THE CELL

A Molecular Approach
Sixth Edition
Geoffrey M. Cooper Robert E. Hausman
Boston University
Sinauer Associates, Inc. Publishers
Sunderland, Massachusetts U.S.A.
2013 Sinauer Associates, Inc. This material cannot be copied, reproduced, manufactured
or disseminated in any form without express written permission from the publisher.
Brief Contents
PART I
Introduction 1
Chapter 1 An Overview of Cells
and Cell Research 3
Chapter 2 The Composition of Cells 43
Chapter 3 Cell Metabolism 73
Chapter 4 Fundamentals of
Molecular Biology 103
PART II
The Flow of Genetic
Information 151
Chapter 5 The Organization and Sequences
of Cellular Genomes 153
Chapter 6 Replication, Maintenance, and
Rearrangements of Genomic
DNA 191
Chapter 7 RNA Synthesis and
Processing 239
Chapter 8 Protein Synthesis,
Processing, and Regulation 297
PART III
Cell Structure and Function 343
Chapter 9 The Nucleus 345
Chapter 10 Protein Sorting and
Transport 373
Chapter 11 Bioenergetics and
Metabolism 421
Chapter 12 The Cytoskeleton and
Cell Movement 459
Chapter 13 The Plasma Membrane 515
Chapter 14 Cell Walls, the Extracellular
Matrix, and Cell
Interactions 557
PART IV
Cell Regulation 587
Chapter 15 Cell Signaling 589
Chapter 16 The Cell Cycle 641
Chapter 17 Cell Death and Cell
Renewal 681
Chapter 18 Cancer 713
2013 Sinauer Associates, Inc. This material cannot be copied, reproduced, manufactured
or disseminated in any form without express written permission from the publisher.
Contents
Preface xix
Organization and Features of The Cell xxi
Media and Supplements to Accompany The Cell xxiii
Part I Introduction 1
CHAPTER 1
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 9
The origin of eukaryotes 10
The development of multicellular organisms 13
Cells as Experimental Models 17
E. coli 17
Yeasts 18
Caenorhabditis elegans 18
Drosophila melanogaster 19
Arabidopsis thaliana 19
Vertebrates 20
Tools of Cell Biology 22
Light microscopy 22
Electron microscopy 28
Subcellular fractionation 31
Growth of animal cells in culture 32
Culture of plant cells 36
Viruses 36
KEY EXPERIMENT
Animal Cell Culture 34
MOLECULAR MEDICINE
Viruses and Cancer 37
Summary and Key Terms 39
Questions 40
References and Further Reading 41
CHAPTER 2
The Composition of
Cells 43
The Molecules of Cells 43
Carbohydrates 44
Lipids 46
Nucleic acids 49
Proteins 52
Cell Membranes 58
Membrane lipids 58
Membrane proteins 59
Transport across cell membranes 62
Proteomics: Large-Scale Analysis of Cell
Proteins 65
Identification of cell proteins 65
Global analysis of protein localization 67
Protein interactions 68
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Contents ix
KEY EXPERIMENT
The Folding of Polypeptide Chains 54
KEY EXPERIMENT
The Structure of Cell Membranes 62
Summary and Key Terms 70
Questions 71
References and Further Reading 71
CHAPTER 3
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
Free energy and ATP 81
The generation of ATP from glucose 84
The derivation of energy from other organic
molecules 89
Photosynthesis 90
The Biosynthesis of Cell Constituents 91
Carbohydrates 92
Lipids 93
Proteins 94
Nucleic acids 98
KEY EXPERIMENT
Antimetabolites and Chemotherapy 97
MOLECULAR MEDICINE
Phenylketonuria 98
Summary and Key Terms 99
Questions 100
References and Further Reading 101
CHAPTER 4
Fundamentals of
Molecular Biology 103
Heredity, Genes, and DNA 103
Genes and chromosomes 103
Genes and enzymes 105
Identification of DNA as the genetic material 107
The structure of DNA 108
Replication of DNA 109
Expression of Genetic Information 110
Colinearity of genes and proteins 111
The role of messenger RNA 112
The genetic code 113
RNA viruses and reverse transcription 115
Recombinant DNA 118
Restriction endonucleases 118
Generation of recombinant DNA molecules 120
Vectors for recombinant DNA 122
DNA sequencing 124
Expression of cloned genes 126
Detection of Nucleic Acids and Proteins 127
Amplification of DNA by the polymerase chain
reaction 127
Nucleic acid hybridization 129
Antibodies as probes for proteins 132
Gene Function in Eukaryotes 135
Genetic analysis in yeasts 135
Gene transfer in plants and animals 136
Mutagenesis of cloned DNAs 139
Introducing mutations into cellular genes 140
Interfering with cellular gene expression 142
KEY EXPERIMENT
The DNA Provirus Hypothesis 117
KEY EXPERIMENT
RNA Interference 144
Summary and Key Terms 146
Questions 148
References and Further Reading 148
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x Contents
Part II The Flow of
Genetic Information 151
CHAPTER 5
The Organization and
Sequences of Cellular
Genomes 153
The Complexity of Eukaryotic Genomes 153
Introns and exons 155
Repetitive DNA sequences 159
Gene duplication and pseudogenes 161
The Sequences of Complete Genomes 162
The genomes of bacteria and yeast 163
The genomes of Caenorhabditis elegans, Drosophila
melanogaster, and other invertebrates 165
Plant genomes 166
The human genome 166
The genomes of other vertebrates 169
Chromosomes and Chromatin 171
Chromatin 172
Centromeres 176
Telomeres 180
Bioinformatics and Systems Biology 181
Systematic screens of gene function 181
Regulation of gene expression 182
Variation among individuals and genomic
medicine 184
KEY EXPERIMENT
The Discovery of Introns 156
KEY EXPERIMENT
The Human Genome 167
Summary and Key Terms 186
Questions 187
References and Further Reading 188
CHAPTER 6
Replication, Maintenance,
and Rearrangements
of Genomic DNA 191
DNA Replication 191
DNA polymerases 192
The replication fork 193
The fidelity of replication 200
Origins and the initiation of replication 201
Telomeres and telomerase: maintaining the
ends of chromosomes 205
DNA Repair 207
Direct reversal of DNA damage 208
Excision repair 210
Base-excision repair 210
Nucleotide-excision repair 210
Transcription-coupled repair 213
Mismatch repair 213
Translesion DNA synthesis 216
Repair of double-strand breaks 216
DNA Rearrangements 219
Site-specific recombination 219
Transposition via DNA intermediates 227
Transposition via RNA intermediates 228
Gene amplification 232
MOLECULAR MEDICINE
Colon Cancer and DNA Repair 215
KEY EXPERIMENT
Rearrangement of Immunoglobulin Genes 220
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Contents xi
Summary and Key Terms 233
Questions 235
References and Further Reading 236
CHAPTER 7
RNA Synthesis and
Processing 239
Transcription in Prokaryotes 239
RNA polymerase and transcription 240
Repressors and negative control of
transcription 243
Positive control of transcription 245
Eukaryotic RNA Polymerases and General
Transcription Factors 245
Eukaryotic RNA polymerases 246
General transcription factors and initiation
of transcription by RNA polymerase II 246
Transcription by RNA polymerases I and III 250
Regulation of Transcription in
Eukaryotes 251
cis-acting regulatory sequences: promoters and
enhancers 251
Transcription factor binding sites 255
Transcriptional regulatory proteins 258
Structure and function of transcriptional
activators 260
Eukaryotic repressors 263
Regulation of elongation 264
Relationship of chromatin structure to
transcription 266
Regulation of transcription by noncoding RNAs 271
DNA methylation 273
RNA Processing and Turnover 275
Processing of ribosomal and transfer RNAs 275
Processing of mRNA in eukaryotes 277
Splicing mechanisms 279
Alternative splicing 286
RNA editing 288
RNA degradation 289
KEY EXPERIMENT
Isolation of a Eukaryotic Transcription Factor 259
KEY EXPERIMENT
The Discovery of snRNPs 284
Summary and Key Terms 291
Questions 293
References and Further Reading 294
CHAPTER 8
Protein Synthesis,
Processing, and
Regulation 297
Translation of mRNA 297
Transfer RNAs 298
The ribosome 299
The organization of mRNAs and the initiation of
translation 305
The process of translation 307
Regulation of translation 313
Protein Folding and Processing 319
Chaperones and protein folding 319
Enzymes that catalyze protein folding 322
Protein cleavage 323
Glycosylation 325
Attachment of lipids 327
Regulation of Protein Function 329
Regulation by small molecules 329
Protein phosphorylation and other
modifications 330
Protein-protein interactions 335
Protein Degradation 335
The ubiquitin-proteasome pathway 335
Lysosomal proteolysis 338
KEY EXPERIMENT
Catalytic Role of Ribosomal RNA 304
KEY EXPERIMENT
The Discovery of Protein-Tyrosine Kinases 333
Summary and Key Terms 339
Questions 340
References and Further Reading 341
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xii Contents
Part III Cell Structure
and Function 343
CHAPTER 9
The Nucleus 345
The Nuclear Envelope and Traffic between
the Nucleus and the Cytoplasm 345
Structure of the nuclear envelope 346
The nuclear pore complex 350
Selective transport of proteins to and from the
nucleus 353
Regulation of nuclear protein import 356
Transport of RNAs 357
Internal Organization of the Nucleus 359
Chromosome organization and gene expression 359
Sub-compartments within the nucleus 362
The Nucleolus and rRNA Processing 365
Ribosomal RNA genes and the organization of the
nucleolus 365
Transcription and processing of rRNA 367
Ribosome assembly 368
Additional functions of the nucleolus 369
MOLECULAR MEDICINE
Nuclear Lamina Diseases 348
KEY EXPERIMENT
Identification of Nuclear Localization Signals 352
Summary and Key Terms 370
Questions 371
References and Further Reading 372
CHAPTER 10
Protein Sorting and
Transport 373
The Endoplasmic Reticulum 373
The endoplasmic reticulum and protein
secretion 374
Targeting proteins to the endoplasmic reticulum 376
Insertion of proteins into the ER membrane 381
Protein folding and processing in the ER 386
Quality control in the ER 389
The smooth ER and lipid synthesis 392
Export of proteins and lipids from the ER 395
The Golgi Apparatus 398
Organization of the Golgi 398
Protein glycosylation within the Golgi 400
Lipid and polysaccharide metabolism in the
Golgi 402
Protein sorting and export from the Golgi
apparatus 403
The Mechanism of Vesicular Transport 406
Experimental approaches to understanding vesicular
transport 406
Cargo selection, coat proteins, and
vesicle budding 407
Vesicle fusion 410
Lysosomes 412
Lysosomal acid hydrolases 412
Endocytosis and lysosome formation 414
Phagocytosis and autophagy 416
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or disseminated in any form without express written permission from the publisher.
Contents xiii
KEY EXPERIMENT
The Signal Hypothesis 378
MOLECULAR MEDICINE
Gaucher Disease 413
Summary and Key Terms 417
Questions 419
References and Further Reading 419
CHAPTER 11
Bioenergetics and
Metabolism 421
Mitochondria 421
Organization and function of mitochondria 422
The genetic system of mitochondria 424
Protein import and mitochondrial assembly 425
The Mechanism of Oxidative
Phosphorylation 431
The electron transport chain 431
Chemiosmotic coupling 432
Transport of metabolites across the inner
membrane 436
Chloroplasts and Other Plastids 438
The structure and function of chloroplasts 438
The chloroplast genome 440
Import and sorting of chloroplast proteins 441
Other plastids 444
Photosynthesis 446
Electron transport 446
ATP synthesis 449
Peroxisomes 450
Functions of peroxisomes 451
Peroxisome assembly 453
MOLECULAR MEDICINE
Diseases of Mitochondria:
Lebers Hereditary Optic Neuropathy 426
KEY EXPERIMENT
The Chemiosmotic Theory 434
Summary and Key Terms 455
Questions 457
References and Further Reading 458
CHAPTER 12
The Cytoskeleton and
Cell Movement 459
Structure and Organization of Actin
Filaments 459
Assembly and disassembly of actin filaments 460
Organization of actin filaments 465
Association of actin filaments with the plasma
membrane 467
Protrusions of the cell surface 471
Actin, Myosin, and Cell Movement 472
Muscle contraction 473
Contractile assemblies of actin and myosin in
nonmuscle cells 477
Unconventional myosins 479
Formation of protrusions and cell movement 480
Microtubules 482
Structure and dynamic organization of
microtubules 482
Assembly of microtubules 485
Organization of microtubules within cells 488
Microtubule Motors and Movement 490
Identification of microtubule motor proteins 490
Cargo transport and intracellular organization 493
Cilia and flagella 496
Reorganization of microtubules during mitosis 499
Chromosome movement 500
Intermediate Filaments 502
Intermediate filament proteins 502
Assembly of intermediate filaments 504
Intracellular organization of intermediate
filaments 505
Functions of intermediate filaments: keratins and
diseases of the skin 507
KEY EXPERIMENT
The Isolation of Kinesin 491
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xiv Contents
KEY EXPERIMENT
Expression of Mutant Keratin
Causes Abnormal Skin Development 508
Summary and Key Terms 510
Questions 512
References and Further Reading 512
CHAPTER 13
The Plasma Membrane 515
Structure of the Plasma Membrane 515
The phospholipid bilayer 515
Membrane proteins 519
Mobility of membrane proteins 524
The glycocalyx 525
Transport of Small Molecules 526
Passive diffusion 526
Facilitated diffusion and carrier proteins 527
Ion channels 529
Active transport driven by ATP hydrolysis 537
Active transport driven by ion gradients 540
Endocytosis 544
Phagocytosis 544
Receptor-mediated endocytosis 545
Protein trafficking in endocytosis 550
MOLECULAR MEDICINE
Cystic Fibrosis 541
KEY EXPERIMENT
The LDL Receptor 548
Summary and Key Terms 553
Questions 554
References and Further Reading 555
CHAPTER 14
Cell Walls, the Extracellular
Matrix, and Cell
Interactions 557
Cell Walls 557
Bacterial cell walls 557
Eukaryotic cell walls 557
The Extracellular Matrix and Cell-Matrix
Interactions 564
Matrix structural proteins 564
Matrix polysaccharides 568
Matrix adhesion proteins 569
Cell-matrix interactions 571
Cell-Cell Interactions 574
Adhesion junctions 574
Tight junctions 577
Gap junctions 578
Plasmodesmata 581
KEY EXPERIMENT
The Characterization of Integrin 572
MOLECULAR MEDICINE
Gap Junction Diseases 580
Summary and Key Terms 582
Questions 583
References and Further Reading 584
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Contents xv
Part IV Cell
Regulation 587
CHAPTER 15
Cell Signaling 589
Signaling Molecules and Their
Receptors 589
Modes of cell-cell signaling 590
Steroid hormones and the nuclear receptor
superfamily 591
Nitric oxide and carbon monoxide 593
Neurotransmitters 594
Peptide hormones and growth factors 594
Eicosanoids 596
Plant hormones 598
Functions of Cell Surface Receptors 599
G protein-coupled receptors 600
Receptor protein-tyrosine kinases 603
Cytokine receptors and nonreceptor protein-tyrosine
kinases 606
Receptors linked to other enzymatic activities 607
Pathways of Intracellular Signal
Transduction 608
The cAMP pathway: second messengers and protein
phosphorylation 608
Cyclic GMP 611
Phospholipids and Ca
2+
612
The PI 3-kinase/Akt and mTOR pathways 615
MAP kinase pathways 617
The JAK/STAT and TGF-b/Smad pathways 623
NF-kB signaling 625
The Hedgehog, Wnt, and Notch pathways 625
Signal Transduction and the
Cytoskeleton 628
Integrins and signal transduction 628
Signaling from cell adhesion molecules 630
Regulation of the actin cytoskeleton 630
Signaling Networks 632
Feedback and crosstalk 632
Networks of cellular signal transduction 634
KEY EXPERIMENT
G Protein-Coupled Receptors and Odor
Detection 601
MOLECULAR MEDICINE
Cancer: Signal Transduction
and the ras Oncogenes 620
Summary and Key Terms 635
Questions 637
References and Further Reading 638
CHAPTER 16
The Cell Cycle 641
The Eukaryotic Cell Cycle 641
Phases of the cell cycle 642
Regulation of the cell cycle by cell growth and
extracellular signals 644
Cell cycle checkpoints 646
Restricting DNA replication to once per cell
cycle 647
Regulators of Cell Cycle Progression 647
Protein kinases and cell cycle regulation 647
Families of cyclins and cyclin-dependent
kinases 653
Growth factors and the regulation of G
1
Cdks 655
DNA damage checkpoints 658
The Events of M Phase 659
Stages of mitosis 659
Entry into mitosis 662
The spindle assembly checkpoint and progression
to anaphase 666
Part IV Cell Regulation 587
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xvi Contents
Cytokinesis 667
Meiosis and Fertilization 668
The process of meiosis 668
Regulation of oocyte meiosis 671
Fertilization 673
KEY EXPERIMENT
The Discovery of MPF 649
KEY EXPERIMENT
The Identification of Cyclin 652
Summary and Key Terms 675
Questions 677
References and Further Reading 677
CHAPTER 17
Cell Death and Cell
Renewal 681
Programmed Cell Death 681
The events of apoptosis 682
Caspases: the executioners of apoptosis 685
Central regulators of apoptosis: the Bcl-2
family 686
Signaling pathways that regulate apoptosis 689
Alternative pathways of programmed cell death 692
Stem Cells and the Maintenance of Adult
Tissues 692
Proliferation of differentiated cells 693
Stem cells 695
Medical applications of adult stem cells 701
Pluripotent Stem Cells, Cellular
Reprogramming, and
Regenerative Medicine 703
Embryonic stem cells 704
Somatic cell nuclear transfer 705
Induced pluripotent stem cells 707
Transdifferentiation of somatic cells 708
KEY EXPERIMENT
Identification of Genes Required
for Programmed Cell Death 684
KEY EXPERIMENT
Culture of Embryonic Stem Cells 702
Summary and Key Terms 708
Questions 710
References and Further Reading 710
CHAPTER 18
Cancer 713
The Development and Causes of
Cancer 713
Types of cancer 713
The development of cancer 715
Causes of cancer 717
Properties of cancer cells 718
Transformation of cells in culture 722
Tumor Viruses 723
Hepatitis B and C viruses 723
Small DNA tumor viruses 724
Herpesviruses 726
Retroviruses 726
Oncogenes 727
Retroviral oncogenes 727
Proto-oncogenes 728
Oncogenes in human cancer 731
Functions of oncogene products 735
Tumor Suppressor Genes 741
Identification of tumor suppressor genes 741
Functions of tumor suppressor gene products 745
Roles of oncogenes and tumor suppressor genes in
tumor development 748
Molecular Approaches to Cancer
Treatment 749
Prevention and early detection 749
Treatment 750
KEY EXPERIMENT
The Discovery of Proto-Oncogenes 730
MOLECULAR MEDICINE
Imatinib: Cancer Treatment Targeted
against the bcr/abl Oncogene 752
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or disseminated in any form without express written permission from the publisher.
Contents xvii
Summary and Key Terms 755
Questions 757
References and Further Reading 757
Answers to Questions 761
Glossary 773
Illustration Credits 797
Index 799
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or disseminated in any form without express written permission from the publisher.