in Plant Pathology     Full-text available via subscription   (Followers: 5)
Advances in Porous Media     Full-text available via subscription   (Followers: 4)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 17)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 20, SJR: 1.5, h-index: 62)
Advances in Psychology     Full-text available via subscription   (Followers: 61)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 5, SJR: 0.478, h-index: 32)
Advances in Radiation Oncology     Open Access  
Advances in Small Animal Medicine and Surgery     Hybrid Journal   (Followers: 3, SJR: 0.1, h-index: 2)
Advances in Space Research     Full-text available via subscription   (Followers: 355, SJR: 0.606, h-index: 65)
Advances in Structural Biology     Full-text available via subscription   (Followers: 8)
Advances in Surgery     Full-text available via subscription   (Followers: 7, SJR: 0.823, h-index: 27)
Advances in the Study of Behavior     Full-text available via subscription   (Followers: 30, SJR: 1.321, h-index: 56)
Advances in Veterinary Medicine     Full-text available via subscription   (Followers: 17)
Advances in Veterinary Science and Comparative Medicine     Full-text available via subscription   (Followers: 13)
Advances in Virus Research     Full-text available via subscription   (Followers: 5, SJR: 1.878, h-index: 68)
Advances in Water Resources     Hybrid Journal   (Followers: 44, SJR: 2.408, h-index: 94)
Aeolian Research     Hybrid Journal   (Followers: 5, SJR: 0.973, h-index: 22)
Aerospace Science and Technology     Hybrid Journal   (Followers: 326, SJR: 0.816, h-index: 49)
AEU - Intl. J. of Electronics and Communications     Hybrid Journal   (Followers: 8, SJR: 0.318, h-index: 36)
African J. of Emergency Medicine     Open Access   (Followers: 5, SJR: 0.344, h-index: 6)
Ageing Research Reviews     Hybrid Journal   (Followers: 8, SJR: 3.289, h-index: 78)
Aggression and Violent Behavior     Hybrid Journal   (Followers: 406, SJR: 1.385, h-index: 72)
Agri Gene     Hybrid Journal  
Agricultural and Forest Meteorology     Hybrid Journal   (Followers: 16, SJR: 2.18, h-index: 116)
Agricultural Systems     Hybrid Journal   (Followers: 30, SJR: 1.275, h-index: 74)
Agricultural Water Management     Hybrid Journal   (Followers: 39, SJR: 1.546, h-index: 79)
Agriculture and Agricultural Science Procedia     Open Access  
Agriculture and Natural Resources     Open Access   (Followers: 1)
Agriculture, Ecosystems & Environment     Hybrid Journal   (Followers: 54, SJR: 1.879, h-index: 120)
Ain Shams Engineering J.     Open Access   (Followers: 5, SJR: 0.434, h-index: 14)
Air Medical J.     Hybrid Journal   (Followers: 5, SJR: 0.234, h-index: 18)
AKCE Intl. J. of Graphs and Combinatorics     Open Access   (SJR: 0.285, h-index: 3)
Alcohol     Hybrid Journal   (Followers: 11, SJR: 0.922, h-index: 66)
Alcoholism and Drug Addiction     Open Access   (Followers: 8)
Alergologia Polska : Polish J. of Allergology     Full-text available via subscription   (Followers: 1)
Alexandria Engineering J.     Open Access   (Followers: 1, SJR: 0.436, h-index: 12)
Alexandria J. of Medicine     Open Access  
Algal Research     Partially Free   (Followers: 8, SJR: 2.05, h-index: 20)
Alkaloids: Chemical and Biological Perspectives     Full-text available via subscription   (Followers: 3)
Allergologia et Immunopathologia     Full-text available via subscription   (Followers: 1, SJR: 0.46, h-index: 29)
Allergology Intl.     Open Access   (Followers: 4, SJR: 0.776, h-index: 35)
Alpha Omegan     Full-text available via subscription   (SJR: 0.121, h-index: 9)
ALTER - European J. of Disability Research / Revue Européenne de Recherche sur le Handicap     Full-text available via subscription   (Followers: 8, SJR: 0.158, h-index: 9)
Alzheimer's & Dementia     Hybrid Journal   (Followers: 48, SJR: 4.289, h-index: 64)
Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring     Open Access   (Followers: 6)
Alzheimer's & Dementia: Translational Research & Clinical Interventions     Open Access   (Followers: 5)
American Heart J.     Hybrid Journal   (Followers: 49, SJR: 3.157, h-index: 153)
American J. of Cardiology     Hybrid Journal   (Followers: 47, SJR: 2.063, h-index: 186)
American J. of Emergency Medicine     Hybrid Journal   (Followers: 39, SJR: 0.574, h-index: 65)
American J. of Geriatric Pharmacotherapy     Full-text available via subscription   (Followers: 8, SJR: 1.091, h-index: 45)
American J. of Geriatric Psychiatry     Hybrid Journal   (Followers: 15, SJR: 1.653, h-index: 93)
American J. of Human Genetics     Hybrid Journal   (Followers: 31, SJR: 8.769, h-index: 256)
American J. of Infection Control     Hybrid Journal   (Followers: 25, SJR: 1.259, h-index: 81)
American J. of Kidney Diseases     Hybrid Journal   (Followers: 32, SJR: 2.313, h-index: 172)
American J. of Medicine     Hybrid Journal   (Followers: 45, SJR: 2.023, h-index: 189)
American J. of Medicine Supplements     Full-text available via subscription   (Followers: 3)
American J. of Obstetrics and Gynecology     Hybrid Journal   (Followers: 231, SJR: 2.255, h-index: 171)
American J. of Ophthalmology     Hybrid Journal   (Followers: 58, SJR: 2.803, h-index: 148)
American J. of Ophthalmology Case Reports     Open Access   (Followers: 5)
American J. of Orthodontics and Dentofacial Orthopedics     Full-text available via subscription   (Followers: 6, SJR: 1.249, h-index: 88)
American J. of Otolaryngology     Hybrid Journal   (Followers: 25, SJR: 0.59, h-index: 45)
American J. of Pathology     Hybrid Journal   (Followers: 26, SJR: 2.653, h-index: 228)
American J. of Preventive Medicine     Hybrid Journal   (Followers: 22, SJR: 2.764, h-index: 154)
American J. of Surgery     Hybrid Journal   (Followers: 34, SJR: 1.286, h-index: 125)
American J. of the Medical Sciences     Hybrid Journal   (Followers: 12, SJR: 0.653, h-index: 70)
Ampersand : An Intl. J. of General and Applied Linguistics     Open Access   (Followers: 5)
Anaerobe     Hybrid Journal   (Followers: 4, SJR: 1.066, h-index: 51)
Anaesthesia & Intensive Care Medicine     Full-text available via subscription   (Followers: 57, SJR: 0.124, h-index: 9)
Anaesthesia Critical Care & Pain Medicine     Full-text available via subscription   (Followers: 11)
Anales de Cirugia Vascular     Full-text available via subscription  
Anales de Pediatría     Full-text available via subscription   (Followers: 2, SJR: 0.209, h-index: 27)
Anales de Pediatría (English Edition)     Full-text available via subscription  
Anales de Pediatría Continuada     Full-text available via subscription   (SJR: 0.104, h-index: 3)
Analytic Methods in Accident Research     Hybrid Journal   (Followers: 4, SJR: 2.577, h-index: 7)
Analytica Chimica Acta     Hybrid Journal   (Followers: 37, SJR: 1.548, h-index: 152)
Analytical Biochemistry     Hybrid Journal   (Followers: 168, SJR: 0.725, h-index: 154)
Analytical Chemistry Research     Open Access   (Followers: 8, SJR: 0.18, h-index: 2)
Analytical Spectroscopy Library     Full-text available via subscription   (Followers: 11)
Anesthésie & Réanimation     Full-text available via subscription   (Followers: 1)
Anesthesiology Clinics     Full-text available via subscription   (Followers: 22, SJR: 0.421, h-index: 40)
Angiología     Full-text available via subscription   (SJR: 0.124, h-index: 9)
Angiologia e Cirurgia Vascular     Open Access  
Animal Behaviour     Hybrid Journal   (Followers: 161, SJR: 1.907, h-index: 126)
Animal Feed Science and Technology     Hybrid Journal   (Followers: 5, SJR: 1.151, h-index: 83)
Animal Reproduction Science     Hybrid Journal   (Followers: 5, SJR: 0.711, h-index: 78)
Annales d'Endocrinologie     Full-text available via subscription   (Followers: 1, SJR: 0.394, h-index: 30)
Annales d'Urologie     Full-text available via subscription  
Annales de Cardiologie et d'Angéiologie     Full-text available via subscription   (SJR: 0.177, h-index: 13)
Annales de Chirurgie de la Main et du Membre Supérieur     Full-text available via subscription  
Annales de Chirurgie Plastique Esthétique     Full-text available via subscription   (Followers: 2, SJR: 0.354, h-index: 22)
Annales de Chirurgie Vasculaire     Full-text available via subscription   (Followers: 1)

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Journal Cover Advances in Biological Regulation
  [SJR: 2.277]   [H-I: 43]   [4 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 2212-4926
   Published by Elsevier Homepage  [3043 journals]
  • ASK1 in neurodegeneration
    • Authors: Yuriko Azuchi; Atsuko Kimura; Xiaoli Guo; Goichi Akiyama; Takahiko Noro; Chikako Harada; Atsuko Nishigaki; Kazuhiko Namekata; Takayuki Harada
      Pages: 82 - 87
      Abstract: Publication date: Available online 1 September 2017
      Source:Advances in Biological Regulation
      Author(s): Xiaoli Guo, Kazuhiko Namekata, Atsuko Kimura, Chikako Harada, Takayuki Harada
      Neurodegenerative diseases (NDDs) such as glaucoma, multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD) are characterized by the progressive loss of neurons, causing irreversible damage to patients. Longer lifespans may be leading to an increase in the number of people affected by NDDs worldwide. Among the pathways strongly impacting the pathogenesis of NDDs, oxidative stress, a condition that occurs because of an imbalance in oxidant and antioxidant levels, has been known to play a vital role in the pathophysiology of NDDs. One of the molecules activated by oxidative stress is apoptosis signal-regulating kinase 1 (ASK1), which has been shown to play a role in NDDs. ASK1 activation is regulated by multiple steps, including oligomerization, phosphorylation, and protein-protein interactions. In the oxidative stress state, reactive oxygen species (ROS) induce the dissociation of thioredoxin, a protein regulating cellular reduction and oxidation (redox), from the N-terminal region of ASK1, and ASK1 is subsequently activated by the oligomerization and phosphorylation of a critical threonine residue, leading to cell death. Here, we review experimental evidence that links ASK1 signaling with the pathogenesis of several NDDs. We propose that ASK1 may be a new point of therapeutic intervention to prevent or treat NDDs.

      PubDate: 2017-09-05T23:02:23Z
      DOI: 10.1016/j.neulet.2016.12.057
      Issue No: Vol. 639 (2017)
       
  • Acknowledgements
    • Authors: Lucio Cocco
      Abstract: Publication date: January 2017
      Source:Advances in Biological Regulation, Volume 63
      Author(s): Lucio Cocco


      PubDate: 2017-02-05T09:26:01Z
      DOI: 10.1016/s2212-4926(17)30018-0
      Issue No: Vol. 63 (2017)
       
  • The importance of blood platelet lipid signaling in thrombosis and in
           sepsis
    • Authors: Fanny Vardon Bounes; Abdulrahman Mujalli; Claire Cenac; Sonia Severin; Pauline Lefaouder; Gaëtan Chicanne; Frédérique Gaits-Iacovoni; Vincent Minville; Marie-Pierre Gratacap; Bernard Payrastre
      Abstract: Publication date: Available online 29 September 2017
      Source:Advances in Biological Regulation
      Author(s): Fanny Vardon Bounes, Abdulrahman Mujalli, Claire Cenac, Sonia Severin, Pauline Le Faouder, Gaëtan Chicanne, Frédérique Gaits-Iacovoni, Vincent Minville, Marie-Pierre Gratacap, Bernard Payrastre
      Blood platelets are the first line of defense against hemorrhages and are also strongly involved in the processes of arterial thrombosis, a leading cause of death worldwide. Besides their well-established roles in hemostasis, vascular wall repair and thrombosis, platelets are now recognized as important players in other processes such as inflammation, healing, lymphangiogenesis, neoangiogenesis or cancer. Evidence is accumulating they are key effector cells in immune and inflammatory responses to host infection. To perform their different functions platelets express a wide variety of membrane receptors triggering specific intracellular signaling pathways and largely use lipid signaling systems. Lipid metabolism is highly active in stimulated platelets including the phosphoinositide metabolism with the phospholipase C (PLC) and the phosphoinositide 3-kinase (PI3K) pathways but also other enzymatic systems producing phosphatidic acid, lysophosphatidic acid, platelet activating factor, sphingosine 1-phosphate and a number of eicosanoids. While several of these bioactive lipids regulate intracellular platelet signaling mechanisms others are released by activated platelets acting as autocrine and/or paracrine factors modulating neighboring cells such as endothelial and immune cells. These bioactive lipids have been shown to play important roles in hemostasis and thrombosis but also in vessel integrity and dynamics, inflammation, tissue remodeling and wound healing. In this review, we will discuss some important aspects of platelet lipid signaling in thrombosis and during sepsis that is an important cause of death in intensive care unit. We will particularly focus on the implication of the different isoforms of PI3Ks and on the generation of eicosanoids released by activated platelets.

      PubDate: 2017-10-06T23:46:57Z
      DOI: 10.1016/j.jbior.2017.09.011
       
  • Phosphatidic acid-producing enzymes regulating the synaptic vesicle cycle:
           Role for PLD'
    • Authors: Casey N. Barber; Richard L. Huganir; Daniel M. Raben
      Abstract: Publication date: Available online 28 September 2017
      Source:Advances in Biological Regulation
      Author(s): Casey N. Barber, Richard L. Huganir, Daniel M. Raben
      In cortical and hippocampal neurons of the mammalian brain, the synaptic vesicle cycle is a series of steps that tightly regulate exo- and endocytosis of vesicles. Many proteins contribute to this regulation, but lipids have recently emerged as critical regulators as well. Of all the many lipid signaling molecules, phosphatidic acid is important to the physical processes of membrane fusion. Therefore, the lipid-metabolizing enzymes that produce phosphatidic acid are vital to the regulation of the cycle. Our lab is particularly interested in the potential regulatory mechanisms and neuronal roles of two phosphatidic acid-producing enzymes: diacylglycerol kinase theta (DGKθ) and phospholipase D (PLD). We recently discovered a regulatory role of DGKθ on evoked endocytosis (Goldschmidt et al., 2016). In addition to this enzyme, studies implicate PLD1 in neurotransmission, although its precise role is of some debate. Altogether, the production of phosphatidic acid by these enzymes offer an interesting and novel pathway for the regulation of the synaptic vesicle cycle.

      PubDate: 2017-10-06T23:46:57Z
      DOI: 10.1016/j.jbior.2017.09.009
       
  • DGKζ ablation engenders upregulation of p53 level in the spleen upon
           whole-body ionizing radiation
    • Authors: Toshiaki Tanaka; Ken Iseki; Ken Tanaka; Tomoyuki Nakano; Mitsuyoshi Iino; Kaoru Goto
      Abstract: Publication date: Available online 28 September 2017
      Source:Advances in Biological Regulation
      Author(s): Toshiaki Tanaka, Ken Iseki, Ken Tanaka, Tomoyuki Nakano, Mitsuyoshi Iino, Kaoru Goto
      The tumor suppressor gene product p53, which coordinates the cellular response to various stresses, is subject to tight regulation by a complex network of signal transduction. The DGK family metabolizes lipidic second messenger diacylglycerol to produce phosphatidic acid. Our earlier studies showed that one isozyme, DGKζ, is involved in the regulatory mechanism of p53. In a cellular model of doxorubicin-induced DNA damage, overexpression of wild-type DGKζ suppresses p53 protein induction and reduces apoptosis, whereas knockdown of DGKζ upregulates p53 protein level and promotes apoptosis. Further examination reveals that DGKζ facilitates p53 degradation via ubiquitin-proteasome system in the cytoplasm. However, it remains undetermined whether the regulatory mechanism of DGKζ on p53 function found in cell-based experiments is also functional at the animal level. This study was conducted to elucidate this point using an experiment with DGKζ-KO mice under DNA damage induced by whole-body ionizing radiation. Our results reveal that p53 protein is induced robustly in the spleen of DGKζ-KO mice upon exposure to ionizing radiation, thereby promoting apoptosis in this organ. Taken together, the results demonstrate that DGKζ plays a sentinel role in p53 expression at the cellular and organismal levels after DNA damaging stress conditions.

      PubDate: 2017-09-28T23:19:25Z
      DOI: 10.1016/j.jbior.2017.09.010
       
  • Splicing factor mutations in the myelodysplastic syndromes: Target genes
           and therapeutic approaches
    • Authors: Richard N. Armstrong; Violetta Steeples; Shalini Singh; Andrea Sanchi; Jacqueline Boultwood; Andrea Pellagatti
      Abstract: Publication date: Available online 22 September 2017
      Source:Advances in Biological Regulation
      Author(s): Richard N. Armstrong, Violetta Steeples, Shalini Singh, Andrea Sanchi, Jacqueline Boultwood, Andrea Pellagatti
      Mutations in splicing factor genes (SF3B1, SRSF2, U2AF1 and ZRSR2) are frequently found in patients with myelodysplastic syndromes (MDS), suggesting that aberrant spliceosome function plays a key role in the pathogenesis of MDS. Splicing factor mutations have been shown to result in aberrant splicing of many downstream target genes. Recent functional studies have begun to characterize the splicing dysfunction in MDS, identifying some key aberrantly spliced genes that are implicated in disease pathophysiology. These findings have led to the development of therapeutic strategies using splicing-modulating agents and rapid progress is being made in this field. Splicing inhibitors are promising agents that exploit the preferential sensitivity of splicing factor-mutant cells to these compounds. Here, we review the known target genes associated with splicing factor mutations in MDS, and discuss the potential of splicing-modulating therapies for these disorders.

      PubDate: 2017-09-22T23:14:37Z
      DOI: 10.1016/j.jbior.2017.09.008
       
  • Microbial inositol polyphosphate metabolic pathway as drug development
           target
    • Authors: Adolfo Saiardi; Cristina Azevedo; Yann Desfougères; Paloma Portela-Torres; Miranda S.C. Wilson
      Abstract: Publication date: Available online 22 September 2017
      Source:Advances in Biological Regulation
      Author(s): Adolfo Saiardi, Cristina Azevedo, Yann Desfougères, Paloma Portela-Torres, Miranda S.C. Wilson
      Inositol polyphosphates are a diverse and multifaceted class of intracellular messengers omnipresent in eukaryotic cells. These water-soluble molecules regulate many aspects of fundamental cell physiology. Removing this metabolic pathway is deleterious: inositol phosphate kinase null mutations can result in lethality or substantial growth phenotypes. Inositol polyphosphate synthesis occurs through the actions of a set of kinases that phosphorylate phospholipase-generated IP3 to higher phosphorylated forms, such as the fully phosphorylated IP6 and the inositol pyrophosphates IP7 and IP8. Unicellular organisms have a reduced array of the kinases for synthesis of higher phosphorylated inositol polyphosphates, while human cells possess two metabolic routes to IP6. The enzymes responsible for inositol polyphosphate synthesis have been identified in all eukaryote genomes, although their amino acid sequence homology is often barely detectable by common search algorithms. Homology between human and microbial inositol phosphate kinases is restricted to a few catalytically important residues. Recent studies of the inositol phosphate metabolic pathways in pathogenic fungi (Cryptococcus neoformans) and protozoa (Trypanosome brucei) have revealed the importance of the highly phosphorylated inositol polyphosphates to the fitness and thus virulence of these pathogens. Given this, identification of inositol kinase inhibitors specifically targeting the kinases of pathogenic microorganisms is desirable and achievable.

      PubDate: 2017-09-22T23:14:37Z
      DOI: 10.1016/j.jbior.2017.09.007
       
  • MYO18A: An unusual myosin
    • Authors: Matthew D. Buschman; Seth J. Field
      Abstract: Publication date: Available online 18 September 2017
      Source:Advances in Biological Regulation
      Author(s): Matthew D. Buschman, Seth J. Field
      MYO18A is a divergent member of the myosin family characterized by the presence of an amino-terminal PDZ domain. MYO18A has been found in a few different complexes involved in intracellular transport processes. MYO18A is found in a complex with LURAP1 and MRCK that functions in retrograde treadmilling of actin. It also has been found in a complex with PAK2, βPIX, and GIT1, functioning to transport that protein complex from focal adhesions to the leading edge. Finally, a high proportion of MYO18A is found in complex with GOLPH3 at the trans Golgi, where it functions to promote vesicle budding for Golgi-to-plasma membrane trafficking. Interestingly, MYO18A has been implicated as a cancer driver, as have other components of the GOLPH3 pathway. It remains uncertain as to whether or not MYO18A has intrinsic motor activity. While many questions remain, MYO18A is a fascinatingly unique myosin that is essential in higher organisms.

      PubDate: 2017-09-22T23:14:37Z
      DOI: 10.1016/j.jbior.2017.09.005
       
  • Sphingosine 1-phosphate and cancer
    • Authors: Nigel J. Pyne; Ashref El Buri; David R. Adams; Susan Pyne
      Abstract: Publication date: Available online 15 September 2017
      Source:Advances in Biological Regulation
      Author(s): Nigel J. Pyne, Ashref El Buri, David R. Adams, Susan Pyne
      The bioactive lipid, sphingosine 1-phosphate (S1P) is produced by phosphorylation of sphingosine and this is catalysed by two sphingosine kinase isoforms (SK1 and SK2). Here we discuss structural functional aspects of SK1 (which is a dimeric quaternary enzyme) that relate to coordinated coupling of membrane association with phosphorylation of Ser225 in the ‘so-called’ R-loop, catalytic activity and protein-protein interactions (e.g. TRAF2, PP2A and Gq). S1P formed by SK1 at the plasma-membrane is released from cells via S1P transporters to act on S1P receptors to promote tumorigenesis. We discuss here an additional novel mechanism that can operate between cancer cells and fibroblasts and which involves the release of the S1P receptor, S1P2 in exosomes from breast cancer cells that regulates ERK-1/2 signalling in fibroblasts. This novel mechanism of signalling might provide an explanation for the role of S1P2 in promoting metastasis of cancer cells and which is dependent on the micro-environmental niche.

      PubDate: 2017-09-17T23:11:19Z
      DOI: 10.1016/j.jbior.2017.09.006
       
  • Where do substrates of diacylglycerol kinases come from'
           Diacylglycerol kinases utilize diacylglycerol species supplied from
           phosphatidylinositol turnover-independent pathways
    • Authors: Fumio Sakane; Satoru Mizuno; Daisuke Takahashi; Hiromichi Sakai
      Abstract: Publication date: Available online 9 September 2017
      Source:Advances in Biological Regulation
      Author(s): Fumio Sakane, Satoru Mizuno, Daisuke Takahashi, Hiromichi Sakai
      Diacylglycerol kinase (DGK) phosphorylates diacylglycerol (DG) to produce phosphatidic acid (PA). Mammalian DGK comprises ten isozymes (α–κ) and regulates a wide variety of physiological and pathological events, such as cancer, type II diabetes, neuronal disorders and immune responses. DG and PA consist of various molecular species that have different acyl chains at the sn-1 and sn-2 positions, and consequently, mammalian cells contain at least 50 structurally distinct DG/PA species. Because DGK is one of the components of phosphatidylinositol (PI) turnover, the generally accepted dogma is that all DGK isozymes utilize 18:0/20:4-DG derived from PI turnover. We recently established a specific liquid chromatography-mass spectrometry method to analyze which PA species were generated by DGK isozymes in a cell stimulation-dependent manner. Interestingly, we determined that DGKδ, which is closely related to the pathogenesis of type II diabetes, preferentially utilized 14:0/16:0-, 14:0/16:1-, 16:0/16:0-, 16:0/16:1-, 16:0/18:0- and 16:0/18:1-DG species (X:Y = the total number of carbon atoms: the total number of double bonds) supplied from the phosphatidylcholine-specific phospholipase C pathway, but not 18:0/20:4-DG, in high glucose-stimulated C2C12 myoblasts. Moreover, DGKα mainly consumed 14:0/16:0-, 16:0/18:1-, 18:0/18:1- and 18:1/18:1-DG species during cell proliferation in AKI melanoma cells. Furthermore, we found that 16:0/16:0-PA was specifically produced by DGKζ in Neuro-2a cells during retinoic acid- and serum starvation-induced neuronal differentiation. These results indicate that DGK isozymes utilize a variety of DG molecular species derived from PI turnover-independent pathways as substrates in different stimuli and cells. DGK isozymes phosphorylate various DG species to generate various PA species. It was revealed that the modes of activation of conventional and novel protein kinase isoforms by DG molecular species varied considerably. However, PA species-selective binding proteins have not been found to date. Therefore, we next attempted to identify PA species-selective binding proteins from the mouse brain and identified α-synuclein, which has causal links to Parkinson's disease. Intriguingly, we determined that among phospholipids, including several PA species (16:0/16:0-PA, 16:0/18:1-PA, 18:1/18:1-PA, 18:0/18:0-PA and 18:0/20:4-PA); 18:1/18:1-PA was the most strongly bound PA to α-synuclein. Moreover, 18:1/18:1-PA strongly enhanced secondary structural changes from the random coil form to the α-helix form and generated a multimeric and proteinase K-resistant α-synuclein protein. In contrast with the dogma described above, our recent studies strongly suggest that PI turnover-derived DG species and also various DG species derived from PI turnover-independent pathways are utilized by DGK isozymes. DG species supplied from distinct pathways may be utilized by DGK isozymes based on different stimuli present in different types of cells, and individual PA molecular species would have specific targets and exert their own physiological functions.

      PubDate: 2017-09-11T23:07:13Z
      DOI: 10.1016/j.jbior.2017.09.003
       
  • Phospholipase Cβ interacts with cytosolic partners to regulate cell
           proliferation
    • Authors: Suzanne Scarlata; Ashima Singla; Osama Garwain
      Abstract: Publication date: Available online 9 September 2017
      Source:Advances in Biological Regulation
      Author(s): Suzanne Scarlata, Ashima Singla, Osama Garwain
      Phospholipase Cβ (PLCβ) is the main effector of the Gαq signaling pathway relaying different extracellular sensory information to generate intracellular calcium signals. Besides this classic function, we have found that PLCβ plays an important but unknown role in regulating PC12 cell differentiation by interacting with components in the RNA-induced silencing machinery. In trying to understand the role of PLCβ in PC12 cell differentiation, we find that over-expressing PLCβ reduces PC12 cell proliferation while down-regulating PLCβ increases the rate of cell proliferation. However, this behavior is not seen in other cancerous cell lines. To determine the underlying mechanism, we carried out mass spectrometry analysis of PLCβ complexes in PC12 cells. We find that in unsynchronized cells, PLCβ primarily binds cyclin-dependent kinase (CDK) 16 whose activity plays a key role in cell proliferation. In vitro studies show a direct association between the two proteins that result in loss in CKD16 activity. When cells are arrested in the G2/M phase, a large population of PLCβ is bound to Ago2 in a complex that contains C3PO and proteins commonly found in stress granules. Additionally, another population of PLCβ complexes with CDK18 and cyclin B1. Fluorescence lifetime imaging microscopy (FLIM) confirms cell cycle dependent associations between PLCβ and these other protein binding partners. Taken together, our studies suggest that PLCβ may play an active role in mediating interactions required to move through the cell cycle.

      PubDate: 2017-09-11T23:07:13Z
      DOI: 10.1016/j.jbior.2017.09.004
       
  • Molecular basis of the human ribosomopathy Shwachman-Diamond syndrome
    • Authors: Alan J. Warren
      Abstract: Publication date: Available online 6 September 2017
      Source:Advances in Biological Regulation
      Author(s): Alan J. Warren
      Mutations that target the ubiquitous process of ribosome assembly paradoxically cause diverse tissue-specific disorders (ribosomopathies) that are often associated with an increased risk of cancer. Ribosomes are the essential macromolecular machines that read the genetic code in all cells in all kingdoms of life. Following pre-assembly in the nucleus, precursors of the large 60S and small 40S ribosomal subunits are exported to the cytoplasm where the final steps in maturation are completed. Here, I review the recent insights into the conserved mechanisms of ribosome assembly that have come from functional characterisation of the genes mutated in human ribosomopathies. In particular, recent advances in cryo-electron microscopy, coupled with genetic, biochemical and prior structural data, have revealed that the SBDS protein that is deficient in the inherited leukaemia predisposition disorder Shwachman-Diamond syndrome couples the final step in cytoplasmic 60S ribosomal subunit maturation to a quality control assessment of the structural and functional integrity of the nascent particle. Thus, study of this fascinating disorder is providing remarkable insights into how the large ribosomal subunit is functionally activated in the cytoplasm to enter the actively translating pool of ribosomes.

      PubDate: 2017-09-11T23:07:13Z
      DOI: 10.1016/j.jbior.2017.09.002
       
  • Phosphoinositide 5-phosphatase activities control cell motility in
           glioblastoma: Two phosphoinositides PI(4,5)P2 and PI(3,4)P2 are involved
    • Authors: Ana Raquel Ramos; William's Elong Edimo; Christophe Erneux
      Abstract: Publication date: Available online 5 September 2017
      Source:Advances in Biological Regulation
      Author(s): Ana Raquel Ramos, William's Elong Edimo, Christophe Erneux
      Inositol polyphosphate 5-phosphatases or phosphoinositide 5-phosphatases (PI 5-phosphatases) are enzymes that can act on soluble inositol phosphates and/or phosphoinositides (PIs). Several PI 5-phosphatases have been linked to human genetic diseases, in particular the Lowe protein or OCRL which is mutated in the Lowe syndrome. There are 10 different members of this family and 9 of them can use PIs as substrate. One of these substrates, PI(3,4,5)P3 binds to specific PH domains and recruits as effectors specific proteins to signaling complexes. Protein kinase B is one target protein and activation of the kinase will have a major impact on cell proliferation, survival and cell metabolism. Two other PIs, PI(4,5)P2 and PI(3,4)P2, are produced or used as substrates of PI 5-phosphatases (OCRL, INPP5B, SHIP1/2, SYNJ1/2, INPP5K, INPP5J, INPP5E). The inositol lipids may influence many aspects of cytoskeletal organization, lamellipodia formation and F-actin polymerization. PI 5-phosphatases have been reported to control cell migration, adhesion, polarity and cell invasion particularly in cancer cells. In glioblastoma, reducing SHIP2 expression can positively or negatively affect the speed of cell migration depending on the glioblastoma cell type. The two PI 5-phosphatases SHIP2 or SKIP could be localized at the plasma membrane and can reduce either PI(3,4,5)P3 or PI(4,5)P2 abundance. In the glioblastoma 1321 N1 cells, SHIP2 controls plasma membrane PI(4,5)P2 thereby participating in the control of cell migration.

      PubDate: 2017-09-05T23:02:23Z
      DOI: 10.1016/j.jbior.2017.09.001
       
  • How miRs and mRNA deadenylases could post-transcriptionally regulate
           expression of tumor-promoting protein PLD
    • Authors: Julian Gomez-Cambronero; Kristen Fite; Taylor E. Miller
      Abstract: Publication date: Available online 24 August 2017
      Source:Advances in Biological Regulation
      Author(s): Julian Gomez-Cambronero, Kristen Fite, Taylor E. Miller
      Phospholipase D (PLD) plays a key role in both cell membrane lipid reorganization and architecture, as well as a cell signaling protein via the product of its enzymatic reaction, phosphatidic acid (PA). PLD is involved in promoting breast cancer cell growth, proliferation, and metastasis and both gene and protein expression are upregulated in breast carcinoma human samples. In spite of all this, the ultimate reason as to why PLD expression is high in cancer cells vs. their normal counterparts remains largely unknown. Until we understand this and the associated signaling pathways, it will be difficult to establish PLD as a bona fide target to explore new potential cancer therapeutic approaches. Recently, our lab has identified several molecular mechanisms by which PLD expression is high in breast cancer cells and they all involve post-transcriptional control of its mRNA. First, PA, a mitogen, functions as a protein and mRNA stabilizer that counteracts natural decay and degradation. Second, there is a repertoire of microRNAs (miRs) that keep PLD mRNA translation at low levels in normal cells, but their effects change with starvation and during endothelial-to-mesenchymal transition (EMT) in cancer cells. Third, there is a novel way of post-transcriptional regulation of PLD involving 3′-exonucleases, specifically the deadenylase, Poly(A)-specific Ribonuclease (PARN). PARN targets mRNA containing AU-rich elements (AREs) for poly-A tail removal, which tags the mRNA for degradation. This mechanism operates well in non-cancerous cells, but is again subverted in cancerous cells where PARN expression is abnormally low. This enables PLD accumulation and ultimately breast cancer cell growth, proliferation, and metastasis. We review in depth the emerging field of post-transcriptional regulation of PLD, which is only recently beginning to be understood. We also advance here the concept of a common thread of miRs, PARN and a combination of the two by a singular "miR-dependent PARN deadenylation". Since, surprisingly, so little is known about post-transcriptional regulation of PLD and related phospholipases (PLC or PLA), this new knowledge could help our understanding of how post-transcriptional deregulation of a lipid enzyme expression impacts tumor growth.

      PubDate: 2017-08-27T22:33:50Z
      DOI: 10.1016/j.jbior.2017.08.002
       
  • Phosphatidate phosphatase regulates membrane phospholipid synthesis via
           phosphatidylserine synthase
    • Authors: George M. Carman; Gil-Soo Han
      Abstract: Publication date: Available online 16 August 2017
      Source:Advances in Biological Regulation
      Author(s): George M. Carman, Gil-Soo Han
      The yeast Saccharomyces cerevisiae serves as a model eukaryote to elucidate the regulation of lipid metabolism. In exponentially growing yeast, a diverse set of membrane lipids are synthesized from the precursor phosphatidate via the liponucleotide intermediate CDP-diacylglycerol. As cells exhaust nutrients and progress into the stationary phase, phosphatidate is channeled via diacylglycerol to the synthesis of triacylglycerol. The CHO1-encoded phosphatidylserine synthase, which catalyzes the committed step in membrane phospholipid synthesis via CDP-diacylglycerol, and the PAH1-encoded phosphatidate phosphatase, which catalyzes the committed step in triacylglycerol synthesis are regulated throughout cell growth by genetic and biochemical mechanisms to control the balanced synthesis of membrane phospholipids and triacylglycerol. The loss of phosphatidate phosphatase activity (e.g., pah1Δ mutation) increases the level of phosphatidate and its conversion to membrane phospholipids by inducing Cho1 expression and phosphatidylserine synthase activity. The regulation of the CHO1 expression is mediated through the inositol-sensitive upstream activation sequence (UASINO), a cis-acting element for the phosphatidate-controlled Henry (Ino2–Ino4/Opi1) regulatory circuit. Consequently, phosphatidate phosphatase activity regulates phospholipid synthesis through the transcriptional regulation of the phosphatidylserine synthase enzyme.

      PubDate: 2017-08-23T22:22:17Z
      DOI: 10.1016/j.jbior.2017.08.001
       
  • Forward—GSK-3 in health
    • Authors: James McCubrey; Lucio Cocco
      Abstract: Publication date: Available online 1 July 2017
      Source:Advances in Biological Regulation
      Author(s): James A. McCubrey, Lucio Cocco


      PubDate: 2017-07-10T14:43:06Z
       
  • GSK3 and its interactions with the PI3K/AKT/mTOR signalling network
    • Authors: Miguel A. Hermida; J. Dinesh Kumar; Nick R. Leslie
      Abstract: Publication date: Available online 27 June 2017
      Source:Advances in Biological Regulation
      Author(s): Miguel A. Hermida, J. Dinesh Kumar, Nick R. Leslie
      Glycogen Synthase Kinase-3 (GSK3 or GSK-3) is a promiscuous protein kinase and its phosphorylation of its diverse substrates has major influences on many areas of physiology and pathology, including cellular metabolism, lineage commitment and neuroscience. GSK3 was one of the first identified substrates of the heavily studied oncogenic kinase AKT, phosphorylation by which inhibits GSK3 activity via the formation of an autoinhibitory pseudosubstrate sequence. This has led to investigation of the role of GSK3 inhibition as a key component of the cellular responses to growth factors and insulin, which stimulate the class I PI 3-Kinases and in turn AKT activity and GSK3 phosphorylation. GSK3 has been shown to phosphorylate several upstream and downstream components of the PI3K/AKT/mTOR signalling network, including AKT itself, RICTOR, TSC1 and 2, PTEN and IRS1 and 2, with the potential to apply feedback control within the network. However, it has been clear for some time that functionally distinct, insulated pools of GSK3 exist which are regulated independently, so that for some GSK3 substrates such as β-catenin, phosphorylation by GSK3 is not controlled by input from PI3K and AKT. Instead, as almost all GSK3 substrates require a priming phosphorylated residue to be 4 amino acids C-terminal to the Ser/Thr phosphorylated by GSK3, the predominant form of regulation of the activity of GSK3 often appears to be through control over these priming events, specific to individual substrates. Therefore, a major role of GSK3 can be viewed as an amplifier of the electrostatic effects on protein function which are caused by phosphorylation. Here we discuss these different aspects to GSK3 regulation and function, and the functions of GSK3 as it integrates with signalling through the PI3K-AKT-mTOR signalling axis.

      PubDate: 2017-06-30T14:13:58Z
      DOI: 10.1016/j.jbior.2017.06.003
       
  • Casein Kinase II (CK2), Glycogen Synthase Kinase-3 (GSK-3) and Ikaros
           mediated regulation of leukemia
    • Authors: Chandrika Gowda; Mario Soliman; Malika Kapadia; Yali Ding; Kimberly Payne; Sinisa Dovat
      Abstract: Publication date: Available online 6 June 2017
      Source:Advances in Biological Regulation
      Author(s): Chandrika Gowda, Mario Soliman, Malika Kapadia, Yali Ding, Kimberly Payne, Sinisa Dovat
      Signaling networks that regulate cellular proliferation often involve complex interactions between several signaling pathways. In this manuscript we review the crosstalk between the Casein Kinase II (CK2) and Glycogen Synthase Kinase-3 (GSK-3) pathways that plays a critical role in the regulation of cellular proliferation in leukemia. Both CK2 and GSK-3 are potential targets for anti-leukemia treatment. Previously published data suggest that CK2 and GSK-3 act synergistically to promote the phosphatidylinositol-3 kinase (PI3K) pathway via phosphorylation of PTEN. More recent data demonstrate another mechanism through which CK2 promotes the PI3K pathway – via transcriptional regulation of PI3K pathway genes by the newly-discovered CK2-Ikaros axis. Together, these data suggest that the CK2 and GSK-3 pathways regulate AKT/PI3K signaling in leukemia via two complementary mechanisms: a) direct phosphorylation of PTEN and b) transcriptional regulation of PI3K-promoting genes. Functional interactions between CK2, Ikaros and GSK3 define a novel signaling network that regulates proliferation of leukemia cells. This regulatory network involves both direct posttranslational modifications (by CK and GSK-3) and transcriptional regulation (via CK2-mediated phosphorylation of Ikaros). This information provides a basis for the development of targeted therapy for leukemia.

      PubDate: 2017-06-16T13:32:08Z
      DOI: 10.1016/j.jbior.2017.06.001
       
  • Pivotal roles of glycogen synthase-3 in hepatocellular carcinoma
    • Authors: Melchiorre Cervello; Giuseppa Augello; Antonella Cusimano; Maria Rita Emma; Daniele Balasus; Antonina Azzolina; James A. McCubrey; Giuseppe Montalto
      Abstract: Publication date: Available online 6 June 2017
      Source:Advances in Biological Regulation
      Author(s): Melchiorre Cervello, Giuseppa Augello, Antonella Cusimano, Maria Rita Emma, Daniele Balasus, Antonina Azzolina, James A. McCubrey, Giuseppe Montalto
      Hepatocellular carcinoma (HCC) is one of the most common cancers in the world, and represents the second most frequently cancer and third most common cause of death from cancer worldwide. At advanced stage, HCC is a highly aggressive tumor with a poor prognosis and with very limited response to common therapies. Therefore, there is still the need for new effective and well-tolerated therapeutic strategies. Molecular-targeted therapies hold promise for HCC treatment. One promising molecular target is the multifunctional serine/threonine kinase glycogen synthase kinase 3 (GSK-3). The roles of GSK-3β in HCC remain controversial, several studies suggested a possible role of GSK-3β as a tumor suppressor gene in HCC, whereas, other studies indicate that GSK-3β is a potential therapeutic target for this neoplasia. In this review, we will focus on the different roles that GSK-3 plays in HCC and its interaction with signaling pathways implicated in the pathogenesis of HCC, such as Insulin-like Growth Factor (IGF), Notch, Wnt/β-catenin, Hedgehog (HH), and TGF-β pathways. In addition, the pivotal roles of GSK3 in epithelial-mesenchymal transition (EMT), invasion and metastasis will be also discussed.

      PubDate: 2017-06-11T13:09:53Z
      DOI: 10.1016/j.jbior.2017.06.002
       
  • Regulation of GSK-3 activity by curcumin, berberine and resveratrol:
           Potential effects on multiple diseases
    • Authors: James McCubrey; Kvin Lertpiriyapong Linda Steelman Steve Abrams Lucio Cocco
      Abstract: Publication date: Available online 26 May 2017
      Source:Advances in Biological Regulation
      Author(s): James A. McCubrey, Kvin Lertpiriyapong, Linda S. Steelman, Steve L. Abrams, Lucio Cocco, Stefano Ratti, Alberto M. Martelli, Saverio Candido, Massimo Libra, Giuseppe Montalto, Melchiorre Cervello, Agnieszka Gizak, Dariusz Rakus
      Natural products or nutraceuticals promote anti-aging, anti-cancer and other health-enhancing effects. A key target of the effects of natural products may be the regulation of the PI3K/PTEN/Akt/mTORC1/GSK-3 pathway. This review will focus on the effects of curcumin (CUR), berberine (BBR) and resveratrol (RES), on the PI3K/PTEN/Akt/mTORC1/GSK-3 pathway, with a special focus on GSK-3. These natural products may regulate the pathway by multiple mechanisms including: reactive oxygen species (ROS), cytokine receptors, mirco-RNAs (miRs) and many others. CUR is present the root of turmeric (Curcuma longa). CUR is used in the treatment of many disorders, especially in those involving inflammatory processes which may contribute to abnormal proliferation and promote cancer growth. BBR is also isolated from various plants (Berberis coptis and others) and is used in traditional medicine to treat multiple diseases/conditions including: diabetes, hyperlipidemia, cancer and bacterial infections. RES is present in red grapes, other fruits and berries such as blueberries and raspberries. RES may have some anti-diabetic and anti-cancer effects. Understanding the effects of these natural products on the PI3K/PTEN/Akt/mTORC1/GSK-3 pathway may enhance their usage as anti-proliferative agent which may be beneficial for many health problems.

      PubDate: 2017-05-27T17:43:11Z
       
  • The regulatory and signaling mechanisms of the ASK family
    • Authors: Takuto Nishida; Kazuki Hattori; Kengo Watanabe
      Abstract: Publication date: Available online 22 May 2017
      Source:Advances in Biological Regulation
      Author(s): Takuto Nishida, Kazuki Hattori, Kengo Watanabe
      Apoptosis signal-regulating kinase 1 (ASK1) was identified as a MAP3K that activates the JNK and p38 pathways, and subsequent studies have reported ASK2 and ASK3 as members of the ASK family. The ASK family is activated by various intrinsic and extrinsic stresses, including oxidative stress, ER stress and osmotic stress. Numerous lines of evidence have revealed that members of the ASK family are critical for signal transduction systems to control a wide range of stress responses such as cell death, differentiation and cytokine induction. In this review, we focus on the precise signaling mechanisms of the ASK family in response to diverse stressors.

      PubDate: 2017-05-22T17:21:14Z
      DOI: 10.1016/j.jbior.2017.05.004
       
  • ASK family and cancer
    • Authors: Hiroki Ryuno; Isao Naguro; Miki Kamiyama
      Abstract: Publication date: Available online 20 May 2017
      Source:Advances in Biological Regulation
      Author(s): Hiroki Ryuno, Isao Naguro, Miki Kamiyama
      Cancer is a major problem in public health and is one of the leading causes of mortality worldwide. Many types of cancer cells exhibit aberrant cellular signal transduction in response to stress, which often leads to oncogenesis. Mitogen-activated protein kinase (MAPK) signal cascades are one of the important intracellular stress signaling pathways closely related to cancer. The key molecules in MAPK signal cascades that respond to various types of stressors are apoptosis signal-regulating kinase (ASK) family members; ASK1, ASK2 and ASK3. ASK family members are activated by a wide variety of stressors, and they regulate various cellular responses, such as cell proliferation, inflammation and apoptosis. In this review, we will discuss both the oncogenic and anti-oncogenic roles of the ASK family members in various contexts of cancer development with deeper insights into the involvement of ASK family members in cancer pathology.

      PubDate: 2017-05-22T17:21:14Z
      DOI: 10.1016/j.jbior.2017.05.003
       
  • Targeting the Akt, GSK-3, Bcl-2 axis in acute myeloid leukemia
    • Authors: Maria Rosaria Ricciardi; Simone Mirabilii; Roberto Licchetta; Monica Piedimonte; Agostino Tafuri
      Abstract: Publication date: Available online 19 May 2017
      Source:Advances in Biological Regulation
      Author(s): Maria Rosaria Ricciardi, Simone Mirabilii, Roberto Licchetta, Monica Piedimonte, Agostino Tafuri
      Over the last few decades, there has been significant progress in the understanding of the pathogenetic mechanisms of the Acute Myeloid Leukemia (AML). However, despite important advances in elucidating molecular mechanisms, the treatment of AML has not improved significantly, remaining anchored at the standard chemotherapy regimen “3 + 7”, with the prognosis of patients remaining severe, especially for the elderly and for those not eligible for transplant procedures. The biological and clinical heterogeneity of AML represents the major obstacle that hinders the improvement of prognosis and the identification of new effective therapeutic approaches. To date, abundant information has been collected on the genetic and molecular alterations of AML carrying prognostic significance. However, not enough is known on how AML progenitors regulate proliferation and survival by redundant and cross-talking signal transduction pathways (STP). Furthermore, it remains unclear how such complicated network affects prognosis and therapeutic treatment options, although many of these molecular determinants are potentially attractive for their druggable characteristics. In this review, some of the key STP frequently deregulated in AML, such as PI3k/Akt/mTOR pathway, GSK3 and components of Bcl-2 family of proteins, are summarized, highlighting in addition their interplay. Based on this information, we reviewed new targeted therapeutic approaches, focusing on the aberrant networks that sustain the AML blast proliferation, survival and drug resistance, aiming to improve disease treatment. Finally, we reported the approaches aimed at disrupting key signaling cross-talk overcoming resistances based on the combination of different targeting therapeutic strategies.

      PubDate: 2017-05-22T17:21:14Z
      DOI: 10.1016/j.jbior.2017.05.002
       
  • GSK-3 as a novel prognostic indicator in leukemia
    • Authors: Peter P. Ruvolo
      Abstract: Publication date: Available online 8 May 2017
      Source:Advances in Biological Regulation
      Author(s): Peter P. Ruvolo
      While leukemias represent a diverse set of diseases with malignant cells derived from myeloid or lymphoid origin, a common feature is the dysregulation of signal transduction pathways that influence leukemogeneisis, promote drug resistance, and favor leukemia stem cells. Mutations in PI3K, PTEN, RAS, or other upstream regulators can activate the AKT kinase which has central roles in supporting cell proliferation and survival. A major target of AKT is Glycogen Synthase Kinase 3 (GSK3). GSK3 has two isoforms (alpha and beta) that were studied as regulators of metabolism but emerged as central players in cancer in the early 1990s. GSK3 is unique in that the isoforms are constitutively active. Active GSK3 promotes destruction of oncogenic proteins such as beta Catenin, c-MYC, and MCL-1 and thus has tumor suppressor properties. In AML, inactivation of GSK3 is associated with poor overall survival. Interestingly in some leukemias GSK3 targets a tumor suppressor and thus the kinases can act as tumor promoters in those instances. An example is GSK3 targeting p27Kip1 in AML with MLL translocation. This review will cover the role of GSK3 in various leukemias both as tumor suppressor and tumor promoter. We will also briefly cover current state of GSK3 inhibitors for leukemia therapy.

      PubDate: 2017-05-12T16:52:19Z
      DOI: 10.1016/j.jbior.2017.05.001
       
  • Cross-talk between the CK2 and AKT signaling pathways in cancer
    • Authors: Maria Ruzzene; Jessika Bertacchini; Alex Toker; Sandra Marmiroli
      Abstract: Publication date: Available online 28 March 2017
      Source:Advances in Biological Regulation
      Author(s): Maria Ruzzene, Jessika Bertacchini, Alex Toker, Sandra Marmiroli
      CK2 and AKT display a high degree of cross-regulation of their respective functions, both directly, through physical interaction and phosphorylation, and indirectly, through an intense cross-talk of key downstream effectors, ultimately leading to sustained AKT activation. Being CK2 and AKT attractive targets for therapeutic intervention, here we would like to emphasize how AKT and CK2 might influence cell fate through their complex isoform-specific and contextual-dependent cross-talk, to the extent that such functional interplay should be considered when devising therapies that target one or both these key signaling kinases.

      PubDate: 2017-04-03T21:42:14Z
      DOI: 10.1016/j.jbior.2017.03.002
       
  • Inositol phosphate multikinase dependent transcriptional control
    • Authors: Ace J. Hatch; Audrey R. Odom; John D. York
      Abstract: Publication date: Available online 21 March 2017
      Source:Advances in Biological Regulation
      Author(s): Ace J. Hatch, Audrey R. Odom, John D. York
      Production of lipid-derived inositol phosphates including IP4 and IP5 is an evolutionarily conserved process essential for cellular adaptive responses that is dependent on both phospholipase C and the inositol phosphate multikinase Ipk2 (also known as Arg82 and IPMK). Studies of Ipk2, along with Arg82 prior to demonstrating its IP kinase activity, have provided an important link between control of gene expression and IP metabolism as both kinase dependent and independent functions are required for proper transcriptional complex function that enables cellular adaptation in response to extracellular queues such as nutrient availability. Here we define a promoter sequence cis-element, 5′-CCCTAAAAGG-3′, that mediates both kinase-dependent and independent functions of Ipk2. Using a synthetic biological strategy, we show that proper gene expression in cells lacking Ipk2 may be restored through add-back of two components: IP4/IP5 production and overproduction of the MADS box DNA binding protein, Mcm1. Our results are consistent with a mechanism by which Ipk2 harbors a dual functionality that stabilizes transcription factor levels and enzymatically produces a small molecule code, which together coordinate control of biological processes and gene expression.

      PubDate: 2017-03-27T21:21:50Z
      DOI: 10.1016/j.jbior.2017.03.001
       
  • Genomic instability and proliferation/survival pathways in Rb-deficient
           malignancies
    • Authors: Lara Pappas; Xiaoliang Leon Xu; David H. Abramson; Suresh C. Jhanwar
      Abstract: Publication date: Available online 8 February 2017
      Source:Advances in Biological Regulation
      Author(s): Lara Pappas, Xiaoliang Leon Xu, David H. Abramson, Suresh C. Jhanwar
      Genomic instability (GIN) is a hallmark of most cancer cells. However, compared to most human cancer cell types, the retinoblastoma tumor cells show a relatively stable genome. The fundamental basis of this genomic stability has yet to be elucidated, and the role of certain proteins involved in cell cycle regulation may be the key to the development of these specific genotypes. We examined whether thyroid hormone receptor beta 1 and 2 (TRβ1 and TRβ2), known to regulate tumorigenesis, and PTTG1, a mitotic checkpoint protein, play a role in maintaining genomic stability in retinoblastoma. In order to elucidate the role of these proteins in development of aneuploidy/polyploidy, an indicator of GIN, we first studied comparative GIN in retinoblastomas and multiple RB mutant cancer cell lines using single nucleotide polymorphism (SNP) analysis. We then utilized pLKO lentiviral vectors to selectively modify expression of the targeted cell cycle proteins and interpret their effect on downstream cell cycle proteins and their relative effects on the development of polyploidy in multiple tumor cell lines. The SNP analysis showed that retinoblastomas displayed relatively fewer genomic copy number changes as compared to other Rb-deficient cancer cell lines. Both TRβ1 and TRβ2 knockdown led to accumulation of E2F1 and PTTG1 and increased GIN as demonstrated by an increase in polyploidy. Downregulation of PTTG1 led to a relative decrease in GIN while upregulation of PTTG1 led to a relative increase in GIN. Knockdown of E2F1 led to a downstream decrease in PTTG1 expression. RB knockdown also upregulated E2F1 and PTTG1 leading to increased GIN. We showed that RB is necessary for PTTG1 inhibition and genomic stability. A relatively stable genome in retinoblastoma tumor cells is maintained by TRβ1 and TRβ2-mediated PTTG1 inhibition, counteracting RB deficiency-related GIN. TRβ1, TRβ2 and RB KD all led to the downstream PTTG1 accumulation, apparently through an activation of E2F1 resulting in extensive genomic instability as seen in other Rb-deficient tumors.

      PubDate: 2017-02-11T10:39:45Z
      DOI: 10.1016/j.jbior.2017.01.002
       
  • The photograph of PHILIP W. MAJERUS
    • Abstract: Publication date: January 2017
      Source:Advances in Biological Regulation, Volume 63


      PubDate: 2017-02-05T09:26:01Z
       
  • Flimsy Overlay for photograph
    • Abstract: Publication date: January 2017
      Source:Advances in Biological Regulation, Volume 63


      PubDate: 2017-02-05T09:26:01Z
       
  • Photograph of Participants
    • Abstract: Publication date: January 2017
      Source:Advances in Biological Regulation, Volume 63


      PubDate: 2017-02-05T09:26:01Z
       
  • Foreword
    • Authors: Lucio Cocco
      Abstract: Publication date: January 2017
      Source:Advances in Biological Regulation, Volume 63
      Author(s): Lucio Cocco


      PubDate: 2017-02-05T09:26:01Z
       
  • Aberrant proteolytic processing and therapeutic strategies in Alzheimer
           disease
    • Authors: Taisuke Tomita
      Abstract: Publication date: Available online 5 January 2017
      Source:Advances in Biological Regulation
      Author(s): Taisuke Tomita
      Amyloid-β peptide (Aβ) and tau are major components of senile plaques and neurofibrillary tangles, respectively, deposited in the brains of Alzheimer disease (AD) patients. Aβ is derived from amyloid-β precursor protein that is sequentially cleaved by two aspartate proteases, β- and γ-secretases. Secreted Aβ is then catabolized by several proteases. Several lines of evidence suggest that accumulation of Aβ by increased production or decreased degradation induces the tau-mediated neuronal toxicity and symptomatic manifestations of AD. Thus, the dynamics of cerebral Aβ, called as “Aβ economy”, would be the mechanistic basis of AD pathogenesis. Partial loss of γ-secretase activity leads to the increased generation of toxic Aβ isoforms, indicating that activation of γ-secretase would provide a beneficial effect for AD. After extensive discovery and development efforts, BACE1, which is a β-secretase enzyme, has emerged as a prime drug target for lowering brain Aβ levels. Recent studies revealed the decreased clearance of Aβ in sporadic AD patients, suggesting the importance of the catabolic mechanism in the pathogenesis of AD. I will discuss with these proteolytic mechanisms involved in the regulation of Aβ economy, and development of effective treatment and diagnostics for AD.

      PubDate: 2017-01-08T06:38:45Z
      DOI: 10.1016/j.jbior.2017.01.001
       
  • Discrete signaling mechanisms of mTORC1 and mTORC2: Connected yet apart in
           cellular and molecular aspects
    • Authors: Meena Jhanwar-Uniyal; Anubhav G. Amin; Jared B. Cooper; Kaushik Das; Meic Schmidt; Raj Murali
      Abstract: Publication date: Available online 4 January 2017
      Source:Advances in Biological Regulation
      Author(s): Meena Jhanwar-Uniyal, Anubhav G. Amin, Jared B. Cooper, Kaushik Das, Meic Schmidt, Raj Murali
      Activation of PI3K/Akt/mTOR (mechanistic target of rapamycin) signaling cascade has been shown in tumorigenesis of numerous malignancies including glioblastoma (GB). This signaling cascade is frequently upregulated due to loss of the tumor suppressor PTEN, a phosphatase that functions antagonistically to PI3K. mTOR regulates cell growth, motility, and metabolism by forming two multiprotein complexes, mTORC1 and mTORC2, which are composed of special binding partners. These complexes are sensitive to distinct stimuli. mTORC1 is sensitive to nutrients and mTORC2 is regulated via PI3K and growth factor signaling. mTORC1 regulates protein synthesis and cell growth through downstream molecules: 4E-BP1 (also called EIF4E-BP1) and S6K. Also, mTORC2 is responsive to growth factor signaling by phosphorylating the C-terminal hydrophobic motif of some AGC kinases like Akt and SGK. mTORC2 plays a crucial role in maintenance of normal and cancer cells through its association with ribosomes, and is involved in cellular metabolic regulation. Both complexes control each other as Akt regulates PRAS40 phosphorylation, which disinhibits mTORC1 activity, while S6K regulates Sin1 to modulate mTORC2 activity. Allosteric inhibitors of mTOR, rapamycin and rapalogs, have essentially been ineffective in clinical trials of patients with GB due to their incomplete inhibition of mTORC1 or unexpected activation of mTOR via the loss of negative feedback loops. Novel ATP binding inhibitors of mTORC1 and mTORC2 suppress mTORC1 activity completely by total dephosphorylation of its downstream substrate pS6KSer235/236, while effectively suppressing mTORC2 activity, as demonstrated by complete dephosphorylation of pAKTSer473. Another significant component of mTORC2 is Sin1, which is crucial for mTORC2 complex formation and function. Furthermore, proliferation and self-renewal of GB cancer stem cells are effectively targetable by these novel mTORC1 and mTORC2 inhibitors. Therefore, the effectiveness of inhibitors of mTOR complexes can be estimated by their ability to suppress both mTORC1 and 2 and their ability to impede both cell proliferation and migration.

      PubDate: 2017-01-08T06:38:45Z
      DOI: 10.1016/j.jbior.2016.12.001
       
 
 
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