Lodish 8th Ed.

Part I: Chemical and Molecular Foundations

1 Molecules, Cells, and Model Organisms

1.1 The Molecules of Life

• Proteins Give Cells Structure and Perform Most Cellular Tasks
• Nucleic Acids Carry Coded Information for Making Proteins at the Right Time and Place
• Phospholipids Are the Conserved Building Blocks of All Cellular Membranes

1.2 Prokaryotic Cell Structure and Function

• Prokaryotes Comprise Two Kingdoms: Archaea and Eubacteria
• Escherichia coli Is Widely Used in Biological Research

1.3 Eukaryotic Cell Structure and Function

• The Cytoskeleton Has Many Important Functions
• The Nucleus Contains the DNA Genome, RNA Synthetic Apparatus, and a Fibrous Matrix
• Eukaryotic Cells Contain a Large Number of Internal Membrane Structures
• Mitochondria Are the Principal Sites of ATP Production in Aerobic Cells
• Chloroplasts Contain Internal Compartments in Which Photosynthesis Takes Place
• All Eukaryotic Cells Use a Similar Cycle to Regulate Their Division

1.4 Unicellular Eukaryotic Model Organisms

• Yeasts Are Used to Study Fundamental Aspects of Eukaryotic Cell Structure and Function
• Mutations in Yeast Led to the Identification of Key Cell Cycle Proteins
• Studies in the Alga Chlamydomonas reinhardtii Led to the Development of a Powerful Technique to Stud
• The Parasite That Causes Malaria Has Novel Organelles That Allow It to Undergo a Remarkable Life Cyc

1.5 Metazoan Structure, Differentiation, and Model Organisms

• Multicellularity Requires Cell-Cell and Cell-Matrix Adhesions
• Epithelia Originated Early in Evolution
• Tissues Are Organized into Organs
• Genomics Has Revealed Important Aspects of Metazoan Evolution and Cell Function
• Embryonic Development Uses a Conserved Set of Master Transcription Factors
• Planaria Are Used to Study Stem Cells and Tissue Regeneration
• Invertebrates, Fish, Mice, and Other Organisms Serve as Experimental Systems for Study of Human Deve
• Genetic Diseases Elucidate Important Aspects of Cell Function
• The Following Chapters Present Much Experimental Data That Explains How We Know What We Know About C

2 Chemical Foundations

2.1 Covalent Bonds and Noncovalent Interactions

• The Electronic Structure of an Atom Determines the Number and Geometry of the Covalent Bonds It Can
• Electrons May Be Shared Equally or Unequally in Covalent Bonds
• Covalent Bonds Are Much Stronger and More Stable Than Noncovalent Interactions
• Ionic Interactions Are Attractions Between Oppositely Charged Ions
• Hydrogen Bonds Are Noncovalent Interactions That Determine the Water Solubility of Uncharged Molecul
• Van der Waals Interactions Are Weak Attractive Interactions Caused by Transient Dipoles
• The Hydrophobic Effect Causes Nonpolar Molecules to Adhere to One Another
• Molecular Complementarity Due to Noncovalent Interactions Leads to a Lock-and-Key Fit Between Biomol

2.2 Chemical Building Blocks of Cells

• Amino Acids Differing Only in Their Side Chains Compose Proteins
• Five Different Nucleotides Are Used to Build Nucleic Acids
• Monosaccharides Covalently Assemble into Linear and Branched Polysaccharides
• Phospholipids Associate Noncovalently to Form the Basic Bilayer Structure of Biomembranes

2.3 Chemical Reactions and Chemical Equilibrium

• A Chemical Reaction Is in Equilibrium When the Rates of the Forward and Reverse Reactions Are Equal
• The Equilibrium Constant Reflects the Extent of a Chemical Reaction
• Chemical Reactions in Cells Are at Steady State
• Dissociation Constants of Binding Reactions Reflect the Affinity of Interacting Molecules
• Biological Fluids Have Characteristic pH Values
• Hydrogen Ions Are Released by Acids and Taken Up by Bases
• Buffers Maintain the pH of Intracellular and Extracellular Fluids

2.4 Biochemical Energetics

• Several Forms of Energy Are Important in Biological Systems
• Cells Can Transform One Type of Energy into Another
• The Change in Free Energy Determines If a Chemical Reaction Will Occur Spontaneously
• The (omitted)G(omitted) of a Reaction Can Be Calculated from Its K(sub[eq])
• The Rate of a Reaction Depends on the Activation Energy Necessary to Energize the Reactants into a T
• Life Depends on the Coupling of Unfavorable Chemical Reactions with Energetically Favorable Ones
• Hydrolysis of ATP Releases Substantial Free Energy and Drives Many Cellular Processes
• ATP Is Generated During Photosynthesis and Respiration
• NAD(sup[+]) and FAD Couple Many Biological Oxidation and Reduction Reactions

3 Protein Structure and Function

3.1 Hierarchical Structure of Proteins

• The Primary Structure of a Protein Is Its Linear Arrangement of Amino Acids
• Secondary Structures Are the Core Elements of Protein Architecture
• Tertiary Structure Is the Overall Folding of a Polypeptide Chain
• There Are Four Broad Structural Categories of Proteins
• Different Ways of Depicting the Conformation of Proteins Convey Different Types of Information
• Structural Motifs Are Regular Combinations of Secondary Structures
• Domains Are Modules of Tertiary Structure
• Multiple Polypeptides Assemble into Quaternary Structures and Supramolecular Complexes
• Comparing Protein Sequences and Structures Provides Insight into Protein Function and Evolution

3.2 Protein Folding

• Planar Peptide Bonds Limit the Shapes into Which Proteins Can Fold
• The Amino Acid Sequence of a Protein Determines How It Will Fold
• Folding of Proteins in Vivo Is Promoted by Chaperones
• Protein Folding Is Promoted by Proline Isomerases
• Abnormally Folded Proteins Can Form Amyloids That Are Implicated in Diseases

3.3 Protein Binding and Enzyme Catalysis

• Specific Binding of Ligands Underlies the Functions of Most Proteins
• Enzymes Are Highly Efficient and Specific Catalysts
• An Enzyme’s Active Site Binds Substrates and Carries Out Catalysis
• Serine Proteases Demonstrate How an Enzyme’s Active Site Works
• Enzymes in a Common Pathway Are Often Physically Associated with One Another

3.4 Regulating Protein Function

• Regulated Synthesis and Degradation of Proteins Is a Fundamental Property of Cells
• The Proteasome Is a Molecular Machine Used to Degrade Proteins
• Ubiquitin Marks Cytosolic Proteins for Degradation in Proteasomes
• Noncovalent Binding Permits Allosteric, or Cooperative, Regulation of Proteins
• Noncovalent Binding of Calcium and GTP Are Widely Used as Allosteric Switches to Control Protein Act
• Phosphorylation and Dephosphorylation Covalently Regulate Protein Activity
• Ubiquitinylation and Deubiquitinylation Covalently Regulate Protein Activity
• Proteolytic Cleavage Irreversibly Activates or Inactivates Some Proteins
• Higher-Order Regulation Includes Control of Protein Location

3.5 Purifying, Detecting, and Characterizing Proteins

• Centrifugation Can Separate Particles and Molecules That Differ in Mass or Density
• Electrophoresis Separates Molecules on the Basis of Their Charge-to-Mass Ratio
• Liquid Chromatography Resolves Proteins by Mass, Charge, or Affinity
• Highly Specific Enzyme and Antibody Assays Can Detect Individual Proteins
• Radioisotopes Are Indispensable Tools for Detecting Biological Molecules
• Mass Spectrometry Can Determine the Mass and Sequence of Proteins
• Protein Primary Structure Can Be Determined by Chemical Methods and from Gene Sequences
• Protein Conformation Is Determined by Sophisticated Physical Methods

3.6 Proteomics

• Proteomics Is the Study of All or a Large Subset of Proteins in a Biological System
• Advanced Techniques in Mass Spectrometry Are Critical to Proteomic Analysis

4 Culturing and Visualizing Cells

4.1 Growing and Studying Cells in Culture

• Culture of Animal Cells Requires Nutrient-Rich Media and Special Solid Surfaces
• Primary Cell Cultures and Cell Strains Have a Finite Life Span
• Transformed Cells Can Grow Indefinitely in Culture
• Flow Cytometry Separates Different Cell Types
• Growth of Cells in Two-Dimensional and Three-Dimensional Culture Mimics the In Vivo Environment
• Hybridomas Produce Abundant Monoclonal Antibodies
• A Wide Variety of Cell Biological Processes Can Be Studied with Cultured Cells
• Drugs Are Commonly Used in Cell Biological Research

4.2 Light Microscopy: Exploring Cell Structure and Visualizing Proteins Within Cells

• The Resolution of the Conventional Light Microscope Is About 0.2 µm
• Phase-Contrast and Differential-Interference-Contrast Microscopy Visualize Unstained Live Cells
• Imaging Subcellular Details Often Requires That Specimens Be Fixed, Sectioned, and Stained
• Fluorescence Microscopy Can Localize and Quantify Specific Molecules in Live Cells
• Intracellular Ion Concentrations Can Be Determined with Ion-Sensitive Fluorescent Dyes
• Immunofluorescence Microscopy Can Detect Specific Proteins in Fixed Cells
• Tagging with Fluorescent Proteins Allows the Visualization of Specific Proteins in Live Cells
• Deconvolution and Confocal Microscopy Enhance Visualization of Three-Dimensional Fluorescent Objects
• Two-Photon Excitation Microscopy Allows Imaging Deep into Tissue Samples
• TIRF Microscopy Provides Exceptional Imaging in One Focal Plane
• FRAP Reveals the Dynamics of Cellular Components
• FRET Measures Distance Between Fluorochromes
• Super-Resolution Microscopy Can Localize Proteins to Nanometer Accuracy
• Light-Sheet Microscopy Can Rapidly Image Cells in Living Tissue

4.3 Electron Microscopy: High-Resolution Imaging

• Single Molecules or Structures Can Be Imaged Using a Negative Stain or Metal Shadowing
• Cells and Tissues Are Cut into Thin Sections for Viewing by Electron Microscopy
• Immunoelectron Microscopy Localizes Proteins at the Ultrastructural Level
• Cryoelectron Microscopy Allows Visualization of Specimens Without Fixation or Staining
• Scanning Electron Microscopy of Metal-Coated Specimens Reveals Surface Features

4.4 Isolation of Cell Organelles

• Disruption of Cells Releases Their Organelles and Other Contents
• Centrifugation Can Separate Many Types of Organelles
• Organelle-Specific Antibodies Are Useful in Preparing Highly Purified Organelles
• Proteomics Reveals the Protein Composition of Organelles

Part II: Biomembranes, Genes, and Gene Regulation

5 Fundamental Molecular Genetic Mechanisms

5.1 Structure of Nucleic Acids

• A Nucleic Acid Strand Is a Linear Polymer with End-to-End Directionality
• Native DNA Is a Double Helix of Complementary Antiparallel Strands
• DNA Can Undergo Reversible Strand Separation
• Torsional Stress in DNA Is Relieved by Enzymes
• Different Types of RNA Exhibit Various Conformations Related to Their Functions

5.2 Transcription of Protein-Coding Genes and Formation of Functional mRNA

• A Template DNA Strand Is Transcribed into a Complementary RNA Chain by RNA Polymerase
• Organization of Genes Differs in Prokaryotic and Eukaryotic DNA
• Eukaryotic Precursor mRNAs Are Processed to Form Functional mRNAs
• Alternative RNA Splicing Increases the Number of Proteins Expressed from a Single Eukaryotic Gene

5.3 The Decoding of mRNA by tRNAs

• Messenger RNA Carries Information from DNA in a Three-Letter Genetic Code
• The Folded Structure of tRNA Promotes Its Decoding Functions
• Nonstandard Base Pairing Often Occurs Between Codons and Anticodons
• Amino Acids Become Activated When Covalently Linked to tRNAs

5.4 Stepwise Synthesis of Proteins on Ribosomes

• Ribosomes Are Protein-Synthesizing Machines
• Methionyl-tRNAi Met Recognizes the AUG Start Codon
• Eukaryotic Translation Initiation Usually Occurs at the First AUG Downstream from the 5′ End of an m
• During Chain Elongation Each Incoming Aminoacyl-tRNA Moves Through Three Ribosomal Sites
• Translation Is Terminated by Release Factors When a Stop Codon Is Reached
• Polysomes and Rapid Ribosome Recycling Increase the Efficiency of Translation
• GTPase-Superfamily Proteins Function in Several Quality-Control Steps of Translation
• Nonsense Mutations Cause Premature Termination of Protein Synthesis

5.5 DNA Replication

• DNA Polymerases Require a Primer to Initiate Replication
• Duplex DNA Is Unwound, and Daughter Strands Are Formed at the DNA Replication Fork
• Several Proteins Participate in DNA Replication
• DNA Replication Occurs Bidirectionally from Each Origin

5.6 DNA Repair and Recombination

• DNA Polymerases Introduce Copying Errors and Also Correct Them
• Chemical and Radiation Damage to DNA Can Lead to Mutations
• High-Fidelity DNA Excision-Repair Systems Recognize and Repair Damage
• Base Excision Repairs T-G Mismatches and Damaged Bases
• Mismatch Excision Repairs Other Mismatches and Small Insertions and Deletions
• Nucleotide Excision Repairs Chemical Adducts that Distort Normal DNA Shape
• Two Systems Use Recombination to Repair Double-Strand Breaks in DNA
• Homologous Recombination Can Repair DNA Damage and Generate Genetic Diversity

5.7 Viruses: Parasites of the Cellular Genetic System

• Most Viral Host Ranges Are Narrow
• Viral Capsids Are Regular Arrays of One or a Few Types of Protein
• Viruses Can Be Cloned and Counted in Plaque Assays
• Lytic Viral Growth Cycles Lead to Death of Host Cells
• Viral DNA Is Integrated into the Host-Cell Genome in Some Nonlytic Viral Growth Cycles

6 Molecular Genetic Techniques

6.1 Genetic Analysis of Mutations to Identify and Study Genes

• Recessive and Dominant Mutant Alleles Generally Have Opposite Effects on Gene Function
• Segregation of Mutations in Breeding Experiments Reveals Their Dominance or Recessivity
• Conditional Mutations Can Be Used to Study Essential Genes in Yeast
• Recessive Lethal Mutations in Diploids Can Be Identified by Inbreeding and Maintained in Heterozygot
• Complementation Tests Determine Whether Different Recessive Mutations Are in the Same Gene
• Double Mutants Are Useful in Assessing the Order in Which Proteins Function
• Genetic Suppression and Synthetic Lethality Can Reveal Interacting or Redundant Proteins
• Genes Can Be Identified by Their Map Position on the Chromosome

6.2 DNA Cloning and Characterization

• Restriction Enzymes and DNA Ligases Allow Insertion of DNA Fragments into Cloning Vectors
• Isolated DNA Fragments Can Be Cloned into E. coli Plasmid Vectors
• Yeast Genomic Libraries Can Be Constructed with Shuttle Vectors and Screened by Functional Complemen
• cDNA Libraries Represent the Sequences of Protein-Coding Genes
• The Polymerase Chain Reaction Amplifies a Specific DNA Sequence from a Complex Mixture
• Cloned DNA Molecules Can Be Sequenced Rapidly by Methods Based on PCR

6.3 Using Cloned DNA Fragments to Study Gene Expression

• Hybridization Techniques Permit Detection of Specific DNA Fragments and mRNAs
• DNA Microarrays Can Be Used to Evaluate the Expression of Many Genes at One Time
• Cluster Analysis of Multiple Expression Experiments Identifies Co-regulated Genes
• E. coli Expression Systems Can Produce Large Quantities of Proteins from Cloned Genes
• Plasmid Expression Vectors Can Be Designed for Use in Animal Cells

6.4 Locating and Identifying Human Disease Genes

• Monogenic Diseases Show One of Three Patterns of Inheritance
• DNA Polymorphisms Are Used as Markers for Linkage Mapping of Human Mutations
• Linkage Studies Can Map Disease Genes with a Resolution of About 1 Centimorgan
• Further Analysis Is Needed to Locate a Disease Gene in Cloned DNA
• Many Inherited Diseases Result from Multiple Genetic Defects

6.5 Inactivating the Function of Specific Genes in Eukaryotes

• Normal Yeast Genes Can Be Replaced with Mutant Alleles by Homologous Recombination
• Genes Can Be Placed Under the Control of an Experimentally Regulated Promoter
• Specific Genes Can Be Permanently Inactivated in the Germ Line of Mice
• Somatic Cell Recombination Can Inactivate Genes in Specific Tissues
• Dominant-Negative Alleles Can Inhibit the Function of Some Genes
• RNA Interference Causes Gene Inactivation by Destroying the Corresponding mRNA
• Engineered CRISPR–Cas9 Systems Allow Precise Genome Editing

7 Biomembrane Structure

7.1 The Lipid Bilayer: Composition and Structural Organization

• Phospholipids Spontaneously Form Bilayers
• Phospholipid Bilayers Form a Sealed Compartment Surrounding an Internal Aqueous Space
• Biomembranes Contain Three Principal Classes of Lipids
• Most Lipids and Many Proteins Are Laterally Mobile in Biomembranes
• Lipid Composition Influences the Physical Properties of Membranes
• Lipid Composition Is Different in the Exoplasmic and Cytosolic Leaflets
• Cholesterol and Sphingolipids Cluster with Specific Proteins in Membrane Microdomains
• Cells Store Excess Lipids in Lipid Droplets

7.2 Membrane Proteins: Structure and Basic Functions

• Proteins Interact with Membranes in Three Different Ways
• Most Transmembrane Proteins Have Membrane-Spanning α Helices
• Multiple ß Strands in Porins Form Membrane-Spanning “Barrels”
• Covalently Attached Lipids Anchor Some Proteins to Membranes
• All Transmembrane Proteins and Glycolipids Are Asymmetrically Oriented in the Bilayer
• Lipid-Binding Motifs Help Target Peripheral Proteins to the Membrane
• Proteins Can Be Removed from Membranes by Detergents or High-Salt Solutions

7.3 Phospholipids, Sphingolipids, and Cholesterol: Synthesis and Intracellular Movement

• Fatty Acids Are Assembled from Two-Carbon Building Blocks by Several Important Enzymes
• Small Cytosolic Proteins Facilitate Movement of Fatty Acids
• Fatty Acids Are Incorporated into Phospholipids Primarily on the ER Membrane
• Flippases Move Phospholipids from One Membrane Leaflet to the Opposite Leaflet
• Cholesterol Is Synthesized by Enzymes in the Cytosol and ER Membrane
• Cholesterol and Phospholipids Are Transported Between Organelles by Several Mechanisms

8 Genes, Genomics, and Chromosomes

8.1 Eukaryotic Gene Structure

• Most Eukaryotic Genes Contain Introns and Produce mRNAs Encoding Single Proteins
• Simple and Complex Transcription Units Are Found in Eukaryotic Genomes
• Protein-Coding Genes May Be Solitary or Belong to a Gene Family
• Heavily Used Gene Products Are Encoded by Multiple Copies of Genes
• Nonprotein-Coding Genes Encode Functional RNAs

8.2 Chromosomal Organization of Genes and Noncoding DNA

• Genomes of Many Organisms Contain Nonfunctional DNA
• Most Simple-Sequence DNAs Are Concentrated in Specific Chromosomal Locations
• DNA Fingerprinting Depends on Differences in Length of Simple-Sequence DNAs
• Unclassified Intergenic DNA Occupies a Significant Portion of the Genome

8.3 Transposable (Mobile) DNA Elements

• Movement of Mobile Elements Involves a DNA or an RNA Intermediate
• DNA Transposons Are Present in Prokaryotes and Eukaryotes
• LTR Retrotransposons Behave Like Intracellular Retroviruses
• Non-LTR Retrotransposons Transpose by a Distinct Mechanism
• Other Retroposed RNAs Are Found in Genomic DNA
• Mobile DNA Elements Have Significantly Influenced Evolution

8.4 Genomics: Genome-Wide Analysis of Gene Structure and Function

• Stored Sequences Suggest Functions of Newly Identified Genes and Proteins
• Comparison of Related Sequences from Different Species Can Give Clues to Evolutionary Relationships
• Genes Can Be Identified Within Genomic DNA Sequences
• The Number of Protein-Coding Genes in an Organism’s Genome Is Not Directly Related to Its Biological

8.5 Structural Organization of Eukaryotic Chromosomes

• Chromatin Exists in Extended and Condensed Forms
• Modifications of Histone Tails Control Chromatin Condensation and Function
• Nonhistone Proteins Organize Long Chromatin Loops
• Additional Nonhistone Proteins Regulate Transcription and Replication

8.6 Morphology and Functional Elements of Eukaryotic Chromosomes

• Chromosome Number, Size, and Shape at Metaphase Are Species-Specific
• During Metaphase, Chromosomes Can Be Distinguished by Banding Patterns and Chromosome Painting
• Chromosome Painting and DNA Sequencing Reveal the Evolution of Chromosomes
• Interphase Polytene Chromosomes Arise by DNA Amplification
• Three Functional Elements Are Required for Replication and Stable Inheritance of Chromosomes
• Centromere Sequences Vary Greatly in Length and Complexity
• Addition of Telomeric Sequences by Telomerase Prevents Shortening of Chromosomes

9 Transcriptional Control of Gene Expression

9.1 Control of Gene Expression in Bacteria

• Transcription Initiation by Bacterial RNA Polymerase Requires Association with a Sigma Factor
• Initiation of lac Operon Transcription Can Be Repressed or Activated
• Small Molecules Regulate Expression of Many Bacterial Genes via DNA-Binding Repressors and Activator
• Transcription Initiation from Some Promoters Requires Alternative Sigma Factors
• Transcription by σ(Sup[54])-RNA Polymerase Is Controlled by Activators That Bind Far from the Promo
• Many Bacterial Responses Are Controlled by Two-Component Regulatory Systems
• Expression of Many Bacterial Operons Is Controlled by Regulation of Transcriptional Elongation

9.2 Overview of Eukaryotic Gene Control

• Regulatory Elements in Eukaryotic DNA Are Found Both Close to and Many Kilobases Away from Transcrip
• Three Eukaryotic RNA Polymerases Catalyze Formation of Different RNAs
• The Largest Subunit in RNA Polymerase II Has an Essential Carboxy-Terminal Repeat

9.3 RNA Polymerase II Promoters and General Transcription Factors

• RNA Polymerase II Initiates Transcription at DNA Sequences Corresponding to the 5′ Cap of mRNAs
• The TATA Box, Initiators, and CpG Islands Function as Promoters in Eukaryotic DNA
• General Transcription Factors Position RNA Polymerase II at Start Sites and Assist in Initiation
• Elongation Factors Regulate the Initial Stages of Transcription in the Promoter-Proximal Region

9.4 Regulatory Sequences in Protein-Coding Genes and the Proteins Through Which They Function

• Promoter-Proximal Elements Help Regulate Eukaryotic Genes
• Distant Enhancers Often Stimulate Transcription by RNA Polymerase II
• Most Eukaryotic Genes Are Regulated by Multiple Transcription-Control Elements
• DNase I Footprinting and EMSA Detect Protein-DNA Interactions
• Activators Are Composed of Distinct Functional Domains
• Repressors Are the Functional Converse of Activators
• DNA-Binding Domains Can Be Classified into Numerous Structural Types
• Structurally Diverse Activation and Repression Domains Regulate Transcription
• Transcription Factor Interactions Increase Gene-Control Options
• Multiprotein Complexes Form on Enhancers

9.5 Molecular Mechanisms of Transcription Repression and Activation

• Formation of Heterochromatin Silences Gene Expression at Telomeres, near Centromeres, and in Other R
• Repressors Can Direct Histone Deacetylation at Specific Genes
• Activators Can Direct Histone Acetylation at Specific Genes
• Chromatin-Remodeling Complexes Help Activate or Repress Transcription
• Pioneer Transcription Factors Initiate the Process of Gene Activation During Cellular Differentiatio
• The Mediator Complex Forms a Molecular Bridge Between Activation Domains and Pol II

9.6 Regulation of Transcription-Factor Activity

• DNase I Hypersensitive Sites Reflect the Developmental History of Cellular Differentiation
• Nuclear Receptors Are Regulated by Extracellular Signals
• All Nuclear Receptors Share a Common Domain Structure
• Nuclear-Receptor Response Elements Contain Inverted or Direct Repeats
• Hormone Binding to a Nuclear Receptor Regulates Its Activity as a Transcription Factor
• Metazoans Regulate the RNA Polymerase II Transition from Initiation to Elongation
• Termination of Transcription Is Also Regulated

9.7 Epigenetic Regulation of Transcription

• DNA Methylation Represses Transcription
• Methylation of Specific Histone Lysines Is Linked to Epigenetic Mechanisms of Gene Repression
• Epigenetic Control by Polycomb and Trithorax Complexes
• Long Noncoding RNAs Direct Epigenetic Repression in Metazoans

9.8 Other Eukaryotic Transcription Systems

• Transcription Initiation by Pol I and Pol III Is Analogous to That by Pol II

10 Post-transcriptional Gene Control

10.1 Processing of Eukaryotic Pre-mRNA

• The 5′ Cap Is Added to Nascent RNAs Shortly After Transcription Initiation
• A Diverse Set of Proteins with Conserved RNA-Binding Domains Associate with Pre-mRNAs
• Splicing Occurs at Short, Conserved Sequences in Pre-mRNAs via Two Transesterification Reactions
• During Splicing, snRNAs Base-Pair with Pre-mRNA
• Spliceosomes, Assembled from snRNPs and a Pre-mRNA, Carry Out Splicing
• Chain Elongation by RNA Polymerase II Is Coupled to the Presence of RNA-Processing Factors
• SR Proteins Contribute to Exon Definition in Long Pre-mRNAs
• Self-Splicing Group II Introns Provide Clues to the Evolution of snRNAs
• 3′ Cleavage and Polyadenylation of Pre-mRNAs Are Tightly Coupled
• Nuclear Exoribonucleases Degrade RNA That Is Processed Out of Pre-mRNAs
• RNA Processing Solves the Problem of Pervasive Transcription of the Genome in Metazoans

10.2 Regulation of Pre-mRNA Processing

• Alternative Splicing Generates Transcripts with Different Combinations of Exons
• A Cascade of Regulated RNA Splicing Controls Drosophila Sexual Differentiation
• Splicing Repressors and Activators Control Splicing at Alternative Sites
• RNA Editing Alters the Sequences of Some Pre-mRNAs

10.3 Transport of mRNA Across the Nuclear Envelope

• Phosphorylation and Dephosphorylation of SR Proteins Imposes Directionality on mRNP Export Across th
• Balbiani Rings in Insect Larval Salivary Glands Allow Direct Visualization of mRNP Export Through NP
• Pre-mRNAs in Spliceosomes Are Not Exported from the Nucleus
• HIV Rev Protein Regulates the Transport of Unspliced Viral mRNAs

10.4 Cytoplasmic Mechanisms of Post-transcriptional Control

• Degradation of mRNAs in the Cytoplasm Occurs by Several Mechanisms
• Adenines in mRNAs and lncRNAs May Be Post-transcriptionally Modified by N6 Methylation
• Micro-RNAs Repress Translation and Induce Degradation of Specific mRNAs
• Alternative Polyadenylation Increases miRNA Control Options
• RNA Interference Induces Degradation of Precisely Complementary mRNAs
• Cytoplasmic Polyadenylation Promotes Translation of Some mRNAs
• Protein Synthesis Can Be Globally Regulated
• Sequence-Specific RNA-Binding Proteins Control Translation of Specific mRNAs
• Surveillance Mechanisms Prevent Translation of Improperly Processed mRNAs
• Localization of mRNAs Permits Production of Proteins at Specific Regions Within the Cytoplasm

10.5 Processing of rRNA and tRNA

• Pre-rRNA Genes Function as Nucleolar Organizers
• Small Nucleolar RNAs Assist in Processing Pre-rRNAs
• Self-Splicing Group I Introns Were the First Examples of Catalytic RNA
• Pre-tRNAs Undergo Extensive Modification in the Nucleus
• Nuclear Bodies Are Functionally Specialized Nuclear Domains

Part III: Cellular Organization and Function

11 Transmembrane Transport of Ions and Small Molecules

11.1 Overview of Transmembrane Transport

• Only Gases and Small Uncharged Molecules Cross Membranes by Simple Diffusion
• Three Main Classes of Membrane Proteins Transport Molecules and Ions Across Cellular Membranes

11.2 Facilitated Transport of Glucose and Water

• Uniport Transport Is Faster and More Specific than Simple Diffusion
• The Low K(sub[m]) of the GLUT1 Uniporter Enables It to Transport Glucose into Most Mammalian Cells
• The Human Genome Encodes a Family of Sugar-Transporting GLUT Proteins
• Transport Proteins Can Be Studied Using Artificial Membranes and Recombinant Cells
• Osmotic Pressure Causes Water to Move Across Membranes
• Aquaporins Increase the Water Permeability of Cellular Membranes

11.3 ATP-Powered Pumps and the Intracellular Ionic Environment

• There Are Four Main Classes of ATP-Powered Pumps
• ATP-Powered Ion Pumps Generate and Maintain Ionic Gradients Across Cellular Membranes
• Muscle Relaxation Depends on Ca(sup[2+]) ATPases That Pump Ca(sup[2+]) from the Cytosol into the Sar
• The Mechanism of Action of the Ca(sup[2+]) Pump Is Known in Detail
• Calmodulin Regulates the Plasma-Membrane Pumps That Control Cytosolic Ca(sup[2+]) Concentrations
• The Na(sup[+])/K(sup[+]) ATPase Maintains the Intracellular Na(sup[+]) and K(sup[+]) Concentrations
• V-Class H(sup[+]) ATPases Maintain the Acidity of Lysosomes and Vacuoles
• ABC Proteins Export a Wide Variety of Drugs and Toxins from the Cell
• Certain ABC Proteins “Flip” Phospholipids and Other Lipid-Soluble Substrates from One Membrane Leafl
• The ABC Cystic Fibrosis Transmembrane Regulator Is a Chloride Channel, Not a Pump

11.4 Nongated Ion Channels and the Resting Membrane Potential

• Selective Movement of Ions Creates a Transmembrane Electric Gradient
• The Resting Membrane Potential in Animal Cells Depends Largely on the Outward Flow of K+ Ions Throug
• Ion Channels Are Selective for Certain Ions by Virtue of a Molecular “Selectivity Filter”
• Patch Clamps Permit Measurement of Ion Movements Through Single Channels
• Novel Ion Channels Can Be Characterized by a Combination of Oocyte Expression and Patch Clamping

11.5 Cotransport by Symporters and Antiporters

• Na(sup[+]) Entry into Mammalian Cells Is Thermodynamically Favored
• Na(sup[+])-Linked Symporters Enable Animal Cells to Import Glucose and Amino Acids Against High Conc
• A Bacterial Na(sup[+])/Amino Acid Symporter Reveals How Symport Works
• A Na(sup[+])-Linked Ca(sup[2])+ Antiporter Regulates the Strength of Cardiac Muscle Contraction
• Several Cotransporters Regulate Cytosolic pH
• An Anion Antiporter Is Essential for Transport of CO(sub[2]) by Erythrocytes
• Numerous Transport Proteins Enable Plant Vacuoles to Accumulate Metabolites and Ions

11.6 Transcellular Transport

• Multiple Transport Proteins Are Needed to Move Glucose and Amino Acids Across Epithelia
• Simple Rehydration Therapy Depends on the Osmotic Gradient Created by Absorption of Glucose and Na(s
• Parietal Cells Acidify the Stomach Contents While Maintaining a Neutral Cytosolic pH
• Bone Resorption Requires the Coordinated Function of a V-Class Proton Pump and a Specific Chloride C

12 Cellular Energetics

12.1 First Step of Harvesting Energy from Glucose: Glycolysis

• During Glycolysis (Stage I), Cytosolic Enzymes Convert Glucose to Pyruvate
• The Rate of Glycolysis Is Adjusted to Meet the Cell’s Need for ATP
• Glucose Is Fermented When Oxygen Is Scarce

12.2 The Structure and Functions of Mitochondria

• Mitochondria Are Multifunctional Organelles
• Mitochondria Have Two Structurally and Functionally Distinct Membranes
• Mitochondria Contain DNA Located in the Matrix
• The Size, Structure, and Coding Capacity of mtDNA Vary Considerably Among Organisms
• Products of Mitochondrial Genes Are Not Exported
• Mitochondria Evolved from a Single Endosymbiotic Event Involving a Rickettsia-Like Bacterium
• Mitochondrial Genetic Codes Differ from the Standard Nuclear Code
• Mutations in Mitochondrial DNA Cause Several Genetic Diseases in Humans
• Mitochondria Are Dynamic Organelles That Interact Directly with One Another
• Mitochondria Are Influenced by Direct Contacts with the Endoplasmic Reticulum

12.3 The Citric Acid Cycle and Fatty Acid Oxidation

• In the First Part of Stage II, Pyruvate Is Converted to Acetyl CoA and High-Energy Electrons
• In the Second Part of Stage II, the Citric Acid Cycle Oxidizes the Acetyl Group in Acetyl CoA to CO(
• Transporters in the Inner Mitochondrial Membrane Help Maintain Appropriate Cytosolic and Matrix Conc
• Mitochondrial Oxidation of Fatty Acids Generates ATP
• Peroxisomal Oxidation of Fatty Acids Generates No ATP

12.4 The Electron-Transport Chain and Generation of the Proton-Motive Force

• Oxidation of NADH and FADH(sub[2]) Releases a Significant Amount of Energy
• Electron Transport in Mitochondria Is Coupled to Proton Pumping
• Electrons Flow “Downhill” Through a Series of Electron Carriers
• Four Large Multiprotein Complexes Couple Electron Transport to Proton Pumping Across the Inner Mitoc
• The Reduction Potentials of Electron Carriers in the Electron-Transport Chain Favor Electron Flow fr
• The Multiprotein Complexes of the Electron-Transport Chain Assemble into Supercomplexes
• Reactive Oxygen Species Are By-Products of Electron Transport
• Experiments Using Purified Electron-Transport Chain Complexes Established the Stoichiometry of Proto
• The Proton-Motive Force in Mitochondria Is Due Largely to a Voltage Gradient Across the Inner Membra

12.5 Harnessing the Proton-Motive Force to Synthesize ATP

• The Mechanism of ATP Synthesis Is Shared Among Bacteria, Mitochondria, and Chloroplasts
• ATP Synthase Comprises F(sub[0]) and F(sub[1]) Multiprotein Complexes
• Rotation of the F(sub[1]) γ Subunit, Driven by Proton Movement Through F(sub[0,]) Powers ATP Synthe
• Multiple Protons Must Pass Through ATP Synthase to Synthesize One ATP
• F(sub[0]) c Ring Rotation Is Driven by Protons Flowing Through Transmembrane Channels
• ATP-ADP Exchange Across the Inner Mitochondrial Membrane Is Powered by the Proton-Motive Force
• The Rate of Mitochondrial Oxidation Normally Depends on ADP Levels
• Mitochondria in Brown Fat Use the Proton-Motive Force to Generate Heat

12.6 Photosynthesis and Light-Absorbing Pigments

• Thylakoid Membranes in Chloroplasts Are the Sites of Photosynthesis in Plants
• Chloroplasts Contain Large DNAs Often Encoding More Than a Hundred Proteins
• Three of the Four Stages in Photosynthesis Occur Only During Illumination
• Photosystems Comprise a Reaction Center and Associated Light-Harvesting Complexes
• Photoelectron Transport from Energized Reaction-Center Chlorophyll α Produces a Charge Separation
• Internal Antennas and Light-Harvesting Complexes Increase the Efficiency of Photosynthesis

12.7 Molecular Analysis of Photosystems

• The Single Photosystem of Purple Bacteria Generates a Proton-Motive Force but N(Sub[o]) O(Sub[2])
• Chloroplasts Contain Two Functionally and Spatially Distinct Photosystems
• Linear Electron Flow Through Both Plant Photosystems Generates a Proton-Motive Force, O(Sub[2]), and
• An Oxygen-Evolving Complex Is Located on the Luminal Surface of the PSII Reaction Center
• Multiple Mechanisms Protect Cells Against Damage from Reactive Oxygen Species During Photoelectron T
• Cyclic Electron Flow Through PSI Generates a Proton-Motive Force but No NADPH or O(Sub[2])
• Relative Activities of Photosystems I and II Are Regulated

12.8 CO(Sub[2]) Metabolism During Photosynthesis

• Rubisco Fixes CO(Sub[2]) in the Chloroplast Stroma
• Synthesis of Sucrose Using Fixed CO(Sub[2]) Is Completed in the Cytosol
• Light and Rubisco Activase Stimulate CO(Sub[2]) Fixation
• Photorespiration Competes with Carbon Fixation and Is Reduced in C(Sub[4]) Plants

13 Moving Proteins into Membranes and Organelles

13.1 Targeting Proteins To and Across the ER Membrane

• Pulse-Chase Experiments with Purified ER Membranes Demonstrated That Secreted Proteins Cross the ER
• A Hydrophobic N-Terminal Signal Sequence Targets Nascent Secretory Proteins to the ER
• Cotranslational Translocation Is Initiated by Two GTP-Hydrolyzing Proteins
• Passage of Growing Polypeptides Through the Translocon Is Driven by Translation
• ATP Hydrolysis Powers Post-translational Translocation of Some Secretory Proteins in Yeast

13.2 Insertion of Membrane Proteins into the ER

• Several Topological Classes of Integral Membrane Proteins Are Synthesized on the ER
• Internal Stop-Transfer Anchor and Signal-Anchor Sequences Determine Topology of Single-Pass Proteins
• Multipass Proteins Have Multiple Internal Topogenic Sequences
• A Phospholipid Anchor Tethers Some Cell-Surface Proteins to the Membrane
• The Topology of a Membrane Protein Can Often Be Deduced from Its Sequence

13.3 Protein Modifications, Folding, and Quality Control in the ER

• A Preformed N-Linked Oligosaccharide Is Added to Many Proteins in the Rough ER
• Oligosaccharide Side Chains May Promote Folding and Stability of Glycoproteins
• Disulfide Bonds Are Formed and Rearranged by Proteins in the ER Lumen
• Chaperones and Other ER Proteins Facilitate Folding and Assembly of Proteins
• Improperly Folded Proteins in the ER Induce Expression of Protein-Folding Catalysts
• Unassembled or Misfolded Proteins in the ER Are Often Transported to the Cytosol for Degradation

13.4 Targeting of Proteins to Mitochondria and Chloroplasts

• Amphipathic N-Terminal Targeting Sequences Direct Proteins to the Mitochondrial Matrix
• Mitochondrial Protein Import Requires Outer-Membrane Receptors and Translocons in Both Membranes
• Studies with Chimeric Proteins Demonstrate Important Features of Mitochondrial Protein Import
• Three Energy Inputs Are Needed to Import Proteins into Mitochondria
• Multiple Signals and Pathways Target Proteins to Submitochondrial Compartments
• Import of Chloroplast Stromal Proteins Is Similar to Import of Mitochondrial Matrix Proteins
• Proteins Are Targeted to Thylakoids by Mechanisms Related to Bacterial Protein Translocation

13.5 Targeting of Peroxisomal Proteins

• A Cytosolic Receptor Targets Proteins with an SKL Sequence at the C-Terminus to the Peroxisomal Matr
• Peroxisomal Membrane and Matrix Proteins Are Incorporated by Different Pathways

13.6 Transport Into and Out of the Nucleus

• Large and Small Molecules Enter and Leave the Nucleus via Nuclear Pore Complexes
• Nuclear Transport Receptors Escort Proteins Containing Nuclear-Localization Signals into the Nucleus
• A Second Type of Nuclear Transport Receptor Escorts Proteins Containing Nuclear-Export Signals Out o
• Most mRNAs Are Exported from the Nucleus by a Ran-Independent Mechanism

14 Vesicular Traffic, Secretion, and Endocytosis

14.1 Techniques for Studying the Secretory Pathway

• Transport of a Protein Through the Secretory Pathway Can Be Assayed in Live Cells
• Yeast Mutants Define Major Stages and Many Components in Vesicular Transport
• Cell-Free Transport Assays Allow Dissection of Individual Steps in Vesicular Transport

14.2 Molecular Mechanisms of Vesicle Budding and Fusion

• Assembly of a Protein Coat Drives Vesicle Formation and Selection of Cargo Molecules
• A Conserved Set of GTPase Switch Proteins Controls the Assembly of Different Vesicle Coats
• Targeting Sequences on Cargo Proteins Make Specific Molecular Contacts with Coat Proteins
• Rab GTPases Control Docking of Vesicles on Target Membranes
• Paired Sets of SNARE Proteins Mediate Fusion of Vesicles with Target Membranes
• Dissociation of SNARE Complexes After Membrane Fusion Is Driven by ATP Hydrolysis

14.3 Early Stages of the Secretory Pathway

• COPII Vesicles Mediate Transport from the ER to the Golgi
• COPI Vesicles Mediate Retrograde Transport Within the Golgi and from the Golgi to the ER
• Anterograde Transport Through the Golgi Occurs by Cisternal Maturation

14.4 Later Stages of the Secretory Pathway

• Vesicles Coated with Clathrin and Adapter Proteins Mediate Transport from the trans-Golgi
• Dynamin Is Required for Pinching Off of Clathrin-Coated Vesicles
• Mannose 6-Phosphate Residues Target Soluble Proteins to Lysosomes
• Study of Lysosomal Storage Diseases Revealed Key Components of the Lysosomal Sorting Pathway
• Protein Aggregation in the trans-Golgi May Function in Sorting Proteins to Regulated Secretory Vesic
• Some Proteins Undergo Proteolytic Processing After Leaving the trans-Golgi
• Several Pathways Sort Membrane Proteins to the Apical or Basolateral Region of Polarized Cells

14.5 Receptor-Mediated Endocytosis

• Cells Take Up Lipids from the Blood in the Form of Large, Well-Defined Lipoprotein Complexes
• Receptors for Macromolecular Ligands Contain Sorting Signals That Target Them for Endocytosis
• The Acidic pH of Late Endosomes Causes Most Receptor-Ligand Complexes to Dissociate
• The Endocytic Pathway Delivers Iron to Cells Without Dissociation of the Transferrin–Transferrin R

14.6 Directing Membrane Proteins and Cytosolic Materials to the Lysosome

• Multivesicular Endosomes Segregate Membrane Proteins Destined for the Lysosomal Membrane from Protei
• Retroviruses Bud from the Plasma Membrane by a Process Similar to Formation of Multivesicular Endoso
• The Autophagic Pathway Delivers Cytosolic Proteins or Entire Organelles to Lysosomes

15 Signal Transduction and G Protein–Coupled Receptors

15.1 Signal Transduction: From Extracellular Signal to Cellular Response

• Signaling Molecules Can Act Locally or at a Distance
• Receptors Bind Only a Single Type of Hormone or a Group of Closely Related Hormones
• Protein Kinases and Phosphatases Are Employed in Many Signaling Pathways
• GTP-Binding Proteins Are Frequently Used in Signal Transduction Pathways as On/Off Switches
• Intracellular “Second Messengers” Transmit Signals from Many Receptors
• Signal Transduction Pathways Can Amplify the Effects of Extracellular Signals

15.2 Studying Cell-Surface Receptors and Signal Transduction Proteins

• The Dissociation Constant Is a Measure of the Affinity of a Receptor for Its Ligand
• Binding Assays Are Used to Detect Receptors and Determine Their Affinity and Specificity for Ligands
• Near-Maximal Cellular Response to a Signaling Molecule Usually Does Not Require Activation of All Re
• Sensitivity of a Cell to External Signals Is Determined by the Number of Cell-Surface Receptors and
• Hormone Analogs Are Widely Used as Drugs
• Receptors Can Be Purified by Affinity Chromatography Techniques
• Immunoprecipitation Assays and Affinity Techniques Can Be Used to Study the Activity of Signal Trans

15.3 G Protein–Coupled Receptors: Structure and Mechanism

• All G Protein–Coupled Receptors Share the Same Basic Structure
• Ligand-Activated G Protein–Coupled Receptors Catalyze Exchange of GTP for GDP on the α Subunit of
• Different G Proteins Are Activated by Different GPCRs and In Turn Regulate Different Effector Protei

15.4 G Protein–Coupled Receptors That Regulate Ion Channels

• Acetylcholine Receptors in the Heart Muscle Activate a G Protein That Opens K(sup[+]) Channels
• Light Activates Rhodopsin in Rod Cells of the Eye
• Activation of Rhodopsin by Light Leads to Closing of cGMP-Gated Cation Channels
• Signal Amplification Makes the Rhodopsin Signal Transduction Pathway Exquisitely Sensitive
• Rapid Termination of the Rhodopsin Signal Transduction Pathway Is Essential for the Temporal Resolut
• Rod Cells Adapt to Varying Levels of Ambient Light by Intracellular Trafficking of Arrestin and Tran

15.5 G Protein–Coupled Receptors That Activate or Inhibit Adenylyl Cyclase

• Adenylyl Cyclase Is Stimulated and Inhibited by Different Receptor-Ligand Complexes
• Structural Studies Established How G(sub[as])·GTP Binds to and Activates Adenylyl Cyclase
• cAMP Activates Protein Kinase A by Releasing Inhibitory Subunits
• Glycogen Metabolism Is Regulated by Hormone-Induced Activation of PKA
• cAMP-Mediated Activation of PKA Produces Diverse Responses in Different Cell Types
• Signal Amplification Occurs in the cAMP-PKA Pathway
• CREB Links cAMP and PKA to Activation of Gene Transcription
• Anchoring Proteins Localize Effects of cAMP to Specific Regions of the Cell
• Multiple Mechanisms Suppress Signaling from the GPCR/cAMP/PKA Pathway

15.6 G Protein–Coupled Receptors That Trigger Elevations in Cytosolic and Mitochondrial Calcium

• Calcium Concentrations in the Mitochondrial Matrix, ER, and Cytosol Can Be Measured with Targeted Fl
• Activated Phospholipase C Generates Two Key Second Messengers Derived from the Membrane Lipid Phosph
• The Ca(sup[2+])-Calmodulin Complex Mediates Many Cellular Responses to External Signals
• DAG Activates Protein Kinase C
• Integration of Ca(sup[2+]) and cAMP Second Messengers Regulates Glycogenolysis
• Signal-Induced Relaxation of Vascular Smooth Muscle Is Mediated by a Ca(sup[2+])-Nitric Oxide-cGMP-A

16 Signaling Pathways That Control Gene Expression

16.1 Receptor Serine Kinases That Activate Smads

• TGF-ß Proteins Are Stored in an Inactive Form in the Extracellular Matrix
• Three Separate TGF-ß Receptor Proteins Participate in Binding TGF-ß and Activating Signal Transduction
• Activated TGF-ß Receptors Phosphorylate Smad Transcription Factors
• The Smad3/Smad4 Complex Activates Expression of Different Genes in Different Cell Types
• Negative Feedback Loops Regulate TGF-ß/Smad Signaling
• Medical: Loss of TGF-b signaling

16.2 Cytokine Receptors and the JAK/STAT Signaling Pathway

• Cytokines Influence the Development of Many Cell Types
• Binding of a Cytokine to Its Receptor Activates One or More Tightly Bound JAK Protein Tyrosine Kinas
• Phosphotyrosine Residues Are Binding Surfaces for Multiple Proteins with Conserved Domains
• SH2 Domains in Action: JAK Kinases Activate STAT Transcription Factors
• Multiple Mechanisms Down-Regulate Signaling from Cytokine Receptors

16.3 Receptor Tyrosine Kinases

• Binding of Ligand Promotes Dimerization of an RTK and Leads to Activation of Its Intrinsic Tyrosine
• Homo-and Hetero-oligomers of Epidermal Growth Factor Receptors Bind Members of the Epidermal Growth
• Activation of the EGF Receptor Results in the Formation of an Asymmetric Active Kinase Dimer
• Multiple Mechanisms Down-Regulate Signaling from RTKs

16.4 The Ras/MAP Kinase Pathway

• Ras, a GTPase Switch Protein, Operates Downstream of Most RTKs and Cytokine Receptors
• Genetic Studies in Drosophila Identified Key Signal-Transducing Proteins in the Ras/MAP Kinase Pathw
• Receptor Tyrosine Kinases Are Linked to Ras by Adapter Proteins
• Binding of Sos to Inactive Ras Causes a Conformational Change That Triggers an Exchange of GTP for G
• Signals Pass from Activated Ras to a Cascade of Protein Kinases Ending with MAP Kinase
• Phosphorylation of MAP Kinase Results in a Conformational Change That Enhances Its Catalytic Activit
• MAP Kinase Regulates the Activity of Many Transcription Factors Controlling Early Response Genes
• G Protein–Coupled Receptors Transmit Signals to MAP Kinase in Yeast Mating Pathways
• Scaffold Proteins Separate Multiple MAP Kinase Pathways in Eukaryotic Cells

16.5 Phosphoinositide Signaling Pathways

• Phospholipase Cγ Is Activated by Some RTKs and Cytokine Receptors
• Recruitment of PI-3 Kinase to Activated Receptors Leads to Synthesis of Three Phosphorylated Phospha
• Accumulation of PI 3-Phosphates in the Plasma Membrane Leads to Activation of Several Kinases
• Activated Protein Kinase B Induces Many Cellular Responses
• The PI-3 Kinase Pathway Is Negatively Regulated by PTEN Phosphatase
• 16.6 Signaling Pathways Controlled by Ubiquitinylation and Protein Degradation: Wnt, Hedgehog, and N
• Wnt Signaling Triggers Release of a Transcription Factor from a Cytosolic Protein Complex
• Concentration Gradients of Wnt Protein Are Essential for Many Steps in Development
• Hedgehog Signaling Relieves Repression of Target Genes
• Hedgehog Signaling in Vertebrates Requires Primary Cilia
• Degradation of an Inhibitor Protein Activates the NF-?B Transcription Factor
• Polyubiquitin Chains Serve as Scaffolds Linking Receptors to Downstream Proteins in the NF-κB Pathw

16.7 Signaling Pathways Controlled by Protein Cleavage: Notch/Delta, SREBP, and Alzheimer’s Disease

• On Binding Delta, the Notch Receptor Is Cleaved, Releasing a Component Transcription Factor
• Matrix Metalloproteases Catalyze Cleavage of Many Signaling Proteins from the Cell Surface
• Inappropriate Cleavage of Amyloid Precursor Protein Can Lead to Alzheimer’s Disease
• Regulated Intramembrane Proteolysis of SREBPs Releases a Transcription Factor That Acts to Maintain
• 16.8 Integration of Cellular Responses to Multiple Signaling Pathways: Insulin Action
• Insulin and Glucagon Work Together to Maintain a Stable Blood Glucose Level
• A Rise in Blood Glucose Triggers Insulin Secretion from the ß Islet Cells
• In Fat and Muscle Cells, Insulin Triggers Fusion of Intracellular Vesicles Containing the GLUT4 Gluc
• Insulin Inhibits Glucose Synthesis and Enhances Storage of Glucose as Glycogen
• Multiple Signal Transduction Pathways Interact to Regulate Adipocyte Differentiation Through PPARγ,
• Inflammatory Hormones Cause Derangement of Adipose Cell Function in Obesity

17 Cell Organization and Movement I: Microfilaments

17.1 Microfilaments and Actin Structures

• Actin Is Ancient, Abundant, and Highly Conserved
• G-Actin Monomers Assemble into Long, Helical F-Actin Polymers
• F-Actin Has Structural and Functional Polarity

17.2 Dynamics of Actin Filaments

• Actin Polymerization In Vitro Proceeds in Three Steps
• Actin Filaments Grow Faster at (+) Ends Than at (-) Ends
• Actin Filament Treadmilling Is Accelerated by Profilin and Cofilin
• Thymosin-ß(sub[4]) Provides a Reservoir of Actin for Polymerization
• Capping Proteins Block Assembly and Disassembly at Actin Filament Ends

17.3 Mechanisms of Actin Filament Assembly

• Formins Assemble Unbranched Filaments
• The Arp2/3 Complex Nucleates Branched Filament Assembly
• Intracellular Movements Can Be Powered by Actin Polymerization
• Microfilaments Function in Endocytosis
• Toxins That Perturb the Pool of Actin Monomers Are Useful for Studying Actin Dynamics

17.4 Organization of Actin-Based Cellular Structures

• Cross-Linking Proteins Organize Actin Filaments into Bundles or Networks
• Adapter Proteins Link Actin Filaments to Membranes

17.5 Myosins: Actin-Based Motor Proteins

• Myosins Have Head, Neck, and Tail Domains with Distinct Functions
• Myosins Make Up a Large Family of Mechanochemical Motor Proteins
• Conformational Changes in the Myosin Head Couple ATP Hydrolysis to Movement
• Myosin Heads Take Discrete Steps Along Actin Filaments

17.6 Myosin-Powered Movements

• Myosin Thick Filaments and Actin Thin Filaments in Skeletal Muscle Slide Past Each Other During Cont
• Skeletal Muscle Is Structured by Stabilizing and Scaffolding Proteins
• Contraction of Skeletal Muscle Is Regulated by Ca(sup[2+]) and Actin-Binding Proteins
• Actin and Myosin II Form Contractile Bundles in Nonmuscle Cells
• Myosin-Dependent Mechanisms Regulate Contraction in Smooth Muscle and Nonmuscle Cells
• Myosin V–Bound Vesicles Are Carried Along Actin Filaments

17.7 Cell Migration: Mechanism, Signaling, and Chemotaxis

• Cell Migration Coordinates Force Generation with Cell Adhesion and Membrane Recycling
• The Small GTP-Binding Proteins Cdc42, Rac, and Rho Control Actin Organization
• Cell Migration Involves the Coordinate Regulation of Cdc42, Rac, and Rho
• Migrating Cells Are Steered by Chemotactic Molecules

18 Cell Organization and Movement II: Microtubules and Intermediate Filaments

18.1 Microtubule Structure and Organization

• Microtubule Walls Are Polarized Structures Built from aß-Tubulin Dimers
• Microtubules Are Assembled from MTOCs to Generate Diverse Configurations

18.2 Microtubule Dynamics

• Individual Microtubules Exhibit Dynamic Instability
• Localized Assembly and “Search and Capture” Help Organize Microtubules
• Drugs Affecting Tubulin Polymerization Are Useful Experimentally and in Treatment of Diseases

18.3 Regulation of Microtubule Structure and Dynamics

• Microtubules Are Stabilized by Side-Binding Proteins
• +TIPs Regulate the Properties and Functions of the Microtubule (+) End
• Other End-Binding Proteins Regulate Microtubule Disassembly

18.4 Kinesins and Dyneins: Microtubule-Based Motor Proteins

• Organelles in Axons Are Transported Along Microtubules in Both Directions
• Kinesin-1 Powers Anterograde Transport of Vesicles Down Axons Toward the (+) Ends of Microtubules
• The Kinesins Form a Large Protein Superfamily with Diverse Functions
• Kinesin-1 Is a Highly Processive Motor
• Dynein Motors Transport Organelles Toward the (-) Ends of Microtubules
• Kinesins and Dyneins Cooperate in the Transport of Organelles Throughout the Cell
• Tubulin Modifications Distinguish Different Classes of Microtubules and Their Accessibility to Motor

18.5 Cilia and Flagella: Microtubule-Based Surface Structures

• Eukaryotic Cilia and Flagella Contain Long Doublet Microtubules Bridged by Dynein Motors
• Ciliary and Flagellar Beating Are Produced by Controlled Sliding of Outer Doublet Microtubules
• Intraflagellar Transport Moves Material Up and Down Cilia and Flagella
• Primary Cilia Are Sensory Organelles on Interphase Cells
• Defects in Primary Cilia Underlie Many Diseases

18.6 Mitosis

• Centrosomes Duplicate Early in the Cell Cycle in Preparation for Mitosis
• Mitosis Can Be Divided into Six Stages
• The Mitotic Spindle Contains Three Classes of Microtubules
• Microtubule Dynamics Increase Dramatically in Mitosis
• Mitotic Asters Are Pushed Apart by Kinesin-5 and Oriented by Dynein
• Chromosomes Are Captured and Oriented During Prometaphase
• Duplicated Chromosomes Are Aligned by Motors and Microtubule Dynamics
• The Chromosomal Passenger Complex Regulates Microtubule Attachment at Kinetochores
• Anaphase A: Moves Chromosomes to Poles by Microtubule Shortening
• Anaphase B: Separates Poles by the Combined Action of Kinesins and Dynein
• Additional Mechanisms Contribute to Spindle Formation
• Cytokinesis Splits the Duplicated Cell in Two
• Plant Cells Reorganize Their Microtubules and Build a New Cell Wall in Mitosis

18.7 Intermediate Filaments

• Intermediate Filaments Are Assembled from Subunit Dimers
• Intermediate Filaments Are Dynamic
• Cytoplasmic Intermediate Filament Proteins Are Expressed in a Tissue-Specific Manner
• Lamins Line the Inner Nuclear Envelope To Provide Organization and Rigidity to the Nucleus
• Lamins Are Reversibly Disassembled by Phosphorylation During Mitosis

18.8 Coordination and Cooperation Between Cytoskeletal Elements

• Intermediate Filament–Associated Proteins Contribute to Cellular Organization
• Microfilaments and Microtubules Cooperate to Transport Melanosomes
• Cdc42 Coordinates Microtubules and Microfilaments During Cell Migration
• Advancement of Neural Growth Cones Is Coordinated by Microfilaments and Microtubules

19 The Eukaryotic Cell Cycle

19.1 Overview of the Cell Cycle and Its Control

• The Cell Cycle Is an Ordered Series of Events Leading to Cell Replication
• Cyclin-Dependent Kinases Control the Eukaryotic Cell Cycle
• Several Key Principles Govern the Cell Cycle

19.2 Model Organisms and Methods of Studying the Cell Cycle

• Budding and Fission Yeasts Are Powerful Systems for Genetic Analysis of the Cell Cycle
• Frog Oocytes and Early Embryos Facilitate Biochemical Characterization of the Cell Cycle Machinery
• Fruit Flies Reveal the Interplay Between Development and the Cell Cycle
• The Study of Tissue Culture Cells Uncovers Cell Cycle Regulation in Mammals
• Researchers Use Multiple Tools to Study the Cell Cycle

19.3 Regulation of CDK Activity

• Cyclin-Dependent Kinases Are Small Protein Kinases That Require a Regulatory Cyclin Subunit for Thei
• Cyclins Determine the Activity of CDKs
• Cyclin Levels Are Primarily Regulated by Protein Degradation
• CDKs Are Regulated by Activating and Inhibitory Phosphorylation
• CDK Inhibitors Control Cyclin-CDK Activity
• Genetically Engineered CDKs Led to the Discovery of CDK Functions

19.4 Commitment to the Cell Cycle and DNA Replication

• Cells Are Irreversibly Committed to Division at a Cell Cycle Point Called START or the Restriction P
• The E2F Transcription Factor and Its Regulator Rb Control the G(sup[1])–S Phase Transition in Meta
• Extracellular Signals Govern Cell Cycle Entry
• Degradation of an S Phase CDK Inhibitor Triggers DNA Replication
• Replication at Each Origin Is Initiated Once and Only Once During the Cell Cycle
• Duplicated DNA Strands Become Linked During Replication

19.5 Entry into Mitosis

• Precipitous Activation of Mitotic CDKs Initiates Mitosis
• Mitotic CDKs Promote Nuclear Envelope Breakdown
• Mitotic CDKs Promote Mitotic Spindle Formation
• Chromosome Condensation Facilitates Chromosome Segregation

19.6 Completion of Mitosis: Chromosome Segregation and Exit from Mitosis

• Separase-Mediated Cleavage of Cohesins Initiates Chromosome Segregation
• APC/C Activates Separase Through Securin Ubiquitinylation
• Mitotic CDK Inactivation Triggers Exit from Mitosis
• Cytokinesis Creates Two Daughter Cells

19.7 Surveillance Mechanisms in Cell Cycle Regulation

• Checkpoint Pathways Establish Dependencies and Prevent Errors in the Cell Cycle
• The Growth Checkpoint Pathway Ensures That Cells Enter the Cell Cycle Only After Sufficient Macromol
• The DNA Damage Response System Halts Cell Cycle Progression When DNA Is Compromised
• The Spindle Assembly Checkpoint Pathway Prevents Chromosome Segregation Until Chromosomes Are Accura
• The Spindle Position Checkpoint Pathway Ensures That the Nucleus Is Accurately Partitioned Between T

19.8 Meiosis: A Special Type of Cell Division

• Extracellular and Intracellular Cues Regulate Germ Cell Formation
• Several Key Features Distinguish Meiosis from Mitosis
• Recombination and a Meiosis-Specific Cohesin Subunit Are Necessary for the Specialized Chromosome Se
• Co-orienting Sister Kinetochores Is Critical for Meiosis I Chromosome Segregation
• DNA Replication Is Inhibited Between the Two Meiotic Divisions

Part IV: Cell Growth and Differentiation

20 Integrating Cells into Tissues

20.1 Cell-Cell and Cell–Extracellular Matrix Adhesion: An Overview

• Cell-Adhesion Molecules Bind to One Another and to Intracellular Proteins
• The Extracellular Matrix Participates in Adhesion, Signaling, and Other Functions
• The Evolution of Multifaceted Adhesion Molecules Made Possible the Evolution of Diverse Animal Tissu
• Cell-Adhesion Molecules Mediate Mechanotransduction

20.2 Cell-Cell and Cell–Extracellular Junctions and Their Adhesion Molecules

• Epithelial Cells Have Distinct Apical, Lateral, and Basal Surfaces
• Three Types of Junctions Mediate Many Cell-Cell and Cell-ECM Interactions
• Cadherins Mediate Cell-Cell Adhesions in Adherens Junctions and Desmosomes
• Integrins Mediate Cell-ECM Adhesions, Including Those in Epithelial-Cell Hemidesmosomes
• Tight Junctions Seal Off Body Cavities and Restrict Diffusion of Membrane Components
• Gap Junctions Composed of Connexins Allow Small Molecules to Pass Directly Between the Cytosols of A

20.3 The Extracellular Matrix I: The Basal Lamina

• The Basal Lamina Provides a Foundation for Assembly of Cells into Tissues
• Laminin, a Multi-adhesive Matrix Protein, Helps Cross-Link Components of the Basal Lamina
• Sheet-Forming Type IV Collagen Is a Major Structural Component of the Basal Lamina
• Perlecan, a Proteoglycan, Cross-Links Components of the Basal Lamina and Cell-Surface Receptors

20.4 The Extracellular Matrix II: Connective Tissue

• Fibrillar Collagens Are the Major Fibrous Proteins in the ECM of Connective Tissues
• Fibrillar Collagen Is Secreted and Assembled into Fibrils Outside the Cell
• Type I and II Collagens Associate with Nonfibrillar Collagens to Form Diverse Structures
• Proteoglycans and Their Constituent GAGs Play Diverse Roles in the ECM
• Hyaluronan Resists Compression, Facilitates Cell Migration, and Gives Cartilage Its Gel-Like Propert
• Fibronectins Connect Cells and ECM, Influencing Cell Shape, Differentiation, and Movement
• Elastic Fibers Permit Many Tissues to Undergo Repeated Stretching and Recoiling
• Metalloproteases Remodel and Degrade the Extracellular Matrix

20.5 Adhesive Interactions in Motile and Nonmotile Cells

• Integrins Mediate Adhesion and Relay Signals Between Cells and Their Three-Dimensional Environment
• Regulation of Integrin-Mediated Adhesion and Signaling Controls Cell Movement
• Connections Between the ECM and Cytoskeleton Are Defective in Muscular Dystrophy
• IgCAMs Mediate Cell-Cell Adhesion in Neural and Other Tissues
• Leukocyte Movement into Tissues Is Orchestrated by a Precisely Timed Sequence of Adhesive Interactio

20.6 Plant Tissues

• The Plant Cell Wall Is a Laminate of Cellulose Fibrils in a Matrix of Glycoproteins
• Loosening of the Cell Wall Permits Plant Cell Growth
• Plasmodesmata Directly Connect the Cytosols of Adjacent Cells
• Tunneling Nanotubes Resemble Plasmodesmata and Transfer Molecules and Organelles Between Animal Cell
• Only a Few Adhesion Molecules Have Been Identified in Plants

21 Stem Cells, Cell Asymmetry, and Cell Death

21.1 Early Mammalian Development

• Fertilization Unifies the Genome
• Cleavage of the Mammalian Embryo Leads to the First Differentiation Events

21.2 Embryonic Stem Cells and Induced Pluripotent Stem Cells

• The Inner Cell Mass Is the Source of ES Cells
• Multiple Factors Control the Pluripotency of ES Cells
• Animal Cloning Shows That Differentiation Can Be Reversed
• Somatic Cells Can Generate iPS Cells
• ES and iPS Cells Can Generate Functional Differentiated Human Cells

21.3 Stem Cells and Niches in Multicellular Organisms

• Adult Planaria Contain Pluripotent Stem Cells
• Multipotent Somatic Stem Cells Give Rise to Both Stem Cells and Differentiating Cells
• Stem Cells for Different Tissues Occupy Sustaining Niches
• Germ-Line Stem Cells Produce Sperm or Oocytes
• Intestinal Stem Cells Continuously Generate All the Cells of the Intestinal Epithelium
• Hematopoietic Stem Cells Form All Blood Cells
• Rare Types of Cells Constitute the Niche for Hematopoietic Stem Cells
• Meristems Are Niches for Stem Cells in Plants
• A Negative Feedback Loop Maintains the Size of the Shoot Apical Stem-Cell Population
• The Root Meristem Resembles the Shoot Meristem in Structure and Function

21.4 Mechanisms of Cell Polarity and Asymmetric Cell Division

• The Intrinsic Polarity Program Depends on a Positive Feedback Loop Involving Cdc42
• Cell Polarization Before Cell Division Follows a Common Hierarchy of Steps
• Polarized Membrane Traffic Allows Yeast to Grow Asymmetrically During Mating
• The Par Proteins Direct Cell Asymmetry in the Nematode Embryo
• The Par Proteins and Other Polarity Complexes Are Involved in Epithelial-Cell Polarity
• The Planar Cell Polarity Pathway Orients Cells Within an Epithelium
• The Par Proteins Are Involved in Asymmetric Division of Stem Cells

21.5 Cell Death and Its Regulation

• Most Programmed Cell Death Occurs Through Apoptosis
• Evolutionarily Conserved Proteins Participate in the Apoptotic Pathway
• Caspases Amplify the Initial Apoptotic Signal and Destroy Key Cellular Proteins
• Neurotrophins Promote Survival of Neurons
• Mitochondria Play a Central Role in Regulation of Apoptosis in Vertebrate Cells
• The Pro-apoptotic Proteins Bax and Bak Form Pores and Holes in the Outer Mitochondrial Membrane
• Release of Cytochrome c and SMAC/DIABLO Proteins from Mitochondria Leads to Formation of the Apoptos
• Trophic Factors Induce Inactivation of Bad, a Pro-apoptotic BH3-Only Protein
• Vertebrate Apoptosis Is Regulated by BH3-Only Pro-apoptotic Proteins That Are Activated by Environme
• Two Types of Cell Murder Are Triggered by Tumor Necrosis Factor, Fas Ligand, and Related Death Signa

22 Cells of the Nervous System

22.1 Neurons and Glia: Building Blocks of the Nervous System

• Information Flows Through Neurons from Dendrites to Axons
• Information Moves Along Axons as Pulses of Ion Flow Called Action Potentials
• Information Flows Between Neurons via Synapses
• The Nervous System Uses Signaling Circuits Composed of Multiple Neurons
• Glial Cells Form Myelin Sheaths and Support Neurons
• Neural Stem Cells Form Nerve and Glial Cells in the Central Nervous System

22.2 Voltage-Gated Ion Channels and the Propagation of Action Potentials

• The Magnitude of the Action Potential Is Close to E(sub[Na]) and Is Caused by Na(sup[+]) Influx Thro
• Sequential Opening and Closing of Voltage-Gated Na(sup[+]) and K(sup[+]) Channels Generate Action Po
• Action Potentials Are Propagated Unidirectionally Without Diminution
• Nerve Cells Can Conduct Many Action Potentials in the Absence of ATP
• All Voltage-Gated Ion Channels Have Similar Structures
• Voltage-Sensing S4 α Helices Move in Response to Membrane Depolarization
• Movement of the Channel-Inactivating Segment into the Open Pore Blocks Ion Flow
• Myelination Increases the Velocity of Impulse Conduction
• Action Potentials “Jump” from Node to Node in Myelinated Axons
• Two Types of Glia Produce Myelin Sheaths
• Light-Activated Ion Channels and Optogenetics

22.3 Communication at Synapses

• Formation of Synapses Requires Assembly of Presynaptic and Postsynaptic Structures
• Neurotransmitters Are Transported into Synaptic Vesicles by H(sup[+])-Linked Antiport Proteins
• Three Pools of Synaptic Vesicles Loaded with Neuro transmitter Are Present in the Presynaptic Termin
• Influx of Ca(sup[2+]) Triggers Release of Neurotransmitters
• A Calcium-Binding Protein Regulates Fusion of Synaptic Vesicles with the Plasma Membrane
• Fly Mutants Lacking Dynamin Cannot Recycle Synaptic Vesicles
• Signaling at Synapses Is Terminated by Degradation or Reuptake of Neurotransmitters
• Opening of Acetylcholine-Gated Cation Channels Leads to Muscle Contraction
• All Five Subunits in the Nicotinic Acetylcholine Receptor Contribute to the Ion Channel
• Nerve Cells Integrate Many Inputs to Make an All-or-None Decision to Generate an Action Potential
• Gap Junctions Allow Direct Communication Between Neurons and Between Glia

22.4 Sensing the Environment: Touch, Pain, Taste, and Smell

• Mechanoreceptors Are Gated Cation Channels
• Pain Receptors Are Also Gated Cation Channels
• Five Primary Tastes Are Sensed by Subsets of Cells in Each Taste Bud
• A Plethora of Receptors Detect Odors
• Each Olfactory Receptor Neuron Expresses a Single Type of Odorant Receptor

22.5 Forming and Storing Memories

• Memories Are Formed by Changing the Number or Strength of Synapses Between Neurons
• The Hippocampus Is Required for Memory Formation
• Multiple Molecular Mechanisms Contribute to Synaptic Plasticity
• Formation of Long-Term Memories Requires Gene Expression

23 Immunology

23.1 Overview of Host Defenses

• Pathogens Enter the Body Through Different Routes and Replicate at Different Sites
• Leukocytes Circulate Throughout the Body and Take Up Residence in Tissues and Lymph Nodes
• Mechanical and Chemical Boundaries Form a First Layer of Defense Against Pathogens
• Innate Immunity Provides a Second Line of Defense
• Inflammation Is a Complex Response to Injury That Encompasses Both Innate and Adaptive Immunity
• Adaptive Immunity, the Third Line of Defense, Exhibits Specificity

23.2 Immunoglobulins: Structure and Function

• Immunoglobulins Have a Conserved Structure Consisting of Heavy and Light Chains
• Multiple Immunoglobulin Isotypes Exist, Each with Different Functions
• Each Naive B Cell Produces a Unique Immunoglobulin
• Immunoglobulin Domains Have a Characteristic Fold Composed of Two ß Sheets Stabilized by a Disulfid
• An Immunoglobulin’s Constant Region Determines Its Functional Properties

23.3 Generation of Antibody Diversity and B-Cell Development

• A Functional Light-Chain Gene Requires Assembly of V and J Gene Segments
• Rearrangement of the Heavy-Chain Locus Involves V, D, and J Gene Segments
• Somatic Hypermutation Allows the Generation and Selection of Antibodies with Improved Affinities
• B-Cell Development Requires Input from a Pre-B-Cell Receptor
• During an Adaptive Response, B Cells Switch from Making Membrane-Bound Ig to Making Secreted Ig
• B Cells Can Switch the Isotype of Immunoglobulin They Make

23.4 The MHC and Antigen Presentation

• The MHC Determines the Ability of Two Unrelated Individuals of the Same Species to Accept or Reject
• The Killing Activity of Cytotoxic T Cells Is Antigen Specific and MHC Restricted
• T Cells with Different Functional Properties Are Guided by Two Distinct Classes of MHC Molecules
• MHC Molecules Bind Peptide Antigens and Interact with the T-Cell Receptor
• Antigen Presentation Is the Process by Which Protein Fragments Are Complexed with MHC Products and P
• The Class I MHC Pathway Presents Cytosolic Antigens
• The Class II MHC Pathway Presents Antigens Delivered to the Endocytic Pathway

23.5 T Cells, T-Cell Receptors, and T-Cell Development

• The Structure of the T-Cell Receptor Resembles the F(ab) Portion of an Immunoglobulin
• TCR Genes Are Rearranged in a Manner Similar to Immunoglobulin Genes
• Many of the Variable Residues of TCRs Are Encoded in the Junctions Between V, D, and J Gene Segments
• Signaling via Antigen-Specific Receptors Triggers Proliferation and Differentiation of T and B Cells
• T Cells Capable of Recognizing MHC Molecules Develop Through a Process of Positive and Negative Sele
• T Cells Commit to the CD4 or CD8 Lineage in the Thymus
• T Cells Require Two Types of Signals for Full Activation
• Cytotoxic T Cells Carry the CD8 Co-receptor and Are Specialized for Killing
• T Cells Produce an Array of Cytokines That Provide Signals to Other Immune-System Cells
• Helper T Cells Are Divided into Distinct Subsets Based on Their Cytokine Production and Expression o
• Leukocytes Move in Response to Chemotactic Cues Provided by Chemokines

23.6 Collaboration of Immune-System Cells in the Adaptive Response

• Toll-Like Receptors Perceive a Variety of Pathogen-Derived Macromolecular Patterns
• Engagement of Toll-Like Receptors Leads to Activation of Antigen-Presenting Cells
• Production of High-Affinity Antibodies Requires Collaboration Between B and T cells
• Vaccines Elicit Protective Immunity Against a Variety of Pathogens
• The Immune System Defends Against Cancer

24 Cancer

24.1 How Tumor Cells Differ from Normal Cells

• The Genetic Makeup of Most Cancer Cells Is Dramatically Altered
• Cellular Housekeeping Functions Are Fundamentally Altered in Cancer Cells
• Uncontrolled Proliferation Is a Universal Trait of Cancer
• Cancer Cells Escape the Confines of Tissues
• Tumors Are Heterogeneous Organs That Are Sculpted by Their Environment
• Tumor Growth Requires Formation of New Blood Vessels
• Invasion and Metastasis Are Late Stages of Tumorigenesis

24.2 The Origins and Development of Cancer

• Carcinogens Induce Cancer by Damaging DNA
• Some Carcinogens Have Been Linked to Specific Cancers
• The Multi-hit Model Can Explain the Progress of Cancer
• Successive Oncogenic Mutations Can Be Traced in Colon Cancers
• Cancer Development Can Be Studied in Cultured Cells and in Animal Models

24.3 The Genetic Basis of Cancer

• Gain-of-Function Mutations Convert Proto-oncogenes into Oncogenes
• Cancer-Causing Viruses Contain Oncogenes or Activate Cellular Proto-oncogenes
• Loss-of-Function Mutations in Tumor-Suppressor Genes Are Oncogenic
• Inherited Mutations in Tumor-Suppressor Genes Increase Cancer Risk
• Epigenetic Changes Can Contribute to Tumorigenesis
• Micro-RNAs Can Promote and Inhibit Tumorigenesis
• Researchers Are Identifying Drivers of Tumorigenesis
• Molecular Cell Biology Is Changing How Cancer Is Diagnosed and Treated

24.4 Misregulation of Cell Growth and Death Pathways in Cancer

• Oncogenic Receptors Can Promote Proliferation in the Absence of External Growth Factors
• Many Oncogenes Encode Constitutively Active Signal-Transducing Proteins
• Inappropriate Production of Nuclear Transcription Factors Can Induce Transformation
• Aberrations in Signaling Pathways That Control Development Are Associated with Many Cancers
• Genes That Regulate Apoptosis Can Function as Proto-oncogenes or Tumor-Suppressor Genes

24.5 Deregulation of the Cell Cycle and Genome Maintenance Pathways in Cancer

• Mutations That Promote Unregulated Passage from G(sub[1]) to S Phase Are Oncogenic
• Loss of p53 Abolishes the DNA Damage Checkpoint
• Loss of DNA-Repair Systems Can Lead to Cancer