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Karp’s Cell Biology, Global Edition continues to build on its strength at connecting key concepts to the experiments that reveal how we know what we know in the world of Cell Biology. This classic text explores core concepts in considerable depth, often adding experimental detail. It is written in an inviting style to assist students in handling the plethora of details encountered in the Cell Biology course. In this edition, two new co-authors take the helm and help to expand upon the hallmark strengths of the book, improving the student learning experience.

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Karp's CELL BIOLOGY

Karp's Cell Biology, Global Edition continues to build on its strength at connecting key concepts to the experiments that reveal how we know what we know in the world of Cell Biology. This classic text explores core concepts in considerable depth, often adding experimental detail. It is written in an inviting style to assist students in handling the plethora of details encountered in the Cell Biology course. In this edition, two new co-authors take the helm and help to expand upon the hallmark strengths of the book, improving the student learning experience.

This book is authorized for sale in Europe, Asia, Africa and the Middle East only and may not be exported. The content is materially different than products for other markets including the authorized U.S. counterpart of this title. Exportation of this book to another region without the Publisher's authorization may be illegal and a violation of the Publisher's rights. The Publisher may take legal action to enforce its rights.

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1 Introduction to Cell Biology 1


1.1 The Discovery of Cells 2


Microscopy 2


Cell Theory 3


1.2 Basic Properties of Cells 3


Cells are Highly Complex and Organized 3


Cells Possess a Genetic 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 8


1.4 Types of Prokaryotic Cells 14


Domain Archaea and Domain Bacteria 14


Prokaryotic Diversity 14


1.5 Types of Eukaryotic Cells 15


Cell Differentiation 16


Model Organisms 16


1.6 The Sizes of Cells and Their Components 18


1.7 Viruses 19


Viroids 22


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


Polar and Nonpolar Molecules 35


Ionization 36


2.2 Noncovalent Bonds 36


Ionic Bonds: Attractions between Charged Atoms 36


Hydrogen Bonds 36


Hydrophobic Interactions and van der Waals Forces 37


The Life-Supporting Properties of Water 38


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 Carbohydrates 42


The Structure of Simple Sugars 43


Stereoisomerism 43


Linking Sugars Together 44


Polysaccharides 45


2.6 Lipids 47


Fats 47


Steroids 48


Phospholipids 48


2.7 Building Blocks of Proteins 49


The Structures of Amino Acids 50


The Properties of the Side Chains 51


2.8 Primary and Secondary Structures of Proteins 54


Primary Structure 54


Secondary Structure 55


2.9 Tertiary Structure of Proteins 56


Myoglobin: The First Globular Protein Whose Tertiary Structure Was Determined 57


Tertiary Structure May Reveal Unexpected Similarities between Proteins 58


Protein Domains 58


Dynamic Changes within Proteins 59


2.10 Quaternary Structure of Proteins 60


The Structure of Hemoglobin 60


Protein-Protein Interactions 61


2.11 Protein Folding 61


Dynamics of Protein Folding 62


The Role of Molecular Chaperones 63


2.12 Proteomics and Interactomics 64


Proteomics 64


Interactomics 66


2.13 Protein Engineering 67


Production of Novel Proteins 67


Structure-Based Drug Design 68


2.14 Protein Adaptation and Evolution 69


2.15 Nucleic Acids 71


2.16 The Formation of Complex Macromolecular Structures 72


The Assembly of Tobacco Mosaic Virus Particles 73


The Assembly of Ribosomal Subunits 73


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


The First Law of Thermodynamics 88


The Second Law of Thermodynamics 89


3.2 Free Energy 90


Free?Energy Changes in Chemical Reactions 91


Free?Energy Changes in Metabolic Reactions 92


3.3 Coupling Endergonic and Exergonic Reactions 94


3.4 Equilibrium versus Steady?State Metabolism 94


3.5 Enzymes as Biological Catalysts 95


The Properties of Enzymes 96


Overcoming the Activation Energy Barrier 96


The Active Site 98


3.6 Mechanisms of Enzyme Catalysis 99


Substrate Orientation 100


Changing Substrate Reactivity 100


Inducing Strain in the Substrate 100


3.7 Enzyme Kinetics 103


The Michaelis?Menten Model of Enzyme Kinetics 103


Enzyme Inhibitors 105


3.8 Metabolism 106


Oxidation and Reduction: A Matter of Electrons 107


The Capture and Utilization of Energy 108


3.9 Glycolysis and ATP Production 108


ATP Production in Glycolysis 109


Anaerobic Oxidation of Pyruvate: The Process of Fermentation 111


3.10 Reducing Power 112


3.11 Metabolic Regulation 113


Altering Enzyme Activity by Covalent Modification 113


Altering Enzyme Activity by Allosteric Modulation 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


The Chromosome as a Linkage Group 127


4.4 Genetic Analysis in Drosophila 127


Crossing Over and Recombination 128


Mutagenesis and Giant Chromosomes 129


4.5 The Structure of DNA 129


The Watson?Crick Proposal 132


The Importance of the Watson?Crick Proposal 132


4.6 DNA Supercoiling 134


4.7 The Structure of the Genome 136


DNA Denaturation 137


DNA Renaturation 137


4.8 The Stability of the Genome 141


Whole?Genome Duplication (Polyploidization) 141


Duplication and Modification of DNA Sequences 141


Evolution of Globin Genes 142


4.9 "Jumping Genes" and the Dynamic Nature of the Genome 143


Transposons 144


The Role of Mobile Genetic Elements in Genome Evolution 144


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


DNA Sequence Variation 150


Structural Variation 151


Copy Number Variation 152


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


Evidence That DNA Is the Genetic Material 166


An Overview of the Flow of Information through the Cell 167


5.2 The Role of RNA Polymerases in Transcription 169


5.3 An Overview of Transcription in Both Prokaryotic and Eukaryotic Cells 171


Transcription in Bacteria 171


Transcription and RNA Processing in Eukaryotic Cells 172


5.4 Synthesis and Processing of Eukaryotic Ribosomal and Transfer RNAs 174


Synthesis and Processing of the rRNA Precursor 174


The Role of snoRNAs in the Processing of Pre?rRNA 176


Synthesis and Processing of the 5S rRNA 176


Transfer RNAs 177


5.5 Synthesis and Structure of Eukaryotic Messenger RNAs 178


The Formation of Heterogeneous Nuclear RNA (hnRNA) 178


The Machinery for mRNA Transcription 178


The Structure of mRNAs 181


5.6 Split Genes: An Unexpected Finding 181


5.7 The Processing of Eukaryotic Messenger RNAs 184


5'' Caps and 3'' Poly(A) Tails 185


RNA Splicing: Removal of Introns from a Pre?RNA 186


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


miRNAs: A Class of Small RNAs that Regulate Gene Expression 193


piRNAs: A Class of Small RNAs that Function in Germ Cells 194


5.12 CRISPR and other Noncoding RNAs 195


CRISPR: Noncoding RNA in Bacteria 195


Other Noncoding RNAs 195


5.13 Encoding Genetic Information 196


The Properties of the Genetic Code 196


Identifying the Codons 197


5.14 Decoding the Codons: The Role of Transfer RNAs 198


The Structure of tRNAs 198


tRNA Charging 200


5.15 Translating Genetic Information: Initiation 201


Initiation of Translation in Prokaryotes 202


Initiation of Translation in Eukaryotes 203


The Role of the Ribosome 203


5.16 Translating Genetic Information: Elongation and Termination 205


Elongation Step 1: Aminoacyl?tRNA Selection 205


Elongation Step 2: Peptide Bond Formation 205


Elongation Step 3: Translocation 205


Elongation Step 4: Releasing the Deacylated tRNA 206


Termination 207


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


Organization of Bacterial Genomes 221


The Bacterial Operon 221


Riboswitches 224


6.2 Control of Gene Expression in Eukaryotes: Structure and Function of the Cell Nucleus 225


The Nuclear Pore Complex and Its Role in Nucleocytoplasmic Trafficking 227


RNA Transport 230


6.3 Chromosomes and Chromatin 230


Nucleosomes: The Lowest Level of Chromosome Organization 230


Higher Levels of Chromatin Structure 232


6.4 Heterochromatin and Euchromatin 234


X Chromosome Inactivation 234


The Histone Code and Formation of Heterochromatin 235


6.5 The Structure of a Mitotic Chromosome 238


Telomeres 240


Centromeres 243


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


DNA Microarrays 249


RNA Sequencing 251


6.10 The Role of Transcription Factors in Regulating Gene Expression 252


The Role of Transcription Factors in Determining a Cell''s Phenotype 252


6.11 The Structure of Transcription Factors 253


Transcription Factor Motifs 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


Coactivators That Interact with the Basal Transcription Machinery 260


Coactivators That Alter Chromatin Structure 260


6.15 Transcriptional Activation from Paused Polymerases 263


6.16 Transcriptional Repression 264


DNA Methylation 264


Genomic Imprinting 265


Long Noncoding RNAs (lncRNAs) as Transcriptional Repressors 266


6.17 RNA Processing Control 267


6.18 Translational Control 269


Initiation of Translation 269


Cytoplasmic Localization of mRNAs 270


The Control of mRNA Stability 271


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


Replication Forks and Bidirectional Replication 287


Unwinding the Duplex and Separating the Strands 287


The Properties of DNA Polymerases 288


Semidiscontinuous Replication 289


7.3 The Machinery Operating at the Replication Fork 291


7.4 The Structure and Functions of DNA Polymerases 293


Exonuclease Activities of DNA Polymerases 293


Ensuring High Fidelity during DNA Replication 294


7.5 Replication in Viruses 296


7.6 DNA Replication in Eukaryotic Cells 296


Initiation of Replication in Eukaryotic Cells 297


Restricting Replication to Once Per Cell Cycle 297


The Eukaryotic Replication Fork 298


Replication and Nuclear Structure 300


7.7 Chromatin Structure and Replication 300


7.8 DNA Repair 302


Nucleotide Excision Repair 302


Base Excision Repair 303


Mismatch Repair 304


Double?Strand Breakage Repair 304


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


An Overview of Membrane Functions 312


A Brief History of Studies on Plasma Membrane Structure 313


8.2 The Chemical Composition of Membranes 315


Membrane Lipids 316


The Nature and Importance of the Lipid Bilayer 317


The Asymmetry of Membrane Lipids 319


8.3 Membrane Carbohydrates 319


8.4 The Structure and Functions of Membrane Proteins 320


Integral Membrane Proteins 321


Peripheral Membrane Proteins 322


Lipid?Anchored Membrane Proteins 322


8.5 Studying the Structure and Properties of Integral Membrane Proteins 323


Identifying Transmembrane Domains 324


Experimental Approaches to Identifying Conformational Changes within an Integral Membrane Protein 325


8.6 Membrane Lipids and Membrane Fluidity 327


The Importance of Membrane Fluidity 328


Maintaining Membrane Fluidity 328


Lipid Rafts 329


8.7 The Dynamic Nature of the Plasma Membrane 329


The Diffusion of Membrane Proteins after Cell Fusion 330


Restrictions on Protein and Lipid Mobility 331


8.8 The Red Blood Cell: An Example of Plasma Membrane Structure 334


Integral Proteins of the Erythrocyte Membrane 334


The Erythrocyte Membrane Skeleton 336


8.9 The Movement of Substances across Cell Membranes 336


The Energetics of Solute Movement 336


Formation of an Electrochemical Gradient 337


8.10 Diffusion through the Lipid Bilayer 338


Diffusion of Substances through Membranes 338


The Diffusion of Water through Membranes 338


8.11 The Diffusion of Ions through Membranes 340


8.12 Facilitated Diffusion 345


8.13 Active Transport 346


Primary Active Transport: Coupling Transport to ATP Hydrolysis 346


Other Primary Ion Transport Systems 347


Using Light Energy to Actively Transport Ions 348


Secondary Active Transport (or Cotransport): Coupling Transport to Existing Ion Gradients 348


8.14 Membrane Potentials 350


The Resting Potential 350


The Action Potential 352


8.15 Propagation of Action Potentials as an Impulse 353


8.16 Neurotransmission: Jumping the Synaptic Cleft 354


Actions of Drugs on Synapses 356


Synaptic Plasticity 357


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


Mitochondrial Membranes 370


The Mitochondrial Matrix 372


9.2 Oxidative Metabolism in the Mitochondrion 372


The Tricarboxylic Acid (TCA) Cycle 373


The Importance of Reduced Coenzymes in the Formation of ATP 375


9.3 The Role of Mitochondria in the Formation of ATP 377


Oxidation-Reduction Potentials 377


Electron Transport 379


Types of Electron Carriers 379


9.4 Electron?Transport Complexes 381


Complex I (NADH dehydrogenase) 383


Complex II (succinate dehydrogenase) 384


Complex III (cytochrome bc1) 384


Complex IV (cytochrome c oxidase) 384


9.5 Translocation of Protons and the Establishment of a Proton? Motive Force 385


9.6 The Machinery for ATP Formation 386


The Structure of ATP Synthase 387


9.7 The Binding Change Mechanism of ATP Formation 388


Components of the Binding Change Hypothesis 388


Evidence to Support the Binding Change Mechanism and Rotary Catalysis 389


9.8 Using the Proton Gradient 391


The Role of the Fo Portion of ATP Synthase in ATP Synthesis 391


Other Roles for the Proton?Motive Force in Addition to ATP Synthesis 392


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


Photosynthetic Pigments 406


10.5 Photosynthetic Units and Reaction Centers 407


Oxygen Formation: Coordinating the Action of Two Different Photosynthetic Systems 408


10.6 The Operations of Photosystem II and Photosystem I 409


PSII Operations: Obtaining Electrons by Splitting Water 409


PSI Operations: The Production of NADPH 412


10.7 An Overview of Photosynthetic Electron Transport 413


Killing Weeds by Inhibiting Electron Transport 414


10.8 Photophosphorylation 415


Noncyclic Versus Cyclic Photophosphorylation 415


10.9 Carbon Dioxide Fixation and the Carbohydrate Synthesis 415


Carbohydrate Synthesis in C3 Plants 416


Redox Control 416


Photorespiration 417


Peroxisomes and Photorespiration 418


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


The Extracellular Matrix 428


11.3 Components of the Extracellular Matrix 430


Collagen 430


Proteoglycans 432


Fibronectin 433


Laminin 433


11.4 Dynamic Properties of the Extracellular Matrix 435


11.5 Interactions of Cells with Extracellular Materials 436


Integrins 436


11.6 Anchoring Cells to Their Substratum 438


Focal Adhesions 438


Hemidesmosomes 440


11.7 Interactions of Cells with Other Cells 441


Selectins 441


The Immunoglobulin Superfamily 442


Cadherins 443


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


Gap Junctions 449


Plasmodesmata 451


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


Insights Gained from Autoradiography 466


Insights Gained from the Use of the Green Fluorescent Protein 467


Insights Gained from the Analysis of Subcellular Fractions 468


Insights Gained from the Use of Cell?Free Systems 469


Insights Gained from the Study of Mutant Phenotypes 470


12.3 The Endoplasmic Reticulum 472


The Smooth Endoplasmic Reticulum 473


The Rough Endoplasmic Reticulum 473


12.4 Functions of the Rough Endoplasmic Reticulum 473


Synthesis of Proteins on Membrane?Bound versus Free Ribosomes 473


Synthesis of Secretory, Lysosomal, or Plant Vacuolar Proteins 475


Processing of Newly Synthesized Proteins in the Endoplasmic Reticulum 476


Synthesis of Integral Membrane Proteins on ER?Bound Ribosomes 476


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


Glycosylation in the Golgi Complex 484


The Movement of Materials through the Golgi Complex 485


12.10 Types of Vesicle Transport and Their Functions 487


COPII?Coated Vesicles: Transporting Cargo from the ER to the Golgi Complex 488


COPI?Coated Vesicles: Transporting Escaped Proteins Back to the ER 489


12.11 Beyond the Golgi Complex: Sorting Proteins at the TGN 491


Sorting and Transport of Lysosomal Enzymes 491


Sorting and Transport of Nonlysosomal Proteins 493


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


Receptor?Mediated Endocytosis and the Role of Coated Pits 499


The Role of Phosphoinositides in the Regulation of Coated Vesicles 501


12.17 The Endocytic Pathway 502


12.18 Phagocytosis 505


12.19 Posttranslational Uptake of Proteins by Peroxisomes, Mitochondria, and Chloroplasts 505


Uptake of Proteins into Peroxisomes 506


Uptake of Proteins into Mitochondria 506


Uptake of Proteins into Chloroplasts 507


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


Structure and Composition of Microtubules 520


Microtubule?Associated Proteins 521


Microtubules as Structural Supports and Organizers 521


Microtubules as Agents of Intracellular Motility 522


13.3 Motor Proteins: Kinesins and Dyneins 524


Motor Proteins Traverse the Microtubular Cytoskeleton 524


Kinesins 524


Cytoplasmic Dynein 526


13.4 Microtubule?Organizing Centers (MTOCs) 527


Centrosomes 528


Basal Bodies and Other MTOCs 530


Microtubule Nucleation 530


13.5 Microtubule Dynamics 530


The Dynamic Properties of Microtubules 530


The Underlying Basis of Microtubule Dynamics 532


13.6 Cilia and Flagella: Structure and Function 534


Structure of Cilia and Flagella 535


Growth by Intraflagellar Transport 537


The Mechanism of Ciliary and Flagellar Locomotion 539


13.7 Intermediate Filaments 541


Intermediate Filament Assembly and Disassembly 541


Types and Functions of Intermediate Filaments 543


13.8 Microfilaments 544


Microfilament Structure 544


Microfilament Assembly and Disassembly 545


13.9 Myosin: The Molecular Motor of Actin Filaments 547


Conventional (Type II) Myosins 547


Unconventional Myosins 548


13.10 Muscle Contractility 552


Organization of Sarcomeres 552


The Sliding Filament Model of Muscle Contraction 553


13.11 Nonmuscle Motility 557


Actin-Binding Proteins 558


13.12 Cellular Motility 560


13.13 Actin?Dependent Processes During Development 564


Axonal Outgrowth 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


Phases of the Cell Cycle 579


Cell Cycles in Vivo 580


14.2 Regulation of the Cell Cycle 581


14.3 Control of the Cell Cycle: The Role of Protein Kinases 582


Cyclin Binding 583


Cdk Phosphorylation/Dephosphorylation 583


Cdk Inhibitors 584


Controlled Proteolysis 584


Subcellular Localization 584


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


Formation of the Mitotic Chromosome 588


Centromeres and Kinetochores 590


Formation of the Mitotic Spindle 591


The Dissolution of the Nuclear Envelope and Partitioning of Cytoplasmic Organelles 594


14.7 Prometaphase 594


14.8 Metaphase 596


14.9 Anaphase 598


The Role of Proteolysis in Progression through Mitosis 598


The Events of Anaphase 600


Forces Required for Chromosome Movements at Anaphase 601


The Spindle Assembly Checkpoint 602


14.10 Telophase and Cytokinesis 603


Motor Proteins Required for Mitotic Movements 603


Cytokinesis 603


Cytokinesis in Plant Cells: Formation of the Cell Plate 607


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


Receptors 629


G Proteins 630


Termination of the Response 631


Bacterial Toxins 632


15.4 Second Messengers 632


The Discovery of Cyclic AMP 633


Phosphatidylinositol?Derived Second Messengers 633


Phospholipase C 635


15.5 The Specificity of G Protein?Coupled Responses 636


15.6 Regulation of Blood Glucose Levels 636


Glucose Mobilization: An Example of a Response Induced by cAMP 637


Signal Amplification 638


Other Aspects of cAMP Signal Transduction Pathways 638


15.7 The Role of GPCRs in Sensory Perception 640


15.8 Protein?Tyrosine Phosphorylation as a Mechanism for Signal Transduction 641


Receptor Dimerization 641


Protein Kinase Activation 643


Phosphotyrosine?Dependent Protein-Protein Interactions 643


Activation of Downstream Signaling Pathways 643


Ending the Response 645


15.9 The Ras?MAP Kinase Pathway 645


Accessory Proteins 645


Adapting the MAP Kinase to Transmit Different Types of Information 647


15.10 Signaling by the Insulin Receptor 648


The Insulin Receptor Is a Protein?Tyrosine Kinase 648


Insulin Receptor Substrates 1 and 2 649


Glucose Transport 650


Diabetes Mellitus 650


15.11 Signaling Pathways in Plants 651


15.12 The Role of Calcium as an Intracellular Messenger 651


IP3 and Voltage?Gated Ca2+ Channels 651


Visualizing Cytoplasmic Ca2+ Concentration in Living Cells 651


Ca2+?Binding Proteins 654


Regulating Calcium Concentrations in Plant Cells 654


15.13 Convergence, Divergence, and Cross?Talk among Different Signaling Pathways 655


15.14 The Role of NO as an Intercellular Messenger 657


NO as an Activator of Guanylyl Cyclase 658


Inhibiting Phosphodiesterase 658


15.15 Apoptosis (Programmed Cell Death) 659


The Extrinsic Pathway of Apoptosis 660


The Intrinsic Pathway of Apoptosis 661


Necroptosis 662


Signaling Cell Survival 663


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


The Role of p53: Guardian of the Genome 684


The Role of p53 in Promoting Senescence 686


16.7 Other Tumor?Suppressor Genes 687


16.8 Oncogenes 688


Oncogenes That Encode Growth Factors or Their Receptors 688


Oncogenes That Encode Cytoplasmic Protein Kinases 689


Oncogenes That Encode Transcription Factors 689


Oncogenes That Encode Proteins That Affect the Epigenetic State of Chromatin 689


Oncogenes That Encode Metabolic Enzymes 690


Oncogenes That Encode Products That Affect Apoptosis 690


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


Innate Immune Responses 711


Adaptive Immune Responses 713


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


Activation of Helper T Cells by Professional APCs 731


Activation of B Cells by TH Cells 732


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


Resolution 744


Visibility 745


18.2 Bright?Field and Phase?Contrast Microscopy 745


Bright?Field Light Microscopy 745


Phase?Contrast Microscopy 746


18.3 Fluorescence Microscopy (and Related Fluorescence?Based Techniques) 746


Laser Scanning Confocal Microscopy 749


Super?Resolution Fluorescence Microscopy 750


Light Sheet Fluorescence Microscopy 751


18.4 Transmission Electron Microscopy 752


18.5 Specimen Preparation for Electron Microscopy 753


Cryofixation and the Use of Frozen Specimens 754


Negative Staining 755


Shadow Casting 755


Freeze?Fracture Replication and Freeze Etching 756


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


Ion?Exchange Chromatography 763


Gel Filtration Chromatography 763


Affinity Chromatography 764


18.12 Determining Protein-Protein Interactions 764


18.13 Characterization of Proteins by


Polyacrylamide Gel Electrophoresis 766


SDS-PAGE 767


Two?Dimensional Gel Electrophoresis 767


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


Separation of DNAs by Gel Electrophoresis 770


Separation of Nucleic Acids by Ultracentrifugation 771


18.18 Nucleic Acid Hybridization 773


18.19 Chemical Synthesis of DNA 774


18.20 Recombinant DNA Technology 774


Restriction Endonucleases 774


Formation of Recombinant DNAs 775


DNA Cloning 776


18.21 Enzymatic Amplification of DNA by PCR 778


Process of PCR 778


Applications of PCR 778


18.22 DNA Sequencing 780


18.23 DNA Libraries 782


Genomic Libraries 782


cDNA Libraries 783


18.24 DNA Transfer into Eukaryotic Cells and Mammalian Embryos 783


Transgenic Animals 785


Transgenic Plants 785


18.25 Gene Editing and Silencing 786


In Vitro Mutagenesis 786


Knockout Mice 787


RNA Interference 788


Genome Editing Using Engineered Nucleases 789


18.26 The Use of Antibodies 789


Glossary G-1


Additional Reading A-1


Index I-1