THE CELL

Fifth Edition

GEOFFREY M. COOPER ROBERT E. HAUSMAN

Boston University

ASM PRESS
Washington, D.C.

SINAUER ASSOCIATES, INC.

Sunderland, Massachusetts

Brief Contents
PARTI

Introduction 1

Chapter 1
Chapter 2
Chapter 3
Chapter 4

An Overview of Cells and Cell Research 3

The Composition of Cells 43
Cell Metabolism 73
Fundamentals of Molecular Biology 103

PART II

The Flow of Genetic Information 153

Chapter 5
Chapter 6
Chapter 7
Chapter 8

The Organization and Sequences of Cellular Genomes 155

Replication, Maintenance, and Rearrangements of Genomic DNA 201
RNA Synthesis and Processing 251
Protein Synthesis, Processing, and Regulation 309

PART III

Cell Structure and Function 353

Chapter 9
Chapter 10

The Nucleus 355

Protein Sorting and Transport:
The Endoplasmic Reticulum, Golgi Apparatus, and Lysosomes 383
Bioenergetics and Metabolism:
Mitochondria, Chloroplasts, and Peroxisomes 433
The Cytoskeleton and Cell Movement 473
The Plasma Membrane 529
Cell Walls, the Extracellular Matrix, and Cell Interactions 571

Chapter 11
Chapter 12
Chapter 13
Chapter 14

PART IV Cell Regulation 601

Chapter 15
Chapter 16
Chapter 17
Chapter 18

Cell Signaling 603

The Cell Cycle 653
Cell Death and Cell Renewal 693
Cancer 725

Contents
Preface xiii
Organization and Features of The Cell xv
Media and Supplements to Accompany The Cell xvii

PART I

An Overview of Cells
and Cell Research 3

The Origin and Evolution

of Cells 4
The First Cell 4
The Evolution of Metabolism 6
Present-Day Prokaryotes 8

Eukaryotic Cells 8
The Origin of Eukaryotes 9
The Development of Multicellular
Organisms 12

INTRODUCTION

Summary and Key Terms 39

Questions 41

References and Further Reading 42

The Composition
of Cells 43

The Molecules
of Cells 43
Carbohydrates 44

Cell Metabolism 73

The Central Role of Enzymes as

Biological Catalysts 73
The Catalytic Activity of Enzymes 73
Mechanisms of Enzymatic Catalysis 74
Coenzymes 76
Regulation of Enzyme Activity 79

Metabolic Energy 81

Lipids 46

Free Energy and ATP 81

Nucleic Acids 49
Proteins 52

The Generation of ATP from

Glucose 84

f. co// 16

Cell Membranes 58

The Derivation of Energy from Other

Organic Molecules 89

Yeasts 17

Membrane Lipids 58

Photosynthesis 89

Caenorhabditis elegans 18

Membrane Proteins 60

Drosophila melanogaster 18

Transport across Cell Membranes 63

The Biosynthesis of Cell

Constituents 91

Arabidopsis thaliana 19

Proteomics: Large-Scale
Analysis of Cell Proteins 64

Carbohydrates 92

Tools of Cell Biology 21

Identification of Cell Proteins 65

Proteins 94

Light Microscopy 21

Global Analysis of Protein

Localization 67

Nucleic Acids 96

Cells as Experimental
Models 16

Vertebrates 19

Electron Microscopy 28
Subcellular Fractionation 30
Growth of Animal Cells in Culture 33

Protein Interactions 68
KEY EXPERIMENT
The Folding of Polypeptide Chains 54

Culture of Plant Cells 36

Viruses 37
KEY EXPERIMENT
Animal Cell Culture 34
MOLECULAR MEDICINE
Viruses and Cancer 37

KEY EXPERIMENT
The Structure of Cell Membranes 60

Lipids 93

MOLECULAR MEDICINE
Phenylketonuria 97
KEY EXPERIMENT
Antimetabolites and Chemotherapy 98
Summary and Key Terms 99
Questions 100

Summary and Key Terms 70

Questions 71

References and Further Reading 71

References and Further Reading 101

CONTENTS

Fundamentals
of Molecular
Biology 103

Heredity, Genes,
and DNA 103
Genes and Chromosomes 104
Genes and Enzymes 105
Identification of DNA as the Genetic
Material 107

The Genetic Code 113

RNA Viruses and Reverse
Transcription 115

Recombinant DNA 118

Restriction Endonucleases 118
Generation of Recombinant DNA
"Molecules V20
Vectors for Recombinant DNA 121
DNA Sequencing 124
Expression of Cloned Genes 124

The Structure of DNA 108

Replication of DNA 109

Detection of Nucleic Acids

and Proteins 127

Expression of Genetic
Information 110

Amplification of DNA by the Polymerase

Chain Reaction 128

Colinearity of Genes and Proteins 111

Nucleic Acid Hybridization 130

The Role of Messenger RNA 112

Antibodies as Probes for Proteins 133

VII

Gene Function in
Eukaryotes 136
Genetic Analysis in Yeasts 136
Gene Transfer in Plants and
Animals 137
Mutagenesis of Cloned DNAs 140
Introducing Mutations into Cellular
Genes 141
Interfering with Cellular Gene
Expression 143
KEY EXPERIMENT
The DNA Provirus Hypothesis 116
KEY EXPERIMENT
RNA Interference 146
Summary and Key Terms 148
Questions ISO
References and Further Reading ISO

PART II THE FLOW OF GENETIC INFORMATION

The Organization
and Sequences
of Cellular
Genomes 155

The Complexity of Eukaryotic

Genomes 155
Intronsand Exons 157
Repetitive DNA Sequences 161
Gene Duplication and
Pseudogenes 164
The Composition of Higher Eukaryotic
Genomes 165

Chromosomes and
Chromatin 166
Chromatin 166
Centromeres 170
Telomeres 174

The Sequences of Complete

Genomes 176

KEY EXPERIMENT
The Human Genome 186

Prokaryotic Genomes 177

Summary and Key Terms 195

The Yeast Genome 178

Questions 198

The Genomes of Caenorhabditis

elegans, Drosophila melanogaster
and Other Invertebrates 180

References and Further Reading 198

Plant Genomes 182

The Human Genome 184
The Genomes of Other Vertebrates 188

Bioinformatics and Systems

Biology 191
Systematic Screens of Gene Function
191

Replication,
Maintenance, and
Rearrangements of
Genomic DNA 201

DNA Replication 201

DNA Polymerases 202

Regulation of Gene Expression 192

The Replication Fork 203

Variation among Individuals and

Genomic Medicine 194

The Fidelity of Replication 210

KEY EXPERIMENT
The Discovery of Introns 158

Origins and the Initiation

of Replication 211
Telomeres and Telomerase: Maintaining
the Ends of Chromosomes 214

VIM

CONTENTS

Excision Repair 219

Eukaryotic RNA Polymerases

and General Transcription
Factors 258

Translesion DNA Synthesis 224

Eukaryotic RNA Polymerases 259

Repair of Double-Strand Breaks 226

General Transcription Factors and

Initiation of Transcription by RNA
Polymerase II 259

DNA Repair 216

Direct Reversal of DNA Damage 216

Recombination between
Homologous DNA
Sequences 227
Models of Homologous
Recombination 228
Enzymes Involved in Homologous
Recombination 229

Transcription by RNA Polymerases I

and III 263

Regulation of Transcription
in Eukaryotes 265
c/5-Acting Regulatory Sequences:
Promoters and Enhancers 265

DNA Rearrangements 233

Transcription Factor Binding Sites 269

Site-Specific Recombination 234

Transcriptional Regulatory Proteins 270

Transposition via DNA

Intermediates 240

Structure and Function of

Transcriptional Activators 273

Transposition via RNAIntermediates 242

Eukaryotic Repressors 276

Gene Amplification 245

Relationship of Chromatin Structure to

Transcription 278

MOLECULAR MEDICINE
Colon Cancer and DNA Repair 225

KEY EXPERIMENT
Rearrangement of Immunoglobulin
Genes 236

Summary and Key Terms 247

Questions 249
References and Further Reading 249

Regulation of Elongation 278

Regulation of Transcription by
Noncoding RNAs 285
DNA Methylation 286

RNA Processing and

Turnover 287
Processing of Ribosomal and Transfer
RNAs 288
Processing of mRNA in Eukaryotes 290

RNA Synthesis and

Processing 251

Transcription in
Prokaryotes 251
RNA Polymerase and Transcription 252
Repressors and Negative Control of
Transcription 256
Positive Control of Transcription 258

Splicing Mechanisms 293

Alternative Splicing 298

Protein Synthesis,
Processing, and
Regulation 309

Translation of mRNA

309

Transfer RNAs 310

TheRibosome 311
The Organization of mRNAs and the
Initiation of Translation 317
The Process of Translation 318
Regulation of Translation 323

Protein Folding and

Processing 329
Chaperones and Protein Folding 330
Enzymes that Catalyze Protein
Folding 332
Protein Cleavage 333
Glycosylation 335
Attachment of Lipids 337

Regulation of Protein
Function 340
Regulation by Small Molecules 340
Protein Phosphorylation 341
Protein-Protein Interactions 343

Protein Degradation 345

The Ubiquitin-Proteasome
Pathway 345
Lysosomal Proteolysis 348
KEY EXPERIMENT
Catalytic Role of Ribosomal RNA 316

RNA Editing 300

RNA Degradation 301
KEY EXPERIMENT
Isolation of a Eukaryotic Transcription
Factor 272

KEY EXPERIMENT
The Discovery of Protein-Tyrosine
Kinases 344

Summary and Key Terms 349

Questions 351

KEY EXPERIMENT
The Discovery of snRNPs 294

Summary and Key Terms 303

Questions 305
References and Further Reading 306

References and Further Reading 351

CONTENTS

IX

PART III CELL STRUCTURE AND FUNCTION

The Nucleus 355

The Nuclear Envelope and

Traffic between the Nucleus
and the Cytoplasm 355
Structure of the Nuclear Envelope 356
The Nuclear Pore Complex 360
Selective Transport of Proteins to and
from the Nucleus 361
Regulation of Nuclear Protein
Import 367
Transport of RNAs 368

Internal Organization of
the Nucleus 369
Chromosomes and Higher-Order
Chromatin Structure 370
Sub-Compartments within the
Nucleus 372

The Nucleolus and rRNA

Processing 374
Ribosomal RNA Genes and the
Organization of the Nucleolus 375
Transcription and Processing
of rRNA 376
Ribosome Assembly 378
MOLECULAR MEDICINE

11 Protein Sorting
V and Transport:

The Endoplasmic Reticulum,

Golgi Apparatus, and
Lysosomes 383
The Endoplasmic
Reticulum 383
The Endoplasmic Reticulum and Protein
Secretion 384
Targeting Proteins to the Endoplasmic
Reticulum 386
Insertion of Proteins into the ER
Membrane 391
Protein Folding and Processing
in the ER 396
Quality Control in the ER 398
The Smooth ER and Lipid Synthesis 402
Export of Proteins and Lipids from
the ER 405

The Golgi Apparatus 408

Summary and Key Terms 379

Phagocytosis and Autophagy 426

KEY EXPERIMENT
The Signal Hypothesis 388

MOLECULAR MEDICINE
Caucher Disease 425

Summary and Key Terms 429

Questions 431
References and Further Reading 431

1 Bioenergetics and
I Metabolism:

Mitochondria, Chloroplasts,
and Peroxisomes 433
Mitochondria 433
Organization and Function of
Mitochondria 434
The Genetic System of Mitochondria 435

Organization of the Golgi 408

Protein Import and Mitochondrial

Assembly 437

Protein Glycosylation within

the Golgi 410

The Mechanism of Oxidative

Phosphorylation 445

Lipid and Polysaccharide Metabolism

in the Golgi 412

The Electron Transport Chain 445

Protein Sorting and Export from the

Golgi Apparatus 413

Nuclear Lamina Diseases 358

KEY EXPERIMENT
Identification of Nuclear Localization
Signals 362

Endocytosis and Lysosome Formation 426

The Mechanism of Vesicular

Transport 416
Experimental Approaches to Understanding Vesicular Transport 416

Chemiosmotic Coupling 446

Transport of Metabolites across the
Inner Membrane 450

Chloroplasts and Other

Plastids 452
The Structure and Function
of Chloroplasts 452

Questions 381

Cargo Selection, Coat Proteins, and

Vesicle Budding 418

References and Further Reading 381

Vesicle Fusion 420

Import and Sorting of Chloroplast

Proteins 455

Lysosomes 423

Other Plastids 457

Lysosomal Acid Hydrolases 423

The Chloroplast Genome 454

CONTENTS

Photosynthesis 459
Electron Flow through Photosystems I
and II 460

Functions of Keratins and

Neurofilaments: Diseases of the Skin
and Nervous System 501

Cyclic Electron Flow 463

Microtubules 504

ATP Synthesis 464

Structure and Dynamic Organization

of Microtubules 504

Peroxisomes 464
Functions of Peroxisomes 465

Assembly of Microtubules 507

Peroxisome Assembly 467

Organization of Microtubules within

Cells 509

MOLECULAR MEDICINE
Diseases of Mitochondria: Leber's
Hereditary Optic Neuropathy 438

Microtubule Motors and

Movement 511

KEY EXPERIMENT
The Chemiosmotic Theory 448

Identification of Microtubule Motor

Proteins 511

Summary and Key Terms 469

Cargo Transport and Intracellular

Organization 515

Questions 471

Cilia and Flagella 516

References and Further Reading 471

Reorganization of Microtubules
during Mitosis 519
Chromosome Movement 520

12

The Cytoskeleton
and Cell
Movement 473

Structure and Organization of

Actin Filaments 473

Assembly and Disassembly of Actin

Filaments 474
Organization of Actin Filaments 479
Association of Actin Filaments with the
Plasma Membrane 481
Protrusions of the Cell Surface 485

Actin, Myosin, and Cell

Movement 487
Muscle Contraction 487

KEY EXPERIMENT
Expression of Mutant Keratin Causes
Abnormal Skin Development 502

Active Transport Driven by Ion

Gradients 555

Endocytosis 557
Phagocytosis 557
Receptor-Mediated Endocytosis 558
Protein Trafficking in Endocytosis 563
MOLECULAR MEDICINE
Cystic Fibrosis 554
KEY EXPERIMENT
The LDL Receptor 560
Summary and Key Terms 567
Questions 568
References and Further Reading 568

Cell Walls, the

Extracellular
Matrix, and Cell
Interactions 571

14

Cell Walls 571

KEY EXPERIMENT
The Isolation of Kinesin 512

Bacterial Cell Walls 571

Summary and Key Terms 522

Questions 525

The Extracellular Matrix and

Cell-Matrix Interactions 577

References and Further Reading 525

Matrix Structural Proteins 578

13

Eukaryotic Cell Walls 572

Matrix Polysaccharides 581

The Plasma
Membrane 529

Structure of the Plasma

Membrane 529

Matrix Adhesion Proteins 582

Cell-Matrix Interactions 583

Cell-Cell Interactions 587

Adhesion junctions 587
Tight Junctions 590

Contractile Assemblies of Actin and

Myosin in Nonmuscle Cells 492

The Phospholipid Bilayer 529

Nonmuscle Myosins 493

Mobility of Membrane Proteins 538

Formation of Protrusions and Cell

Movement 494

The Glycocalyx 540

KEY EXPERIMENT
The Characterization of Integrins 584

Intermediate Filaments 496

Transport of Small
Molecules 540

MOLECULAR MEDICINE
Gap Junction Diseases 594

Intermediate Filament Proteins 496

Passive Diffusion 541

Summary and Key Terms 596

Assembly of Intermediate Filaments 498

Facilitated Diffusion and Carrier

Proteins 542

Questions 598

Intracellular Organization of
Intermediate Filaments 499

Membrane Proteins 533

Ion Channels 544

Active Transport Driven by ATP
Hydrolysis 551

Gap Junctions 591

Plasmodesmata 595

References and Further Reading 598

CONTENTS

XI

PART IV CELL REGULATION

k Cell Signaling
J 603

Signaling Molecules and

Their Receptors 603
Modes of Cell-Cell Signaling 604
Steroid Hormones and the Nuclear
Receptor Superfamily 605
Nitric Oxide and Carbon
Monoxide 607
Neurotransmitters 608
Peptide Hormones and Growth
Factors 609
Eicosanoids 610
Plant Hormones 612

Functions of Cell Surface

Receptors 613

Growth Factors and the Regulation

of G, Cdk's 667

Signal Transduction and

the Cytoskeleton 641
Integrins and Signal Transduction 641

DNA Damage Checkpoints 670

Regulation of the Actin

Cytoskeleton 642

The Events of M Phase 672

Signaling Networks 644

Cdk1 /Cyclin B and Progression to

Metaphase 675

Stages of Mitosis 672

Feedback and Crosstalk 644

The Spindle Assembly Checkpoint and

Progression to Anaphase 678

Networks of Cellular Signal

Transduction 646
KEY EXPERIMENT
C Protein-Coupled Receptors and Odor
Detection 616
MOLECULAR MEDICINE
Cancer: Signal Transduction and the
rasOncogenes 633

Cytokinesis 680

Meiosis and Fertilization 681

The Process of Meiosis 681
Regulation of Oocyte Meiosis 684
Fertilization 687
KEY EXPERIMENT
The Discovery of MPF 660

Summary and Key Terms 647

Questions 650

G Protein-Coupled Receptors 613

KEY EXPERIMENT
The Identification of Cyclin 663

Receptor Protein-Tyrosine Kinases 615

Summary and Key Terms 688

Cytokine Receptors and Nonreceptor

Protein-Tyrosine Kinases 620
Receptors Linked to Other Enzymatic
Activities 620

Pathways of Intracellular
Signal Transduction 621
The cAMP Pathway: Second Messengers
and Protein Phosphorylation 622
Cyclic GMP 624
Phospholipids and Ca2+ 625
The PI 3-Kinase/Akt and mTOR
Pathways 628
MAP Kinase Pathways 630
The JAK/STAT and TGF-/3/Smad
Pathways 636

References and Further Reading

16

650

Questions 690

The Cell
Cycle 653

The Eukaryotic Cell

Cycle 653
Phases of the Cell Cycle 654
Regulation of the Cell Cycle by Cell
Growth and Extracellular Signals 655

References and Further Reading 691

17

Cell Death and

Cell Renewal 693

Programmed Cell Death 693

Cell Cycle Checkpoints 657

The Events of Apoptosis 694

Restricting DNA Replication to Once

per Cell Cycle 659

Caspases: The Executioners

of Apoptosis 697

Regulators of Cell Cycle

Progression 659

NF-JCB Signaling 637

Protein Kinases and Cell Cycle

Regulation 659

The Hedgehog, Wnt, and Notch

Pathways 638

Families of Cyclins and CyclinDependent Kinases 664

Central Regulators of Apoptosis:

The Bcl-2 Family 699
Signaling Pathways that Regulate
Apoptosis 701
Alternative Pathways of Programmed
Cell Death 705

XII

CONTENTS

Stem Cells and the

Maintenance of Adult
Tissues 705
Proliferation of Differentiated Cells 706
Stem Cells 708
Medical Applications of Adult
Stem Cells 713

Induced Pluripotent Stem Cells

Functions of Tumor Suppressor Gene

Products 756

Types of Cancer 725

Roles of Oncogenes and Tumor

Suppressor Genes in Tumor
Development 759

Properties of Cancer Cells 730

718
719

KEY EXPERIMENT
Identification of Genes Required for
Programmed Cell Death 696

KEY EXPERIMENT
Culture of Embryonic Stem Cells 715

Summary and Key Terms 720

Questions 722
References and Further Reading 722

Identification of Tumor Suppressor

Genes 752

The Development and Causes

of Cancer 725

Causes of Cancer 729

716

Somatic Cell Nuclear Transfer

Cancer 725

The Development of Cancer 727

Embryonic Stem Cells and

Therapeutic Cloning 714
Embryonic Stem Cells

18

Tumor Suppressor
Genes 752

Transformation of Cells in Culture 734

Tumor Viruses 735

Hepatitis B and C Viruses 735
SV40 and Polyomavirus 736
Papillomaviruses 737

Molecular Approaches to
Cancer Treatment 761
Prevention and Early Detection 761
Molecular Diagnosis 762
Treatment 763
KEY EXPERIMENT
The Discovery of Proto-Oncogenes 742

Adenoviruses 737
Herpesviruses 738
Retroviruses 738

MOLECULAR MEDICINE
Imatinib: Cancer Treatment Targeted
against the bcr/abl Oncogene 766

Oncogenes 739

Summary and Key Terms 767

Retroviral Oncogenes 739

Questions 769

Proto-Oncogenes 740

References and Further Reading 770

Oncogenes in Human Cancer 743

Functions of Oncogene Products 747

Answers to Questions 773

Glossary 783
Index 799