This volume presents the response of the eukaryotic translational apparatus to cellular stress and apoptosis, including kinases activated through both the ERK and stress-activated pathways. It further explores two agents that inhibit protein synthesis, calcium and the immunosuppressant rapamycin. Six chapters written by leading experts in the field provide both new data and comprehensive literature reviews. Both the regulation of initiation and elongation are discussed, and the mechanisms of apoptosis are related to changes in the protein synthesis machinery.
The Regulation of eIF4F During Cell Growth and Cell Death Simon J. Morley Introduction 1(1) Mechanism and Regulation of Initiation of Protein Synthesis 1(8) The mRNA-Binding Initiation Factors 3(1) Initiation Factor eIF4E 3(2) eIF4E Phosphorylation 5(1) Initiation Factor eIF4A 5(1) eIF4B and elF4H 6(1) Scaffold Protein eIF4G 7(1) Poly(A)-Binding Protein (PABP) 7(1) eIF4E Binding Proteins 8(1) The Regulation of eIF4F Complex Levels 9(8) eIF4F: An Overview 9(1) eIF4F and Increased Rates of Protein Synthesis 10(2) eIF4F and Decreased Rates of Protein Synthesis 12(2) Internal Ribosome Binding, eIF4E, eIF4G Integrity and Reduced Levels of eIF4F 14(1) Initiation on Viral Internal Ribosome Entry Sites 14(1) Potential IRES in Capped, Cellular mRNAs 14(3) Cell Death and the eIF4F Complex 17(22) Apoptosis: An Overview 17(1) Apoptosis and Protein Synthesis Rates 18(1) Apoptosis and the Initiation Factors Involved in Binding mRNA to the Ribosome 18(1) eIF4GI and eIF4GII 18(2) eIF4B, eIF3p35, 4E-BP1 and eIF2α 20(2) Possible Mechanisms of Translational Control During Apoptosis 22(1) Cleavage of eIF2α, eIF4B, eIF3p35 and the Increased Binding of 4E-BP1 to eIF4E 23(1) Cleavage of eIF4G 24(2) References 26(13) Regulation of the Activity of Eukaryotic Initiation Factors in Stressed Cells Gert C. Scheper Roel Van Wijk Adri A.M. Thomas Stress and Protein Synthesis 39(6) Inhibition of General Protein Synthesis 39(1) Phosphorylation of eIF2 39(2) Inactivation of eIF2B 41(2) Inactivation of the Cap-Binding Complex eIF4F 43(1) Dephosphorylation of eIF4E 44(1) Binding of eIF4E to 4E-BPs 44(1) Preferential Translation of HSP mRNAs 45(5) Experimental Procedures 50(7) References 52(5) Initiation Factor eIF2α Phosphorylation in Stress Responses and Apoptosis Michael J. Clemens Introduction 57(3) EIF2α Kinases and Their Regulation 60(7) Double-Stranded RNA-Activated Protein Kinase (PKR) 61(3) The Saccharomyces cerevisiae Protein Kinase GCN2 64(1) PKR-Like Endoplasmic Reticulum Protein Kinase (PERK) 65(1) Haemin-Regulated Inhibitor (HRI) 66(1) Physiological Regulation of eIF2α Phosphorylation 67(9) Stress Responses 69(1) Heat Shock 69(1) Nutrient Supply 70(1) Regulation by Calcium 71(1) The Relative Importance of eIF2α Phosphorylation and Other Mechanisms in Stress Responses 71(3) Apoptosis 74(2) What Are the Consequences of eIF2α Phosphorylation? 76(2) Summary 78(13) References 78(13) Elongation Factor-2 Phosphorylation and the Regulation of Protein Synthesis by Calcium Angus C. Nairn Masayuki Matsushita Kent Nastiuk Atsuko Horiuchi Ken-Ichi Mitsui Yoshio Shimizu H. Clive Palfrey Introduction 91(1) Phosphorylation of eEF2 and Regulation of Polypeptide Elongation in Vitro 92(3) Structure and Regulation of EF2 Kinase 95(7) Phosphorylation of EF2 Kinase by PKA and Other Kinases 102(1) Regulation of EF2 Kinase Turnover by a Ubiquitination/Proteosome-Dependent pathway 103(2) Hormonal Control of eEF2 Expression and phosphorylation 105(4) Regulation of eEF2 Protein 106(1) Regulation of eEF2 Phosphorylation 107(1) Regulation of eEF2 Dephosphorylation 108(1) Relationship of eEF2 Phosphorylation to Protein Synthesis and Growth in Proliferating Cells 109(2) Cell Cycle-Dependent Phosphorylation of eEF2 111(3) Phosphorylation of eEF2 in Neurons 114(2) eEF2 Phosphorylation and the Regulation of Local Protein Synthesis in Neurons 116(2) eEF2 Phosphorylation and Glutamate-Mediated Control of Protein Synthesis at Developing Synapses 118(2) Concluding Remarks Concerning the Physiological Role of eEF2 Phosphorylation 120(11) References 121(10) Phosphorylation of Mammalian eIF4E by Mnkl and Mnk2: Tantalizing Prospects for a Role in Translation Malathy Mahalingam Jonathan A. Cooper Introduction 131(1) Mnks: Discovery and Kinase Activation 132(2) Mnkl Binding Proteins 134(1) Association With and Phosphorylation of the eIF4G Scaffold 135(1) The eIF4E Kinase? 136(1) Possible Consequences of eIF4E Phosphorylation 137(1) Conclusion 138(5) References 138(5) Control of Translation by the Target of Rapamycin Proteins Anne-Claude Gingras Brian Raught Nahum Sonenberg Introduction 143(1) Rapamycin (Also Known As Sirolimus or Rapamune) 144(2) Discovery and Activity of Rapamycin 144(1) Rapamycin-Related Compound FK506 145(1) Immunophilins 146(1) FK506-Binding Proteins (FKBPs) 146(1) Cyclophilins and Parvulins 147(1) Identification of Rapamycin Targets 147(3) Cloning of Yeast Target of Rapamycin (TOR) Proteins 147(2) Cloning of the Mammalian Target of Rapamycin Proteins 149(1) Modular Structure of the TOR Proteins 150(5) FKBP-Rapamycin Binding (FRB) Site 150(1) Kinase Domain 151(1) Location of the Tor Kinase Domains 151(1) Phosphoinesitide Kinase-Related Kinases {PIKKs) 152(1) Role of the Kinase Domain in Tor Function 152(1) Inhibition of Tor Protein Kinase Activity 153(1) Other Structural Elements in TOR and FRAP/mTOR 154(1) Signaling to TOR (FRAP/mTOR): Activation by Extracellular Stimuli 155(1) Downstream of Tor: Signaling Through Phosphatases 156(2) Tor Proteins as Sensors of Nutrient Availability 158(1) FRAP/mTOR and TOR as Translational Regulators 158(3) FRAP/mTOR Effects on Translation in Mammalian Cells 158(2) Translational Modulation by the Tor Proteins in S. cerevisiae 160(1) Changes in Translation Rates and Specific mRNA Translation 160(1) Putative Effectors of the Translational Effect of the Tor Proteins 160(1) Changes in the Biosynthesis of the Translational Apparatus 161(1) Regulation of 4E-BP1 Activity by FRAP/mTOR 161(2) Involvement of 4E-BP1 in Translation Initiation 161(1) 4E-BP1 Phosphorylation Sites 162(1) FRAP/mTOR Signals Upstream of 4E-BP1 162(1) A Role for FRAP/mTOR in Signaling to 4E-BP1 in Response to Nutrient Availability 163(2) FRAP/mTOR as a Mediator of ``Translational Homeostasis 165(1) Future Prospects 165(10) References 166(9) Subject Index 175
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