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1 Introduction to Cell Biology 1 1.1 The Discovery of Cells 2 1.2 Basic Properties of Cells 3 Cells Are Highly Complex and Organized 3 Cells Possess a Generic Program and the Means to Use It 5 Cells Are Capable of Producing More of Themselves 5 Cells Acquire and Utilize Energy 5 Cells Carry Out a Variety of Chemical Reactions 6 Cells Engage in Mechanical Activities 6 Cells Are Able to Respond to Stimuli 6 Cells Are Capable of Self–Regulation 6 Cells Evolve 7 1.3 Two Fundamentally Different Classes of Cells 7 Characteristics That Distinguish Prokaryotic and Eukaryotic Cells 8 Types of Prokaryotic Cells 14 Types of Eukaryotic Cells: Cell Specialization 15 The Sizes of Cells and Their Components 17 Synthetic Biology 17 ?? THE HUMAN PERSPECTIVE: The Prospect of Cell Replacement Therapy 20 1.4 Viruses 23 Viroids 26 ?? EXPERIMENTAL PATHWAYS: The Origin of Eukaryotic Cells 26 2 The Structure and Functions of Biological Molecules 32 2.1 Covalent Bonds 33 Polar and Nonpolar Molecules 34 Ionizaton 34 2.2 Noncovalent Bonds 34 ?? THE HUMAN PERSPECTIVE: Free Radicals as a Cause of Aging 35 Ionic Bonds: Attractions between Charged Atoms 35 Hydrogen Bonds 36 Hydrophobic Interactions and van der Waals Forces 36 The Life–Supporting Properties of Water 37 2.3 Acids, Bases, and Buffers 39 2.4 The Nature of Biological Molecules 40 Functional Groups 41 A Classification of Biological Molecules by Function 41 2.5 Four Types of Biological Molecules 42 Carbohydrates 43 ?? THE HUMAN PERSPECTIVE: Diseases that Result from Expansion of Trinucleotide Repeats 138 4.5 The Stability of the Genome 140 Whole–Genome Duplication (Polyploidization) 140 Duplication and Modification of DNA Sequences 141 “Jumping Genes” and the Dynamic Nature of the Genome 142 4.6 Sequencing Genomes: The Footprints of Biological Evolution 145 Comparative Genomics: “If It’s Conserved, It Must Be Important” 147 The Genetic Basis of “Being Human” 148 Genetic Variation Within the Human Species Population 150 ?? THE HUMAN PERSPECTIVE: Application of Genomic Analyses to Medicine 151 ?? EXPERIMENTAL PATHWAYS: The Chemical Nature of the Gene 154 5 The Path to Gene Expression 160 5.1 The Relationship between Genes, Proteins, and RNAs 161 An Overview of the Flow of Information through the Cell 162 5.2 An Overview of Transcription in Both Prokaryotic and Eukaryotic Cells 163 Transcription in Bacteria 166 Transcription and RNA Processing in Eukaryotic Cells 167 5.3 Synthesis and Processing of Eukaryotic Ribosomal and Transfer RNAs 169 Synthesizing the rRNA Precursor 170 Processing the rRNA Precursor 171 Synthesis and Processing of the 5S rRNA 174 Transfer RNAs 174 5.4 Synthesis and Processing of Eukaryotic Messenger RNAs 175 The Machinery for mRNA Transcription 175 Split Genes: An Unexpected Finding 178 The Processing of Eukaryotic Messenger RNAs 182 Evolutionary Implications of Split Genes and RNA Splicing 188 Creating New Ribozymes in the Laboratory 188 5.5 Small Regulatory RNAs and RNA Silencing Pathways 189 ?? THE HUMAN PERSPECTIVE: Clinical Applications of RNA Interference 192 MicroRNAs: Small RNAs that Regulate Gene Expression 193 piRNAs: A Class of Small RNAs that Function in Germ Cells 194 Other Noncoding RNAs 195 5.6 Encoding Genetic Information 195 The Properties of the Genetic Code 195 5.7 Decoding the Codons: The Role of Transfer RNAs 198 The Structure of tRNAs 199 5.8 Translating Genetic Information 202 Initiation 202 Elongation 205 Termination 208 mRNA Surveillance and Quality Control 208 Polyribosomes 209 ?? EXPERIMENTAL PATHWAYS: The Role of RNA as a Catalyst 211 6 Controlling Gene Expression 217 6.1 Control of Gene Expression in Bacteria 218 Organization of Bacterial Genomes 218 The Bacterial Operon 218 Riboswitches 221 6.2 Control of Gene Expression in Eukaryotes: Structure and Function of the Cell Nucleus 222 The Nuclear Envelope 222 Chromosomes and Chromatin 227 ?? THE HUMAN PERSPECTIVE: Chromosomal Aberrations and Human Disorders 238 Epigenetics: There’s More to Inheritance than DNA 243 The Nucleus as an Organized Organelle 244 6.3 An Overview of Gene Regulation in Eukaryotes 246 6.4 Transcriptional Control 248 The Role of Transcription Factors in Regulating Gene Expression 251 The Structure of Transcription Factors 253 DNA Sites Involved in Regulating Transcription 256 Transcriptional Activation: The Role of Enhancers, Promoters, and Coactivators 259 Transcriptional Repression 264 6.5 RNA Processing Control 267 6.6 Translational Control 270 Initiation of Translation 270 Cytoplasmic Localization of mRNAs 271 The Control of mRNA Stability 272 The Role of MicroRNAs in Translational Control 273 6.7 Posttranslational Control: Determining Protein Stability 275 7 Replicating and Repairing DNA 279 7.1 DNA Replication 280 Semiconservative Replication 280 Replication in Bacterial Cells 283 The Structure and Functions of DNA Polymerases 288 Replication in Eukaryotic Cells 292 7.2 DNA Repair 298 Nucleotide Excision Repair 299 Base Excision Repair 300 Mismatch Repair 301 Double–Strand Breakage Repair 301 7.3 Between Replication and Repair 302 ?? THE HUMAN PERSPECTIVE: The Consequences of DNA Repair Deficiencies 303 8 Cellular Membranes 306 8.1 An Overview of Membrane Functions 307 8.2 A Brief History of Studies on Plasma Membrane Structure 309 8.3 The Chemical Composition of Membranes 311 Membrane Lipids 311 The Asymmetry of Membrane Lipids 314 Membrane Carbohydrates 315 8.4 The Structure and Functions of Membrane Proteins 316 Integral Membrane Proteins 316 Studying the Structure and Properties of Integral Membrane Proteins 318 Peripheral Membrane Proteins 323 Lipid–Anchored Membrane Proteins 323 8.5 Membrane Lipids and Membrane Fluidity 324 The Importance of Membrane Fluidity 325 Maintaining Membrane Fluidity 325 Lipid Rafts 325 8.6 The Dynamic Nature of the Plasma Membrane 326 The Diffusion of Membrane Proteins after Cell Fusion 327 Restrictions on Protein and Lipid Mobility 328 The Red Blood Cell: An Example of Plasma Membrane Structure 331 8.7 The Movement of Substances Across Cell Membranes 333 The Energetics of Solute Movement 333 Diffusion of Substances through Membranes 335 Facilitated Diffusion 342 Active Transport 343 ?? THE HUMAN PERSPECTIVE: Defects in Ion Channels and Transporters as a Cause of Inherited Disease 348 8.8 Membrane Potentials and Nerve Impulses 350 The Resting Potential 350 The Action Potential 351 Propagation of Action Potentials as an Impulse 353 Neurotransmission: Jumping the Synaptic Cleft 354 ?? EXPERIMENTAL PATHWAYS: The Acetylcholine Receptor 357 9 Mitochondrial Structure and Function 364 9.1 Mitochondrial Structure and Function 365 Mitochondrial Membranes 366 The Mitochondrial Matrix 368 9.2 Oxidative Metabolism in the Mitochondrion 369 The Tricarboxylic Acid (TCA) Cycle 371 The Importance of Reduced Coenzymes in the Formation of ATP 372 ?? THE HUMAN PERSPECTIVE: The Role of Anaerobic and Aerobic Metabolism in Exercise 374 9.3 The Role of Mitochondria in the Formation of ATP 375 Oxidation–Reduction Potentials 375 Electron Transport 376 Types of Electron Carriers 377 9.4 Translocation of Protons and the Establishment of a Proton–Motive Force 384 9.5 The Machinery for ATP Formation 385 The Structure of ATP Synthase 386 The Basis of ATP Formation According to the Binding Change Mechanism 387 Other Roles for the Proton–Motive Force in Addition to ATP Synthesis 391 9.6 Peroxisomes 392 ?? THE HUMAN PERSPECTIVE: Diseases that Result from Abnormal Mitochondrial or Peroxisomal Function 393 10 Chloroplast Structure and Function 397 10.1 Chloroplast Structure and Function 399 10.2 An Overview of Photosynthetic Metabolism 400 10.3 The Absorption of Light 402 Photosynthetic Pigments 402 10.4 Photosynthetic Units and Reaction Centers 404 Oxygen Formation: Coordinating the Action of Two Different Photosynthetic Systems 404 Killing Weeds by Inhibiting Electron Transport 411 10.5 Photophosphorylation 411 Noncyclic Versus Cyclic Photophosphorylation 412 10.6 Carbon Dioxide Fixation and the Synthesis of Carbohydrate 412 Carbohydrate Synthesis in C3 Plants 412 Carbohydrate Synthesis in C4 Plants 417 Carbohydrate Synthesis in CAM Plants 418 11 The Extracellular Matrix and Cell Interactions 421 11.1 The Extracellular Space 422 The Extracellular Matrix 422 11.2 Interactions of Cells with Extracellular Materials 430 Integrins 430 Focal Adhesions and Hemidesmosomes: Anchoring Cells to Their Substratum 433 11.3 Interactions of Cells with Other Cells 436 Selectins 437 The Immunoglobulin Superfamily 438 Cadherins 439 ?? THE HUMAN PERSPECTIVE: The Role of Cell Adhesion in Inflammation and Metastasis 441 Adherens Junctions and Desmosomes: Anchoring Cells to Other Cells 443 The Role of Cell–Adhesion Receptors in Transmembrane Signaling 445 11.4 Tight Junctions: Sealing The Extracellular Space 446 11.5 Gap Junctions and Plasmodesmata: Mediating Intercellular Communication 448 Plasmodesmata 451 11.6 Cell Walls 452 12 Cellular Organelles and Membrane Trafficking 456 12.1 An Overview of the Endomembrane System 457 12.2 A Few Approaches to the Study of Endomembranes 459 Insights Gained from Autoradiography 459 Insights Gained from the Use of the Green Fluorescent Protein 459 Insights Gained from the Biochemical Analysis of Subcellular Fractions 461 Insights Gained from the Use of Cell–Free Systems 462 Insights Gained from the Study of Mutant Phenotypes 463 12.3 The Endoplasmic Reticulum 465 The Smooth Endoplasmic Reticulum 466 Functions of the Rough Endoplasmic Reticulum 466 From the ER to the Golgi Complex: The First Step in Vesicular Transport 475 12.4 The Golgi Complex 476 Glycosylation in the Golgi Complex 478 The Movement of Materials through the Golgi Complex 478 12.5 Types of Vesicle Transport and Their Functions 481 COPII–Coated Vesicles: Transporting Cargo from the ER to the Golgi Complex 482 COPI–Coated Vesicles: Transporting Escaped Proteins Back to the ER 484 Beyond the Golgi Complex: Sorting Proteins at the TGN 484 Targeting Vesicles to a Particular Compartment 486 12.6 Lysosomes 489 Autophagy 490 ?? THE HUMAN PERSPECTIVE: Disorders Resulting from Defects in Lysosomal Function 492 12.7 Plant Cell Vacuoles 493 12.8 The Endocytic Pathway: Moving Membrane and Materials into the Cell Interior 494 Endocytosis 494 Phagocytosis 501 12.9 Posttranslational Uptake of Proteins by Peroxisomes, Mitochondria, and Chloroplasts 502 Uptake of Proteins into Peroxisomes 502 Uptake of Proteins into Mitochondria 502 Uptake of Proteins into Chloroplasts 504 ?? EXPERIMENTAL PATHWAYS: Receptor–Mediated Endocytosis 505 13 The Cytoskeleton 510 13.1 Overview of the Major Functions of the Cytoskeleton 511 13.2 The Study of the Cytoskeleton 512 The Use of Live–Cell Fluorescence Imaging 512 The Use of In Vitro and In Vivo Single–Molecule Assays 513 The Use of Fluorescence Imaging Techniques to Monitor the Dynamics of the Cytoskeleton 515 13.3 Microtubules 516 Structure and Composition 516 Microtubule–Associated Proteins 517 Microtubules as Structural Supports and Organizers 518 Microtubules as Agents of Intracellular Motility 519 Motor Proteins that Traverse the Microtubular Cytoskeleton 520 Microtubule–Organizing Centers (MTOCs) 525 The Dynamic Properties of Microtubules 527 Cilia and Flagella: Structure and Function 531 ?? THE HUMAN PERSPECTIVE: The Role of Cilia in Development and Disease 535 13.4 Intermediate Filaments 540 Intermediate Filament Assembly and Disassembly 540 Types and Functions of Intermediate Filaments 542 13.5 Microfilaments 542 Microfilament Assembly and Disassembly 544 Myosin: The Molecular Motor of Actin Filaments 546 13.6 Muscle Contractility 550 The Sliding Filament Model of Muscle Contraction 552 13.7 Nonmuscle Motility 557 Actin–Binding Proteins 558 Examples of Nonmuscle Motility and Contractility 560 14 Cell Division 572 14.1 The Cell Cycle 573 Cell Cycles in Vivo 574 Control of the Cell Cycle 574 14.2 M Phase: Mitosis and Cytokinesis 581 Prophase 583 Prometaphase 588 Metaphase 590 Anaphase 592 Telophase 597 Motor Proteins Required for Mitotic Movements 597 Cytokinesis 597 14.3 Meiosis 602 The Stages of Meiosis 603 ?? THE HUMAN PERSPECTIVE: Meiotic Nondisjunction and Its Consequences 608 Genetic Recombination During Meiosis 610 ?? EXPERIMENTAL PATHWAYS: The Discovery and Characterization of MPF 611 15 Cell Signaling Pathways 617 15.1 The Basic Elements of Cell Signaling Systems 618 15.2 A Survey of Extracellular Messengers and Their Receptors 621 15.3 G Protein–Coupled Receptors and Their Second Messengers 621 Signal Transduction by G Protein–Coupled Receptors 622 ?? THE HUMAN PERSPECTIVE: Disorders Associated with G Protein–Coupled Receptors 625 Second Messengers 627 The Specificity of G Protein–Coupled Responses 630 Regulation of Blood Glucose Levels 631 The Role of GPCRs in Sensory Perception 634 15.4 Protein–Tyrosine Phosphorylation as a Mechanism for Signal Transduction 636 The Ras–MAP Kinase Pathway 640 Signaling by the Insulin Receptor 644 ?? THE HUMAN PERSPECTIVE: Signaling Pathways and Human Longevity 647 Signaling Pathways in Plants 648 15.5 The Role of Calcium as an Intracellular Messenger 648 Regulating Calcium Concentrations in Plant Cells 652 15.6 Convergence, Divergence, and Cross–Talk Among Different Signaling Pathways 653 Examples of Convergence, Divergence, and Cross–Talk Among Signaling Pathways 654 15.7 The Role of NO as an Intercellular Messenger 655 15.8 Apoptosis (Programmed Cell Death) 656 The Extrinsic Pathway of Apoptosis 658 The Intrinsic Pathway of Apoptosis 659 16 Cancer 664 16.1 Basic Properties of a Cancer Cell 665 16.2 The Causes of Cancer 667 16.3 The Genetics of Cancer 669 Tumor–Suppressor Genes and Oncogenes: Brakes and Accelerators 671 The Cancer Genome 683 Gene–Expression Analysis 685 16.4 New Strategies for Combating Cancer 687 Immunotherapy 688 Inhibiting the Activity of Cancer–Promoting Proteins 689 Inhibiting the Formation of New Blood Vessels (Angiogenesis) 692 ?? EXPERIMENTAL PATHWAYS: The Discovery of Oncogenes 694 17 Immunity 699 17.1 An Overview of the Immune Response 700 Innate Immune Responses 700 Adaptive Immune Responses 703 17.2 The Clonal Selection Theory as It Applies to B Cells 704 Vaccination 706 17.3 T Lymphocytes: Activation and Mechanism of Action 707 17.4 Selected Topics on the Cellular and Molecular Basis of Immunity 710 The Modular Structure of Antibodies 710 DNA Rearrangements that Produce Genes Encoding B– and T–Cell Antigen Receptors 713 Membrane–Bound Antigen Receptor Complexes 716 The Major Histocompatibility Complex 716 Distinguishing Self from Nonself 721 Lymphocytes Are Activated by Cell–Surface Signals 722 Signal Transduction Pathways in Lymphocyte Activation 723 ?? THE HUMAN PERSPECTIVE: Autoimmune Diseases 724 ?? EXPERIMENTAL PATHWAYS: The Role of the Major Histocompatibility Complex in Antigen Presentation 727 18 Methods in Cell Biology 732 18.1 The Light Microscope 733 Resolution 733 Visibility 734 Preparation of Specimens for Bright–Field Light Microscopy 735 Phase–Contrast Microscopy 735 Fluorescence Microscopy (and Related Fluorescence–Based Techniques) 736 Video Microscopy and Image Processing 738 Laser Scanning Confocal Microscopy 739 Super–Resolution Fluorescence Microscopy 740 18.2 Transmission Electron Microscopy 740 Specimen Preparation for Electron Microscopy 742 18.3 Scanning Electron and Atomic Force Microscopy 746 Atomic Force Microscopy 748 18.4 The Use of Radioisotopes 748 18.5 Cell Culture 749 18.6 The Fractionation of a Cell’s Contents by Differential Centrifugation 752 18.7 Isolation, Purification, and Fractionation of Proteins 752 Selective Precipitation 752 Liquid Column Chromatography 753 Polyacrylamide Gel Electrophoresis 756 Protein Measurement and Analysis 757 18.8 Determining the Structure of Proteins and Multisubunit Complexes 758 18.9 Fractionation of Nucleic Acids 760 Separation of DNAs by Gel Electrophoresis 760 Separation of Nucleic Acids by Ultracentrifugation 760 18.10 Nucleic Acid Hybridization 762 18.11 Chemical Synthesis of DNA 764 18.12 Recombinant DNA Technology 764 Restriction Endonucleases 764 Formation of Recombinant DNAs 766 DNA Cloning 766 18.13 Enzymatic Amplification of DNA by PCR 769 Applications of PCR 770 18.14 DNA Sequencing 771 18.15 DNA Libraries 773 Genomic Libraries 773 cDNA Libraries 774 18.16 DNA Transfer into Eukaryotic Cells and Mammalian Embryos 775 18.17 Determining Eukaryotic Gene Function by Gene Elimination or Silencing 778 In Vitro Mutagenesis 778 Knockout Mice 778 RNA Interference 780 18.18 The Use of Antibodies 780 Glossary G–1 Additional Readings A–1 Index I–1