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1 Introduction to Cell Biology 1 1.1 The Discovery of Cells 2 1.2 Basic Properties of Cells 3 1.3 Two Fundamentally Different Classes of Cells 8 1.4 Types of Prokaryotic Cells 14 1.5 Types of Eukaryotic Cells 15 1.6 The Sizes of Cells and Their Components 18 1.7 Viruses 19 THE HUMAN PERSPECTIVE 23 The Prospect of Cell Replacement Therapy 23 EXPERIMENTAL PATHWAYS 27 The Origin of Eukaryotic Cells 27 2 The Structure and Functions of Biological Molecules 33 2.1 Covalent Bonds 34 2.2 Noncovalent Bonds 36 2.3 Acids, Bases, and Buffers 39 2.4 The Nature of Biological Molecules 40 2.5 Carbohydrates 42 2.6 Lipids 47 2.7 Building Blocks of Proteins 49 2.8 Primary and Secondary Structures of Proteins 54 2.9 Tertiary Structure of Proteins 56 2.10 Quaternary Structure of Proteins 60 2.11 Protein Folding 61 2.12 Proteomics and Interactomics 64 2.13 Protein Engineering 67 2.14 Protein Adaptation and Evolution 69 2.15 Nucleic Acids 71 2.16 The Formation of Complex Macromolecular Structures 72 THE HUMAN PERSPECTIVE 73 I. Do Free Radicals Cause Aging? 73 II. Protein Misfolding Can Have Deadly Consequences 74 EXPERIMENTAL PATHWAYS 79 Chaperones-Helping Proteins Reach Their Proper Folded State 79 3 Bioenergetics, Enzymes, and Metabolism 87 3.1 Bioenergetics 88 3.2 Free Energy 90 3.3 Coupling Endergonic and Exergonic Reactions 94 3.4 Equilibrium versus Steady�]State Metabolism 94 3.5 Enzymes as Biological Catalysts 95 3.6 Mechanisms of Enzyme Catalysis 99 3.7 Enzyme Kinetics 103 3.8 Metabolism 106 3.9 Glycolysis and ATP Production 108 3.10 Reducing Power 112 3.11 Metabolic Regulation 113 3.12 Separating Catabolic and Anabolic Pathways 114 THE HUMAN PERSPECTIVE 115 I. The Growing Problem of Antibiotic Resistance 115 II. Caloric Restriction and Longevity 118 4 Genes, Chromosomes, and Genomes 123 4.1 The Concept of a Gene as a Unit of Inheritance 124 4.2 The Discovery of Chromosomes 125 4.3 Chromosomes: The Physical Carriers of the Genes 126 4.4 Genetic Analysis in Drosophila 127 4.5 The Structure of DNA 129 4.6 DNA Supercoiling 134 4.7 The Structure of the Genome 136 4.8 The Stability of the Genome 141 4.9 "Jumping Genes" and the Dynamic Nature of the Genome 143 4.10 Sequencing Genomes: The Footprints of Biological Evolution 146 4.11 Comparative Genomics: "If It's Conserved, It Must Be Important" 148 4.12 The Genetic Basis of "Being Human" 148 4.13 Genetic Variation within the Human Species Population 150 THE HUMAN PERSPECTIVE 152 I. Diseases That Result from Expansion of Trinucleotide Repeats 152 II. Application of Genomic Analyses to Medicine 154 EXPERIMENTAL PATHWAYS 157 The Chemical Nature of the Gene 157 5 The Path to Gene Expression 165 5.1 The Relationship between Genes, Proteins, and RNAs 166 5.2 The Role of RNA Polymerases in Transcription 169 5.3 An Overview of Transcription in Both Prokaryotic and Eukaryotic Cells 171 5.4 Synthesis and Processing of Eukaryotic Ribosomal and Transfer RNAs 174 5.5 Synthesis and Structure of Eukaryotic Messenger RNAs 178 5.6 Split Genes: An Unexpected Finding 181 5.7 The Processing of Eukaryotic Messenger RNAs 184 5.8 Evolutionary Implications of Split Genes and RNA Splicing 189 5.9 Creating New Ribozymes in the Laboratory 191 5.10 Small Regulatory RNAs and RNA Silencing Pathway 191 5.11 Small RNAs: miRNAs and piRNAs 193 5.12 CRISPR and other Noncoding RNAs 195 5.13 Encoding Genetic Information 196 5.14 Decoding the Codons: The Role of Transfer RNAs 198 5.15 Translating Genetic Information: Initiation 201 5.16 Translating Genetic Information: Elongation and Termination 205 5.17 mRNA Surveillance and Quality Control 208 5.18 Polyribosomes 209 THE HUMAN PERSPECTIVE 210 Clinical Applications of RNA Interference 210 EXPERIMENTAL PATHWAYS 212 The Role of RNA as a Catalyst 212 6 Controlling Gene Expression 220 6.1 Control of Gene Expression in Bacteria 221 6.2 Control of Gene Expression in Eukaryotes: Structure and Function of the Cell Nucleus 225 6.3 Chromosomes and Chromatin 230 6.4 Heterochromatin and Euchromatin 234 6.5 The Structure of a Mitotic Chromosome 238 6.6 Epigenetics: There's More to Inheritance than DNA 243 6.7 The Nucleus as an Organized Organelle 244 6.8 An Overview of Gene Regulation in Eukaryotes 247 6.9 Transcriptional Control 248 6.10 The Role of Transcription Factors in Regulating Gene Expression 252 6.11 The Structure of Transcription Factors 253 6.12 DNA Sites Involved in Regulating Transcription 256 6.13 The Glucocorticoid Receptor: An Example of Transcriptional Activation 258 6.14 Transcriptional Activation: The Role of Enhancers, Promoters, and Coactivators 259 6.15 Transcriptional Activation from Paused Polymerases 263 6.16 Transcriptional Repression 264 6.17 RNA Processing Control 267 6.18 Translational Control 269 6.19 The Role of MicroRNAs in Translational Control 273 6.20 Posttranslational Control: Determining Protein Stability 274 THE HUMAN PERSPECTIVE 275 Chromosomal Aberrations and Human Disorders 275 7 DNA Replication and Repair 282 7.1 DNA Replication 283 7.2 DNA Replication in Bacterial Cells 286 7.3 The Machinery Operating at the Replication Fork 291 7.4 The Structure and Functions of DNA Polymerases 293 7.5 Replication in Viruses 296 7.6 DNA Replication in Eukaryotic Cells 296 7.7 Chromatin Structure and Replication 300 7.8 DNA Repair 302 7.9 Between Replication and Repair 305 THE HUMAN PERSPECTIVE 306 Consequences of DNA Repair Deficiencies 306 8 Cellular Membrane 311 8.1 Introduction to the Plasma Membrane 312 8.2 The Chemical Composition of Membranes 315 8.3 Membrane Carbohydrates 319 8.4 The Structure and Functions of Membrane Proteins 320 8.5 Studying the Structure and Properties of Integral Membrane Proteins 323 8.6 Membrane Lipids and Membrane Fluidity 327 8.7 The Dynamic Nature of the Plasma Membrane 329 8.8 The Red Blood Cell: An Example of Plasma Membrane Structure 334 8.9 The Movement of Substances across Cell Membranes 336 8.10 Diffusion through the Lipid Bilayer 338 8.11 The Diffusion of Ions through Membranes 340 8.12 Facilitated Diffusion 345 8.13 Active Transport 346 8.14 Membrane Potentials 350 8.15 Propagation of Action Potentials as an Impulse 353 8.16 Neurotransmission: Jumping the Synaptic Cleft 354 THE HUMAN PERSPECTIVE 357 Defects in Ion Channels and Transporters as a Cause of Inherited Disease 357 EXPERIMENTAL PATHWAYS 359 The Acetylcholine Receptor 359 9 Mitochondrion and Aerobic Respiration 368 9.1 Mitochondrial Structure and Function 369 9.2 Oxidative Metabolism in the Mitochondrion 372 9.3 The Role of Mitochondria in the Formation of ATP 377 9.4 Electron�]Transport Complexes 381 9.5 Translocation of Protons and the Establishment of a Proton�] Motive Force 385 9.6 The Machinery for ATP Formation 386 9.7 The Binding Change Mechanism of ATP Formation 388 9.8 Using the Proton Gradient 391 9.9 Peroxisomes 392 THE HUMAN PERSPECTIVE 394 I. The Role of Anaerobic and Aerobic Metabolism in Exercise 394 II. Diseases that Result from Abnormal Mitochondrial or Peroxisomal Function 395 10 Chloroplast and Photosynthesis 401 10.1 The Origin of Photosynthesis 402 10.2 Chloroplast Structure and Function 403 10.3 An Overview of Photosynthetic Metabolism 404 10.4 The Absorption of Light 405 10.5 Photosynthetic Units and Reaction Centers 407 10.6 The Operations of Photosystem II and Photosystem I 409 10.7 An Overview of Photosynthetic Electron Transport 413 10.8 Photophosphorylation 415 10.9 Carbon Dioxide Fixation and the Carbohydrate Synthesis 415 10.10 Carbohydrate Synthesis in C4 and CAM Plants 420 THE HUMAN PERSPECTIVE 421 Global Warming and Carbon Sequestration 421 11 The Extracellular Matrix and Cell Interactions 426 11.1 Overview of Extracellular Interactions 427 11.2 The Extracellular Space 428 11.3 Components of the Extracellular Matrix 430 11.4 Dynamic Properties of the Extracellular Matrix 435 11.5 Interactions of Cells with Extracellular Materials 436 11.6 Anchoring Cells to Their Substratum 438 11.7 Interactions of Cells with Other Cells 441 11.8 Adherens Junctions and Desmosomes: Anchoring Cells to Other Cells 445 11.9 The Role of Cell�]Adhesion Receptors in Transmembrane Signaling 447 11.10 Tight Junctions: Sealing the Extracellular Space 447 11.11 Gap Junctions and Plasmodesmata: Mediating Intercellular Communication 449 11.12 Cell Walls 453 THE HUMAN PERSPECTIVE 455 The Role of Cell Adhesion in Inflammation and Metastasis 455 EXPERIMENTAL PATHWAYS 457 The Role of Gap Junctions in Intercellular Communication 457 12 Cellular Organelles and Membrane Trafficking 463 12.1 An Overview of the Endomembrane System 464 12.2 A Few Approaches to the Study of Endomembranes 466 12.3 The Endoplasmic Reticulum 472 12.4 Functions of the Rough Endoplasmic Reticulum 473 12.5 Membrane Biosynthesis in the Endoplasmic Reticulum 477 12.6 Glycosylation in the Rough Endoplasmic Reticulum 479 12.7 Mechanisms That Ensure the Destruction of Misfolded Proteins 481 12.8 ER to Golgi Vesicular Transport 482 12.9 The Golgi Complex 482 12.10 Types of Vesicle Transport and Their Functions 487 12.11 Beyond the Golgi Complex: Sorting Proteins at the TGN 491 12.12 Targeting Vesicles to a Particular Compartment 493 12.13 Exocytosis 496 12.14 Lysosomes 496 12.15 Plant Cell Vacuoles 498 12.16 Endocytosis 498 12.17 The Endocytic Pathway 502 12.18 Phagocytosis 505 12.19 Posttranslational Uptake of Proteins by Peroxisomes, Mitochondria, and Chloroplasts 505 THE HUMAN PERSPECTIVE 508 Disorders Resulting from Defects in Lysosomal Function 508 EXPERIMENTAL PATHWAYS 510 Receptor�]Mediated Endocytosis 510 13 The Cytoskeleton 517 13.1 Overview of the Major Functions of the Cytoskeleton 518 13.2 Microtubules: Structure and Function 520 13.3 Motor Proteins: Kinesins and Dyneins 524 13.4 Microtubule�]Organizing Centers (MTOCs) 527 13.5 Microtubule Dynamics 530 13.6 Cilia and Flagella: Structure and Function 534 13.7 Intermediate Filaments 541 13.8 Microfilaments 544 13.9 Myosin: The Molecular Motor of Actin Filaments 547 13.10 Muscle Contractility 552 13.11 Nonmuscle Motility 557 13.12 Cellular Motility 560 13.13 Actin�]Dependent Processes During Development 564 13.14 The Bacterial Cytoskeleton 567 THE HUMAN PERSPECTIVE 568 The Role of Cilia in Development and Disease 568 EXPERIMENTAL PATHWAYS 569 I. The Step Size of Kinesin 569 II. Studying Actin�]Based Motility without Cells 571 14 Cell Division 578 14.1 The Cell Cycle 579 14.2 Regulation of the Cell Cycle 581 14.3 Control of the Cell Cycle: The Role of Protein Kinases 582 14.4 Control of the Cell Cycle: Checkpoints, Cdk Inhibitors, and Cellular Responses 586 14.5 M Phase: Mitosis and Cytokinesis 588 14.6 Prophase 588 14.7 Prometaphase 594 14.8 Metaphase 596 14.9 Anaphase 598 14.10 Telophase and Cytokinesis 603 14.11 Meiosis 608 14.12 The Stages of Meiosis 610 14.13 Genetic Recombination during Meiosis 613 THE HUMAN PERSPECTIVE 615 Meiotic Nondisjunction and Its Consequences 615 EXPERIMENTAL PATHWAYS 616 The Discovery and Characterization of MPF 616 15 Cell Signaling Pathways 624 15.1 The Basic Elements of Cell Signaling Systems 625 15.2 A Survey of Extracellular Messengers and their Receptors 628 15.3 Signal Transduction by G Protein�]Coupled Receptors 629 15.4 Second Messengers 632 15.5 The Specificity of G Protein�]Coupled Responses 636 15.6 Regulation of Blood Glucose Levels 636 15.7 The Role of GPCRs in Sensory Perception 640 15.8 Protein�]Tyrosine Phosphorylation as a Mechanism for Signal Transduction 641 15.9 The Ras�]MAP Kinase Pathway 645 15.10 Signaling by the Insulin Receptor 648 15.11 Signaling Pathways in Plants 651 15.12 The Role of Calcium as an Intracellular Messenger 651 15.13 Convergence, Divergence, and Cross�]Talk among Different Signaling Pathways 655 15.14 The Role of NO as an Intercellular Messenger 657 15.15 Apoptosis (Programmed Cell Death) 659 THE HUMAN PERSPECTIVE 663 Disorders Associated with G Protein�]Coupled Receptors 663 EXPERIMENTAL PATHWAYS 665 The Discovery and Characterization of GTP�]Binding Proteins 665 16 Cancer 673 16.1 Basic Properties of a Cancer Cell 674 16.2 The Causes of Cancer 677 16.3 The Genetics of Cancer 678 16.4 An Overview of Tumor�]Suppressor Genes and Oncogenes 680 16.5 Tumor�]Suppressor Genes: The RB Gene 681 16.6 Tumor�]Suppressor Genes: The TP53 Gene 684 16.7 Other Tumor�]Suppressor Genes 687 16.8 Oncogenes 688 16.9 The Mutator Phenotype: Mutant Genes Involved in DNA Repair 691 16.10 MicroRNAs: A New Player in the Genetics of Cancer 691 16.11 The Cancer Genome 691 16.12 Gene�]Expression Analysis 694 16.13 Strategies for Combating Cancer 696 16.14 Immunotherapy 696 16.15 Inhibiting the Activity of Cancer�]Promoting Proteins 698 16.16 The Concept of a Cancer Stem Cell 701 16.17 Inhibiting the Formation of New Blood Vessels (Angiogenesis) 701 EXPERIMENTAL PATHWAYS 702 The Discovery of Oncogenes 702 17 Immunity 709 17.1 An Overview of the Immune Response 710 17.2 The Clonal Selection Theory as It Applies to B Cells 714 17.3 Vaccination 715 17.4 T Lymphocytes: Activation and Mechanism of Action 717 17.5 The Modular Structure of Antibodies 720 17.6 DNA Rearrangements That Produce Genes Encoding B�] and T�]Cell Antigen Receptors 723 17.7 Membrane�]Bound Antigen Receptor Complexes 725 17.8 The Major Histocompatibility Complex 726 17.9 Distinguishing Self from Nonself 730 17.10 Lymphocytes Are Activated by Cell�]Surface Signals 731 17.11 Signal Transduction Pathways in Lymphocyte Activation 732 THE HUMAN PERSPECTIVE 733 Autoimmune Diseases 733 EXPERIMENTAL PATHWAYS 736 The Role of the Major Histocompatibility Complex in Antigen Presentation 736 18 Techniques in Cell and Molecular Biology 742 18.1 The Light Microscope 743 18.2 Bright�]Field and Phase�]Contrast Microscopy 745 18.3 Fluorescence Microscopy (and Related Fluorescence�]Based Techniques) 746 18.4 Transmission Electron Microscopy 752 18.5 Specimen Preparation for Electron Microscopy 753 18.6 Scanning Electron Microscopy 757 18.7 Atomic Force Microscopy 758 18.8 The Use of Radioisotopes 759 18.9 Cell Culture 760 18.10 The Fractionation of a Cell's Contents by Differential Centrifugation 762 18.11 Purification and Characterization of Proteins by Liquid Column Chromatography 762 18.12 Determining Protein-Protein Interactions 764 18.13 Characterization of Proteins by 18.14 Characterization of Proteins by Spectrometry 767 18.15 Characterization of Proteins by Mass Spectrometry 767 18.16 Determining the Structure of Proteins and Multisubunit Complexes 768 18.17 Fractionation of Nucleic Acids 770 18.18 Nucleic Acid Hybridization 773 18.19 Chemical Synthesis of DNA 774 18.20 Recombinant DNA Technology 774 18.21 Enzymatic Amplification of DNA by PCR 778 18.22 DNA Sequencing 780 18.23 DNA Libraries 782 18.24 DNA Transfer into Eukaryotic Cells and Mammalian Embryos 783 18.25 Gene Editing and Silencing 786 18.26 The Use of Antibodies 789 Glossary G-1 Additional Reading A-1 Index I-1

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