LECTURE PRESENTATIONS For CAMPBELL BIOLOGY, NINTH EDITION Jane B. Reece, Lisa A. Urry, Michael L. Cain, Steven A. Wasserman, Peter V. Minorsky, Robert B. Jackson Chapter 18 Regulation of Gene Expression Overview: Conducting the Genetic Orchestra Prokaryotes and eukaryotes alter gene expression in response to their changing environment In multicellular eukaryotes, gene expression regulates development and is responsible for differences in cell types molecules play many roles in regulating gene expression in eukaryotes Lectures by Erin Barley Kathleen Fitzpatrick Figure 18.1 Concept 18.1: Bacteria often respond to environmental change by regulating transcription Natural selection has favored bacteria that produce only the products needed by that cell A cell can regulate the production of enzymes by feedback inhibition or by gene regulation Gene expression in bacteria is controlled by the operon model Figure 18.2 Feedback inhibition Precursor trpe gene Operons: The Basic Concept - Tryptophan Enzyme 1 Enzyme 2 Enzyme 3 trpd gene trpc gene trpb gene trpa gene Regulation of gene expression - A cluster of functionally related genes can be under coordinated control by a single on-off switch The regulatory switch is a segment of called an operator usually positioned within the promoter An operon is the entire stretch of that includes the operator, the promoter, and the genes that they control (a) Regulation of enzyme activity (b) Regulation of enzyme production 1
The operon can be switched off by a protein The prevents gene transcription by binding to the operator and blocking polymerase The is the product of a separate regulatory gene The can be in an active or inactive form, depending on the presence of other molecules A co is a molecule that cooperates with a protein to switch an operon off For example, E. coli can synthesize the amino acid tryptophan Figure 18.3 trp operon Genes of operon By default the trp operon is on and the genes for tryptophan synthesis are transcribed When tryptophan is present, it binds to the trp protein, which turns the operon off The is active only in the presence of its co tryptophan; thus the trp operon is turned off (repressed) if tryptophan levels are high Regulatory gene 5ʹ trpr 3ʹ Inactive polymerase Operator 5ʹ Start codon (a) Tryptophan absent, inactive, operon on trpe trpd trpc trpb trpa Stop codon E D C B A No made Polypeptide subunits that make up enzymes for tryptophan synthesis Active Tryptophan (co) (b) Tryptophan present, active, operon off Figure 18.3a Figure 18.3b-1 trp operon Regulatory gene 5ʹ trpr 3ʹ Inactive Genes of operon Operator Start codon Stop codon polymerase 5ʹ (a) Tryptophan absent, inactive, operon on trpe trpd trpc trpb trpa E D C B A Polypeptide subunits that make up enzymes for tryptophan synthesis Tryptophan (co) (b) Tryptophan present, active, operon off Active 2
Figure 18.3b-2 Tryptophan (co) (b) Tryptophan present, active, operon off No made Active Repressible and Inducible Operons: Two Types of Negative Gene Regulation A repressible operon is one that is usually on; binding of a to the operator shuts off transcription The trp operon is a repressible operon An inducible operon is one that is usually off; a molecule called an inducer inactivates the and turns on transcription Figure 18.4 Regulatory gene Operator The lac operon is an inducible operon and contains genes that code for enzymes used in the hydrolysis and metabolism of lactose By itself, the lac is active and switches the lac operon off A molecule called an inducer inactivates the to turn the lac operon on 5ʹ laci (a) Lactose absent, active, operon off 5ʹ laci 3ʹ 3ʹ polymerase Active polymerase 5ʹ lacz No made lac operon lacz lacy laca β-galactosidase Permease Transacetylase Allolactose (inducer) Inactive (b) Lactose present, inactive, operon on Figure 18.4a Figure 18.4b Regulatory gene 5ʹ laci 3ʹ polymerase Operator lacz No made 5ʹ laci polymerase 3ʹ 5ʹ lac operon lacz lacy laca β-galactosidase Permease Transacetylase Active Allolactose (inducer) Inactive (b) Lactose present, inactive, operon on (a) Lactose absent, active, operon off 3
Positive Gene Regulation Inducible enzymes usually function in catabolic pathways; their synthesis is induced by a chemical signal Repressible enzymes usually function in anabolic pathways; their synthesis is repressed by high levels of the end product Regulation of the trp and lac operons involves negative control of genes because operons are switched off by the active form of the Some operons are also subject to positive control through a stimulatory protein, such as catabolite activator protein (CAP), an activator of transcription When glucose (a preferred food source of E. coli) is scarce, CAP is activated by binding with cyclic AMP (camp) Activated CAP attaches to the promoter of the lac operon and increases the affinity of polymerase, thus accelerating transcription Figure 18.5 When glucose levels increase, CAP detaches from the lac operon, and transcription returns to a normal rate CAP helps regulate other operons that encode enzymes used in catabolic pathways laci CAP-binding site camp lacz Operator polymerase Active binds and CAP transcribes Inactive CAP Allolactose Inactive lac (a) Lactose present, glucose scarce (camp level high): abundant lac synthesized laci CAP-binding site Inactive CAP lacz Operator polymerase less likely to bind Inactive lac (b) Lactose present, glucose present (camp level low): little lac synthesized Figure 18.5a Figure 18.5b laci CAP-binding site camp Active CAP Inactive CAP Allolactose lacz Operator polymerase binds and transcribes Inactive lac (a) Lactose present, glucose scarce (camp level high): abundant lac synthesized laci CAP-binding site Inactive CAP lacz Operator polymerase less likely to bind Inactive lac (b) Lactose present, glucose present (camp level low): little lac synthesized 4
Concept 18.2: Eukaryotic gene expression is regulated at many stages All organisms must regulate which genes are expressed at any given time In multicellular organisms regulation of gene expression is essential for cell specialization Differential Gene Expression Almost all the cells in an organism are genetically identical Differences between cell types result from differential gene expression, the expression of different genes by cells with the same genome Abnormalities in gene expression can lead to diseases including cancer Gene expression is regulated at many stages Figure 18.6 Signal Figure 18.6a Signal Cap Degradation of Degradation of protein Gene NUCLEUS Chromatin Chromatin modification: unpacking involving histone acetylation and demethylation Exon Intron Gene available for transcription Primary transcript processing Tail in nucleus Transport to cytoplasm CYTOPLASM in cytoplasm Translation Polypeptide processing, such as cleavage and chemical modification Active protein Transport to cellular destination Cellular function (such as enzymatic activity, structural support) Cap Gene NUCLEUS Chromatin Chromatin modification: unpacking involving histone acetylation and demethylation Gene available for transcription Exon Primary transcript Intron processing Tail in nucleus Transport to cytoplasm CYTOPLASM Figure 18.6b CYTOPLASM in cytoplasm Regulation of Chromatin Structure Degradation of Translation Polypeptide processing, such as cleavage and chemical modification Genes within highly packed heterochromatin are usually not expressed Chemical modifications to histones and of chromatin influence both chromatin structure and gene expression Degradation of protein Active protein Transport to cellular destination Cellular function (such as enzymatic activity, structural support) 5
Histone Modifications In histone acetylation, acetyl groups are attached to positively charged lysines in histone tails This loosens chromatin structure, thereby promoting the initiation of transcription The addition of methyl groups (methylation) can condense chromatin; the addition of phosphate groups (phosphorylation) next to a methylated amino acid can loosen chromatin Figure 18.7 Amino acids available for chemical modification Histone tails double helix Nucleosome (end view) (a) Histone tails protrude outward from a nucleosome Animation: Packing Unacetylated histones Acetylated histones (b) Acetylation of histone tails promotes loose chromatin structure that permits transcription Methylation The histone code hypothesis proposes that specific combinations of modifications, as well as the order in which they occur, help determine chromatin configuration and influence transcription methylation, the addition of methyl groups to certain bases in, is associated with reduced transcription in some species methylation can cause long-term inactivation of genes in cellular differentiation In genomic imprinting, methylation regulates expression of either the maternal or paternal alleles of certain genes at the start of development Epigenetic Inheritance Although the chromatin modifications just discussed do not alter sequence, they may be passed to future generations of cells The inheritance of traits transmitted by mechanisms not directly involving the nucleotide sequence is called epigenetic inheritance Regulation of Initiation Chromatin-modifying enzymes provide initial control of gene expression by making a region of either more or less able to bind the transcription machinery 6
Organization of a Typical Eukaryotic Gene Associated with most eukaryotic genes are multiple control elements, segments of noncoding that serve as binding sites for transcription factors that help regulate transcription Control elements and the transcription factors they bind are critical to the precise regulation of gene expression in different cell types Figure 18.8-1 (distal control elements) Upstream Proximal control elements start site Poly-A signal sequence Exon Intron Exon Intron Exon termination region Downstream Figure 18.8-2 Figure 18.8-3 (distal control elements) Proximal control elements start site Poly-A signal sequence Exon Intron Exon Intron Exon termination region (distal control elements) Proximal control elements start site Poly-A signal sequence Exon Intron Exon Intron Exon termination region Upstream Primary transcript 5ʹ (pre-) Downstream Poly-A signal Exon Intron Exon Intron Exon Cleaved 3ʹ end of primary transcript Upstream Primary transcript 5ʹ (pre-) Downstream Poly-A signal Exon Intron Exon Intron Exon Cleaved 3ʹ end of processing primary transcript Intron G P P P 5ʹ Cap 5ʹ UTR Coding segment Start Stop codon codon AAA AAA 3ʹ 3ʹ UTR Poly-A tail The Roles of Factors To initiate transcription, eukaryotic polymerase requires the assistance of proteins called transcription factors General transcription factors are essential for the transcription of all protein-coding genes In eukaryotes, high levels of transcription of particular genes depend on control elements interacting with specific transcription factors s and Specific Factors Proximal control elements are located close to the promoter Distal control elements, groupings of which are called enhancers, may be far away from a gene or even located in an intron 7
Figure 18.9 An activator is a protein that binds to an enhancer and stimulates transcription of a gene Activators have two domains, one that binds and a second that activates transcription Bound activators facilitate a sequence of proteinprotein interactions that result in transcription of a given gene Activation domain -binding domain Animation: Initiation of Some transcription factors function as s, inhibiting expression of a particular gene by a variety of methods Some activators and s act indirectly by influencing chromatin structure to promote or silence transcription Figure 18.10-1 Activators Distal control element TATA box Gene Figure 18.10-2 Activators Distal control element bending protein Gene TATA box General transcription factors Group of mediator proteins Figure 18.10-3 Activators Distal control element bending protein Gene TATA box General transcription factors Group of mediator proteins polymerase II polymerase II initiation complex synthesis 8
Figure 18.11 Control elements Albumin gene Combinatorial Control of Gene Activation A particular combination of control elements can activate transcription only when the appropriate activator proteins are present Available activators LIVER CELL NUCLEUS Crystallin gene LENS CELL NUCLEUS Available activators Albumin gene expressed Albumin gene not expressed (a) Liver cell Crystallin gene not expressed (b) Lens cell Crystallin gene expressed Figure 18.11a Figure 18.11b Control elements Albumin gene Crystallin gene Available activators LIVER CELL NUCLEUS Control elements Albumin gene Crystallin gene Available activators LENS CELL NUCLEUS Albumin gene expressed Albumin gene not expressed (a) Liver cell Crystallin gene not expressed (b) Lens cell Crystallin gene expressed Coordinately Controlled Genes in Eukaryotes Unlike the genes of a prokaryotic operon, each of the co-expressed eukaryotic genes has a promoter and control elements These genes can be scattered over different chromosomes, but each has the same combination of control elements Copies of the activators recognize specific control elements and promote simultaneous transcription of the genes Nuclear Architecture and Gene Expression Loops of chromatin extend from individual chromosomes into specific sites in the nucleus Loops from different chromosomes may congregate at particular sites, some of which are rich in transcription factors and polymerases These may be areas specialized for a common function 9
Figure 18.12 Figure 18.12a Chromosomes in the interphase nucleus Chromosome territory Chromosomes in the interphase nucleus 10 µm 10 µm Chromatin loop factory Mechanisms of Post-al Regulation alone does not account for gene expression Regulatory mechanisms can operate at various stages after transcription Such mechanisms allow a cell to fine-tune gene expression rapidly in response to environmental changes Processing In alternative splicing, different molecules are produced from the same primary transcript, depending on which segments are treated as exons and which as introns Animation: Processing Figure 18.13 Exons Degradation Primary transcript 1 1 2 2 3 4 Troponin T gene 3 4 5 5 The life span of molecules in the cytoplasm is a key to determining protein synthesis Eukaryotic is more long lived than prokaryotic Nucleotide sequences that influence the lifespan of in eukaryotes reside in the untranslated region (UTR) at the 3ʹ end of the molecule splicing 1 2 3 5 or 1 2 4 5 Animation: Degradation 10
Initiation of Translation The initiation of translation of selected s can be blocked by regulatory proteins that bind to sequences or structures of the Alternatively, translation of all s in a cell may be regulated simultaneously For example, translation initiation factors are simultaneously activated in an egg following fertilization Processing and Degradation After translation, various types of protein processing, including cleavage and the addition of chemical groups, are subject to control Proteasomes are giant protein complexes that bind protein molecules and degrade them Animation: Processing Animation: Blocking Translation Animation: Degradation Figure 18.14 to be degraded Ubiquitin Ubiquitinated protein Proteasome entering a proteasome Proteasome and ubiquitin to be recycled fragments (peptides) Concept 18.3: Noncoding s play multiple roles in controlling gene expression Only a small fraction of codes for proteins, and a very small fraction of the non-protein-coding consists of genes for such as r and t A significant amount of the genome may be transcribed into noncoding s (ncs) Noncoding s regulate gene expression at two points: translation and chromatin configuration Effects on s by Micros and Small Interfering s Micros (mis) are small single-stranded molecules that can bind to These can degrade or block its translation Figure 18.15 Hairpin mi 5ʹ 3ʹ (a) Primary mi transcript mi Hydrogen bond Dicer miprotein complex degraded Translation blocked (b) Generation and function of mis 11
The phenomenon of inhibition of gene expression by molecules is called interference (i) i is caused by small interfering s (sis) sis and mis are similar but form from different precursors Chromatin Remodeling and Effects on by ncs In some yeasts sis play a role in heterochromatin formation and can block large regions of the chromosome Small ncs called piwi-associated s (pis) induce heterochromatin, blocking the expression of parasitic elements in the genome, known as transposons -based mechanisms may also block transcription of single genes The Evolutionary Significance of Small ncs Small ncs can regulate gene expression at multiple steps An increase in the number of mis in a species may have allowed morphological complexity to increase over evolutionary time sis may have evolved first, followed by mis and later pis Concept 18.4: A program of differential gene expression leads to the different cell types in a multicellular organism During embryonic development, a fertilized egg gives rise to many different cell types Cell types are organized successively into tissues, organs, organ systems, and the whole organism Gene expression orchestrates the developmental programs of animals A Genetic Program for Embryonic Development Figure 18.16 The transformation from zygote to adult results from cell division, cell differentiation, and morphogenesis 1 mm 2 mm (a) Fertilized eggs of a frog (b) Newly hatched tadpole 12
Figure 18.16a Figure 18.16b 1 mm 2 mm (b) Newly hatched tadpole (a) Fertilized eggs of a frog Cell differentiation is the process by which cells become specialized in structure and function The physical processes that give an organism its shape constitute morphogenesis Differential gene expression results from genes being regulated differently in each cell type Materials in the egg can set up gene regulation that is carried out as cells divide Cytoplasmic Determinants and Inductive Signals An egg s cytoplasm contains, proteins, and other substances that are distributed unevenly in the unfertilized egg Cytoplasmic determinants are maternal substances in the egg that influence early development As the zygote divides by mitosis, cells contain different cytoplasmic determinants, which lead to different gene expression Figure 18.17 Figure 18.17a (a) Cytoplasmic determinants in the egg (a) Cytoplasmic determinants in the egg (b) Induction by nearby cells Unfertilized egg Sperm Unfertilized egg Nucleus Early embryo (32 cells) Sperm Nucleus Fertilization Zygote (fertilized egg) Two-celled embryo Mitotic cell division Molecules of two different cytoplasmic determinants Signal transduction pathway Signal receptor Signaling molecule (inducer) NUCLEUS Fertilization Zygote (fertilized egg) Two-celled embryo Mitotic cell division Molecules of two different cytoplasmic determinants 13
Figure 18.17b (b) Induction by nearby cells Early embryo (32 cells) The other important source of developmental information is the environment around the cell, especially signals from nearby embryonic cells In the process called induction, signal molecules from embryonic cells cause transcriptional changes in nearby target cells Thus, interactions between cells induce differentiation of specialized cell types Animation: Cell Signaling Signal transduction pathway Signal receptor Signaling molecule (inducer) NUCLEUS Sequential Regulation of Gene Expression During Cellular Differentiation Determination commits a cell to its final fate Determination precedes differentiation Cell differentiation is marked by the production of tissue-specific proteins Myoblasts produce muscle-specific proteins and form skeletal muscle cells MyoD is one of several master regulatory genes that produce proteins that commit the cell to becoming skeletal muscle The MyoD protein is a transcription factor that binds to enhancers of various target genes Figure 18.18-1 Nucleus Embryonic precursor cell Master regulatory gene myod OFF Other muscle-specific genes OFF Figure 18.18-2 Nucleus Embryonic precursor cell Master regulatory gene myod OFF Other muscle-specific genes OFF OFF Myoblast (determined) MyoD protein (transcription factor) 14
Figure 18.18-3 Nucleus Embryonic precursor cell Master regulatory gene myod OFF Other muscle-specific genes OFF Pattern Formation: Setting Up the Body Plan Myoblast (determined) MyoD protein (transcription factor) OFF Pattern formation is the development of a spatial organization of tissues and organs In animals, pattern formation begins with the establishment of the major axes Positional information, the molecular cues that control pattern formation, tells a cell its location relative to the body axes and to neighboring cells Part of a muscle fiber (fully differentiated cell) MyoD Another transcription factor Myosin, other muscle proteins, and cell cycle blocking proteins The Life Cycle of Drosophila Pattern formation has been extensively studied in the fruit fly Drosophila melanogaster Combining anatomical, genetic, and biochemical approaches, researchers have discovered developmental principles common to many other species, including humans In Drosophila, cytoplasmic determinants in the unfertilized egg determine the axes before fertilization After fertilization, the embryo develops into a segmented larva with three larval stages Figure 18.19 Figure 18.19a Head Thorax Abdomen Follicle cell 1 Egg Nucleus developing within ovarian follicle Egg 0.5 mm Nurse cell BODY AXES (a) Adult Dorsal Right Anterior Posterior Left Ventral 2 Unfertilized egg Depleted nurse cells 3 Fertilized egg Egg shell Fertilization Laying of egg Head Thorax Abdomen 0.5 mm 4 Segmented embryo Body segments Embryonic development Hatching 0.1 mm BODY AXES (a) Adult Dorsal Right Anterior Posterior Left Ventral 5 Larval stage (b) Development from egg to larva 15
Figure 18.19b 1 Egg developing within ovarian follicle Nurse cell Follicle cell Nucleus Egg Genetic Analysis of Early Development: Scientific Inquiry 2 Unfertilized egg Depleted nurse cells 3 Fertilized egg 4 Segmented embryo Body segments Egg shell Fertilization Laying of egg Embryonic development Hatching 0.1 mm Edward B. Lewis, Christiane Nüsslein-Volhard, and Eric Wieschaus won a Nobel Prize in 1995 for decoding pattern formation in Drosophila Lewis discovered the homeotic genes, which control pattern formation in late embryo, larva, and adult stages 5 Larval stage (b) Development from egg to larva Figure 18.20 Figure 18.20a Eye Eye Antenna Leg Antenna Wild type Mutant Wild type Figure 18.20b Leg Nüsslein-Volhard and Wieschaus studied segment formation They created mutants, conducted breeding experiments, and looked for corresponding genes Many of the identified mutations were embryonic lethals, causing death during embryogenesis They found 120 genes essential for normal segmentation Mutant 16
Axis Establishment Maternal effect genes encode for cytoplasmic determinants that initially establish the axes of the body of Drosophila These maternal effect genes are also called eggpolarity genes because they control orientation of the egg and consequently the fly Bicoid: A Morphogen Determining Head Structures One maternal effect gene, the bicoid gene, affects the front half of the body An embryo whose mother has no functional bicoid gene lacks the front half of its body and has duplicate posterior structures at both ends Animation: Development of Head-Tail Axis in Fruit Flies Figure 18.21 Figure 18.21a Head Tail T1 T2 T3 A1 A2 A3 A4 A5 A6 A7 A8 Head Tail Tail Wild-type larva 250 µm Tail T1 T2 T3 A1 A2 A3 A4 A5 A6 A7 A8 Wild-type larva 250 µm A8 A7 A6 A7 A8 Mutant larva (bicoid) Figure 18.21b Tail A8 A8 A7 A6 A7 Mutant larva (bicoid) Tail This phenotype suggests that the product of the mother s bicoid gene is concentrated at the future anterior end This hypothesis is an example of the morphogen gradient hypothesis, in which gradients of substances called morphogens establish an embryo s axes and other features 17
Figure 18.22 Figure 18.22a RESULTS Anterior end 100 µm Bicoid in mature unfertilized egg Fertilization, translation of bicoid Bicoid protein in early embryo Bicoid in mature unfertilized egg Bicoid in mature unfertilized egg Bicoid protein in early embryo Figure 18.22b Anterior end Bicoid protein in early embryo 100 µm The bicoid research is important for three reasons It identified a specific protein required for some early steps in pattern formation It increased understanding of the mother s role in embryo development It demonstrated a key developmental principle that a gradient of molecules can determine polarity and position in the embryo Concept 18.5: Cancer results from genetic changes that affect cell cycle control The gene regulation systems that go wrong during cancer are the very same systems involved in embryonic development Types of Genes Associated with Cancer Cancer can be caused by mutations to genes that regulate cell growth and division Tumor viruses can cause cancer in animals including humans 18
P P P P P P 12/8/14 Figure 18.23 Oncogenes are cancer-causing genes Proto-oncogenes are the corresponding normal cellular genes that are responsible for normal cell growth and division Conversion of a proto-oncogene to an oncogene can lead to abnormal stimulation of the cell cycle Translocation or transposition: gene moved to new locus, under new controls New promoter Proto-oncogene Gene amplification: multiple copies of the gene within a control element Oncogene Point mutation: within the gene Oncogene Normal growthstimulating protein in excess Normal growth-stimulating protein in excess Normal growthstimulating protein in excess Hyperactive or degradationresistant protein Tumor-Suppressor Genes Proto-oncogenes can be converted to oncogenes by Movement of within the genome: if it ends up near an active promoter, transcription may increase Amplification of a proto-oncogene: increases the number of copies of the gene Point mutations in the proto-oncogene or its control elements: cause an increase in gene expression Tumor-suppressor genes help prevent uncontrolled cell growth Mutations that decrease protein products of tumorsuppressor genes may contribute to cancer onset Tumor-suppressor proteins Repair damaged Control cell adhesion Inhibit the cell cycle in the cell-signaling pathway Interference with Normal Cell-Signaling Pathways Mutations in the ras proto-oncogene and p53 tumor-suppressor gene are common in human cancers Mutations in the ras gene can lead to production of a hyperactive Ras protein and increased cell division Figure 18.24 2 1 Growth factor Receptor 4 3 G protein kinases (phosphorylation cascade) GTP Ras (a) Cell cycle stimulating pathway 5 GTP Ras factor (activator) Hyperactive Ras protein (product of oncogene) issues signals on its own. Gene expression that stimulates the cell cycle MUTATION NUCLEUS UV light 1 (b) Cell cycle inhibiting pathway 2 damage in genome overexpressed kinases 3 Active form of p53 that inhibits the cell cycle EFFECTS OF MUTATIONS MUTATION Defective or missing transcription factor, such as p53, cannot activate transcription. absent Cell cycle overstimulated (c) Effects of mutations Increased cell division Cell cycle not inhibited 19
Figure 18.24a Figure 18.24b 1 Growth MUTATION factor Ras Hyperactive Ras protein 3 G protein GTP (product of oncogene) issues signals on its own. Ras 2 Receptor 4 P P P kinases (phosphorylation cascade) (a) Cell cycle stimulating pathway P P P GTP 5 factor (activator) Gene expression that stimulates the cell cycle NUCLEUS UV light 1 2 kinases damage in genome (b) Cell cycle inhibiting pathway 3 Active form of p53 that inhibits the cell cycle MUTATION Defective or missing transcription factor, such as p53, cannot activate transcription. Figure 18.24c Suppression of the cell cycle can be important in the case of damage to a cell s ; p53 prevents a cell from passing on mutations due to damage Mutations in the p53 gene prevent suppression of the cell cycle overexpressed Cell cycle overstimulated EFFECTS OF MUTATIONS Increased cell division absent Cell cycle not inhibited (c) Effects of mutations The Multistep Model of Cancer Development Multiple mutations are generally needed for fullfledged cancer; thus the incidence increases with age At the level, a cancerous cell is usually characterized by at least one active oncogene and the mutation of several tumor-suppressor genes Figure 18.25 Colon Normal colon epithelial cells 1 Loss of tumorsuppressor gene APC (or other) Colon wall Small benign growth (polyp) 2 Activation of ras oncogene 3 Loss of tumorsuppressor gene DCC Larger benign growth (adenoma) 4 Loss of tumorsuppressor gene p53 5 Additional mutations Malignant tumor (carcinoma) 20
Figure 18.25a Figure 18.25b Colon 1 Loss of tumorsuppressor gene APC (or other) Colon wall Small benign growth (polyp) Normal colon epithelial cells Figure 18.25c Figure 18.25d 2 Activation of ras oncogene 3 Loss of tumor-suppressor gene DCC Larger benign growth (adenoma) 4 Loss of tumor-suppressor gene p53 5 Additional mutations Malignant tumor (carcinoma) Inherited Predisposition and Other Factors Contributing to Cancer Figure 18.26 Individuals can inherit oncogenes or mutant alleles of tumor-suppressor genes Inherited mutations in the tumor-suppressor gene adenomatous polyposis coli are common in individuals with colorectal cancer Mutations in the BRCA1 or BRCA2 gene are found in at least half of inherited breast cancers, and tests using sequencing can detect these mutations 21
Figure 18.UN01 Figure 18.UN02 Operator polymerase Operon Genes A B C A B C Polypeptides Genes expressed Operator Genes Inactive : no co present Genes not expressed Co Active : co bound Figure 18.UN03 Figure 18.UN04 Chromatin modification Genes in highly compacted chromatin are generally not transcribed. Histone acetylation seems to loosen chromatin structure, enhancing transcription. Regulation of transcription initiation: control elements in enhancers bind specific transcription factors. Genes not expressed Genes expressed methylation generally reduces transcription. Bending of the enables activators to contact proteins at the promoter, initiating transcription. Coordinate regulation: for liver-specific genes for lens-specific genes Operator Genes Chromatin modification processing processing Alternative splicing: Active : no inducer present Inactive : inducer bound degradation Translation processing and degradation Primary transcript or Translation Initiation of translation can be controlled via regulation of initiation factors. degradation Each has a characteristic life span, processing and degradation determined in part by sequences in the 5ʹ and 3ʹ UTRs. processing and degradation by proteasomes are subject to regulation. Figure 18.UN04a Chromatin modification Figure 18.UN04b Genes in highly compacted chromatin are generally not transcribed. Histone acetylation seems to loosen chromatin structure, enhancing transcription. Regulation of transcription initiation: control elements in enhancers bind specific transcription factors. Chromatin modification processing methylation generally reduces transcription. Chromatin modification processing degradation Translation processing and degradation Bending of the enables activators to contact proteins at the promoter, initiating transcription. Coordinate regulation: for liver-specific genes processing Alternative splicing: Primary transcript for lens-specific genes or degradation Translation processing and degradation degradation Each has a characteristic life span, determined in part by sequences in the 5ʹ and 3ʹ UTRs. Translation Initiation of translation can be controlled via regulation of initiation factors. processing and degradation processing and degradation by proteasomes are subject to regulation. 22
Figure 18.UN05 Figure 18.UN06 Chromatin modification Chromatin modification Small or large noncoding s can promote the formation of heterochromatin in certain regions, blocking transcription. processing Translation mi or si can block the translation of specific s. Gene 1 Gene 2 degradation Translation processing and degradation Gene 3 Gene 4 degradation mi or si can target specific s for destruction. Gene 5 Figure 18.UN07 Figure 18.UN08 Gene 1 Gene 2 Gene 3 Gene 4 Gene 5 Gene 1 Gene 2 Gene 3 Gene 4 Gene 5 23