Chapter 18 Regulation Gene Expression Regulation of Gene Expression

Chapter 18 Regulation Gene Expression Regulation of Gene Expression
18 Regulation of Gene Expression Lecture Presentation by Nicole Tunbridge and Kathleen Fitzpatrick Unit5: Molecular Basis of Inheritance

Differential Expression of Genes
Chapter 18 Regulation Gene Expression Differential Expression of Genes Gene expression precisely regulated in response to environmental conditions Multicellular Eukaryotes: Gene expression regulates development Differentiation of cell types RNA molecules play many roles in regulating gene expression in eukaryotes Unit5: Molecular Basis of Inheritance

Concept 18.1: Bacteria often respond to environmental change by regulating transcription
Bacteria produce only products needed by the cell Favored by natural selection Mechanism for control of gene expression is operon model Cells can regulate production of enzymes Feedback inhibition Gene regulation

Chapter 18 Regulation Gene Expression
Figure 18.2 Precursor Feedback inhibition trpE Enzyme 1 trpD Regulation of gene expression Enzyme 2 trpC trpB Figure 18.2 Regulation of a metabolic pathway Enzyme 3 trpA Tryptophan (a) Regulation of enzyme activity (b) Regulation of enzyme production Unit5: Molecular Basis of Inheritance

Operons: The Basic Concept
Chapter 18 Regulation Gene Expression Operons: The Basic Concept Cluster of functionally related genes Can be controlled by a single “on-off switch” Operator: “Switch” is segment of DNA Usually positioned within promoter Operon: Entire stretch of DNA that includes the operator, the promoter, and the genes that they control Repressor: Operon can be switched off by a protein Product of a separate regulatory gene Prevents gene transcription Binds to operator  blocks RNA polymerase Unit5: Molecular Basis of Inheritance

Repressor can be active or inactive form Depends on presence of other molecules Corepressor: Molecule that cooperates with repressor protein  switches operon off Ex: E. coli can synthesize tryptophan when it has insufficient tryptophan Repressor is active only in the presence of its corepressor tryptophan trp operon is turned off (repressed) if tryptophan levels are high trp operon is on  genes for tryptophan synthesis are transcribed Presence of tryptophan  Binds to trp repressor protein  Turns operon off Unit5: Molecular Basis of Inheritance

Figure 18.3 trp operon DNA Promoter Promoter Regulatory gene Genes of operon trpR trpE trpD trpC trpB trpA Operator RNA polymerase Start codon Stop codon 3′ mRNA mRNA 5′ 5′ Inactive repressor E D C B A Protein Polypeptide subunits that make up enzymes for tryptophan synthesis (a) Tryptophan absent, repressor inactive, operon on DNA trpR trpE No RNA made Figure 18.3 The trp operon in E. coli: regulated synthesis of repressible enzymes 3′ mRNA 5′ Protein Active repressor Tryptophan (corepressor) (b) Tryptophan present, repressor active, operon off Unit5: Molecular Basis of Inheritance

Repressible and Inducible Operons: Two Types of Negative Gene Regulation
Repressible operon: Usually on Binding of repressor to operator  transcription off The trp operon is a repressible operon Inducible operon: Usually off Inducer molecule inactivates repressor  Transcription on Ex: lac operon: Contains genes that code for enzymes used in the hydrolysis and metabolism of lactose lac repressor is active  switches the lac operon off

Figure 18.4 Regulatory gene Promoter DNA Operator lac I IacZ No RNA made 3′ mRNA 5′ RNA polymerase Protein Active repressor (a) Lactose absent, repressor active, operon off lac operon DNA lac I lacZ lacY lacA RNA polymerase Start codon Stop codon 3′ 3′ Figure 18.4 The lac operon in E. coli: regulated synthesis of inducible enzymes mRNA mRNA 5′ 5′ Protein β-Galactosidase Permease Transacetylase Inactive repressor Allolactose (inducer) (b) Lactose present, repressor inactive, operon on Unit5: Molecular Basis of Inheritance

Video: Cartoon Rendering of the lac Repressor from E. coli

Inducible enzymes usually function in catabolic pathways Synthesis is induced by a chemical signal Repressible enzymes usually function in anabolic pathways Synthesis repressed by high levels of end product Regulation of trp and lac operons Involves negative control of genes Operons are switched off by active form of repressor Unit5: Molecular Basis of Inheritance

Positive Gene Regulation
Chapter 18 Regulation Gene Expression Positive Gene Regulation Some operons subject to positive control Catabolite Activator Protein (CAP): Stimulatory protein, activator of transcription CAP helps regulate other operons that encode enzymes used in catabolic pathways E. coli: When glucose is scarce, CAP is activated Binds with cyclic AMP (cAMP) Activated CAP attaches to promoter of the lac operon Increases affinity of RNA polymerase Transcription accelerates Glucose levels increase  CAP detaches from lac operon  Transcription returns to normal rate Unit5: Molecular Basis of Inheritance

Figure 18.5a Promoter Operator DNA lac I lacZ CAP-binding site RNA polymerase binds and transcribes Active CAP cAMP Inactive lac repressor Inactive CAP Figure 18.5a Positive control of the lac operon by catabolite activator protein (CAP) (part 1: glucose scarce) Allolactose (a) Lactose present, glucose scarce (cAMP level high): abundant lac mRNA synthesized Unit5: Molecular Basis of Inheritance

Figure 18.5b Promoter DNA lac I lacZ CAP-binding site Operator RNA polymerase less likely to bind Inactive CAP Inactive lac repressor Figure 18.5b Positive control of the lac operon by catabolite activator protein (CAP) (part 2: glucose present) (b) Lactose present, glucose present (cAMP level low): little lac mRNA synthesized Unit5: Molecular Basis of Inheritance

Concept 18.2: Eukaryotic gene expression is regulated at many stages
All organisms must regulate which genes are expressed at any given time Multicellular organisms: Regulation of gene expression is essential for cell specialization

Figure 18.6 Signal Chromatin Chromatin modification: DNA unpacking DNA Gene available for transcription Transcription RNA Exon Primary transcript Intron RNA processing Tail Cap mRNA in nucleus Transport to cytoplasm NUCLEUS CYTOPLASM mRNA in cytoplasm Degradation of mRNA Translation Figure 18.6 Stages in gene expression that can be regulated in eukaryotic cells Polypeptide Protein processing Active protein Degradation of protein Transport to cellular destination Cellular function (such as enzymatic activity or structural support) Unit5: Molecular Basis of Inheritance

Differential Gene Expression
Chapter 18 Regulation Gene Expression Differential Gene Expression Almost all the cells in organism genetically identical Differential Gene Expression Differences between cell types result from expression of different genes Abnormalities in gene expression can lead to diseases including cancer Gene expression is regulated at many stages Unit5: Molecular Basis of Inheritance

Animation: Protein Degradation

Animation: Protein Processing

Animation: Blocking Translation

Regulation of Chromatin Structure
Chapter 18 Regulation Gene Expression Regulation of Chromatin Structure Structural organization of chromatin helps regulate gene expression Heterochromatin Packing: Genes within highly packed heterochromatin not expressed Chemical Modifications to Histones and DNA Influence chromatin structure & gene expression Unit5: Molecular Basis of Inheritance

Figure 18.7 Histone tails DNA double helix Amino acids available for chemical modification Nucleosome (end view) (a) Histone tails protrude outward from a nucleosome Acetyl groups DNA Figure 18.7 A simple model of histone tails and the effect of histone acetylation Unacetylated histones (side view) Acetylated histones (b) Acetylation of histone tails promotes loose chromatin structure that permits transcription Unit5: Molecular Basis of Inheritance

Histone Modifications and DNA Methylation
Histone Acetylation: Acetyl groups attach to positively charged lysines in histone tails Loosens chromatin structure Promoting the initiation of transcription Methylation: Adding methyl groups can condense chromatin Phosphorylation: Adding phosphate groups methylated amino acid can loosen chromatin

DNA Methylation Adding methyl groups to certain bases in DNA associated with reduced transcription Cellular Differentiation DNA methylation can cause long-term inactivation of genes Genomic Imprinting (start of development) Methylation regulates expression of maternal or paternal alleles of certain genes

Epigenetic Inheritance! 
Inheritance of traits transmitted by mechanisms not directly involving nucleotide sequence Chromatin Modifications Do not alter DNA sequence May be passed to future generations of cells!

Regulation of Transcription Initiation
Chromatin-modifying Enzymes: Provide initial control of gene expression Makes region of DNA more or less able to bind to the transcription machinery Organization of a Typical Eukaryotic Gene Control Elements: Segments of noncoding DNA Serve as binding sites for transcription factors Help regulate transcription Critical to the precise regulation of gene expression in different cell types

Figure 18.8 Enhancer (group of distal control elements) Proximal control elements Transcription start site Poly-A signal sequence Transcription termination region DNA Exon Intron Exon Intron Exon Upstream Downstream Promoter Transcription Poly-A signal Primary RNA transcript (pre-mRNA) Exon Intron Exon Intron Exon Cleaved 3′ end of primary transcript 5′ RNA processing Intron RNA Coding segment Figure 18.8 A eukaryotic gene and its transcript mRNA G P P P AAA⋯AAA 3′ Start codon Stop codon 5′ Cap 5′ UTR 3′ UTR Poly-A tail Unit5: Molecular Basis of Inheritance

The Roles of Transcription Factors
Initiation: Eukaryotic RNA polymerase requires assistance of transcription factors Essential for transcription of all protein-coding genes High levels of transcription of particular genes depend on control elements interacting with specific transcription factors Enhancers and Specific Transcription Factors Proximal control elements located close to promoter Distal control elements may be far away from a gene or located within an intron Enahncers: Groupings of distal control elements

Animation: Initiation of Transcription

Activators A protein that binds to enhancer and stimulates transcription 2 domains: (1) binds DNA; (2) activates transcription Bound Activators Facilitate a sequence of protein-protein interactions Results in transcription of given gene Repressors Inhibit expression of a particular gene Some activators and repressors act indirectly Influence chromatin structure  promotes or silences transcription Unit5: Molecular Basis of Inheritance

Figure Promoter DNA Activators Gene Distal control element Enhancer TATA box General transcription factors DNA- bending protein Group of mediator proteins RNA polymerase II Figure A model for the action of enhancers and transcription activators (step 3) RNA polymerase II Transcription initiation complex RNA synthesis Unit5: Molecular Basis of Inheritance

Combinatorial Control of Gene Activation A particular combination of control elements can activate transcription only when the appropriate activator proteins are present Unit5: Molecular Basis of Inheritance

Figure 18.11 DNA in both cells contains the albumin gene and the crystallin gene: Enhancer for albumin gene Promoter Albumin gene Enhancer for crystallin gene Control elements Promoter Crystallin gene LIVER CELL NUCLEUS LENS CELL NUCLEUS Available activators Available activators Albumin gene not expressed Figure Cell type–specific transcription Albumin gene expressed Crystallin gene not expressed Crystallin gene expressed (a) Liver cell (b) Lens cell Unit5: Molecular Basis of Inheritance

Coordinately Controlled Genes in Eukaryotes
Co-expressed eukaryotic genes are not organized in operons (with a few minor exceptions) 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 chromosome territories into specific sites in the nucleus Loops from different chromosomes may congregate at particular sites, some of which are rich in transcription factors and RNA polymerases These may be areas specialized for a common function

Mechanisms of Post-Transcriptional Regulation
Transcription alone does not account for gene expression Regulatory mechanisms can operate at various stages after transcription Mechanisms allow a cell to fine-tune gene expression rapidly in response to environmental changes RNA Processing Alternative RNA Splicing: Different mRNA molecules are produced from the same primary transcript Dpends on which RNA segments are treated as exons and which as introns

Animation: RNA Processing

Figure 18.13 Exons DNA Troponin T gene Primary RNA transcript Figure Alternative RNA splicing of the troponin T gene RNA splicing OR mRNA Unit5: Molecular Basis of Inheritance

Initiation of Translation and mRNA Degradation
Initiation of translation of selected mRNAs can be blocked Regulatory proteins bind to sequences or structures of the mRNA Alternatively, translation of all mRNAs in a cell may be regulated simultaneously Ex: Translation initiation factors are simultaneously activated in an egg following fertilization

Animation: mRNA Degradation

Life Span of mRNA Molecules in Cytoplasm
Key to determining protein synthesis Eukaryotic mRNA more long lived than prokaryotic Nucleotide sequences  influence lifespan of mRNA Eukaryotes: Resides in untranslated region (UTR) 3′ end of molecule

Protein Processing and Degradation
After translation, various types of protein processing subject to control Ex: Cleavage; addition of chemical groups Length of time each protein function is regulated by selective degradation Cells mark proteins for degradation Attach ubiquitin Recognized by proteasomes  degrade proteins

Online Activity: Regulation of the Lactase Gene
Go to: Use the “Click and Learn” video to answer the accompanying questions.

Concept 18.3: Noncoding RNAs play multiple roles in controlling gene expression
Small fraction of DNA codes for proteins Very small fraction of non-protein-coding DNA consists of genes for RNA rRNA and tRNA Much of genome may be transcribed into noncoding RNAs (ncRNAs) ncRNAs: Regulate gene expression mRNA translation chromatin configuration

Effects on mRNAs by MicroRNAs and Small Interfering RNAs
MicroRNAs (miRNAs): Small single-stranded RNA molecules Can bind to mRNA Can degrade mRNA or block its translation Regulates ~1/2 of expressed human genes Small interfering RNAs (siRNAs): Size & function similar to miRNAs RNA interference (RNAi): Blocks gene expression Used in the laboratory: Disable gene  Investigate function

Figure 18.14 miRNA miRNA- protein complex 1 The miRNA binds to a target mRNA. Figure Regulation of gene expression by miRNAs OR mRNA degraded Translation blocked 2 If bases are completely complementary, mRNA is degraded. If match is less than complete, translation is blocked. Unit5: Molecular Basis of Inheritance

Chromatin Remodeling by ncRNAs
RNA-based regulation of chromatin structure is likely to play an important role in gene regulation ncRNAs: Remodeling of chromatin structure Piwi-associated RNAs (piRNAs) induce heterochromatin Block expression of transposons, or parasitic DNA elements in the genome siRNAs: Re-form heterochromatin at centromeres after chromosome replication (some yeasts)

Figure 18.15 Centromeric DNA 1 RNA transcripts (red) produced. RNA polymerase Sister chromatids (two DNA molecules) RNA transcript 2 Yeast enzyme synthesizes strands complementary to RNA transcripts. 3 Double-stranded RNA processed into siRNAs that associate with proteins. siRNA-protein complex 4 The siRNA-protein complexes bind RNA transcripts and become tethered to centromere region. 5 The siRNA-protein complexes recruit histone-modifying enzymes. Figure Condensation of chromatin at the centromere Centromeric DNA Chromatin- modifying enzymes 6 Chromatin condensation is initiated and heterochromatin is formed. Heterochromatin at the centromere region Unit5: Molecular Basis of Inheritance

The Evolutionary Significance of Small ncRNAs
Small ncRNAs regulate expression at multiple steps # miRNAs increase  allows morphological complexity to increase over evolutionary time Proposed Evolutionary Timeline: siRNAs miRNAs piRNAs

Concept 18.4: A program of differential gene expression leads to the different cell types in a multicellular organism Embryonic Development Fertilized egg  Many different cell types Cell types organized into tissues, organs, organ systems, and whole organism Gene expression orchestrates developmental programs of animals

Figure 18.16 Figure From fertilized egg to animal: what a difference four days makes 1 mm 2 mm (a) Fertilized eggs of a frog (b) Newly hatched tadpole Unit5: Molecular Basis of Inheritance

A Genetic Program for Embryonic Development
Zygote  Adult Cell division, cell differentiation, and morphogenesis Materials in egg regulate genes carried out as cells divide Differential gene expression results from genes being regulated differently in each cell type Cell Differentiation: Cells become specialized in structure and function Morphogenesis: Physical processes that gives organism its shape

Cytoplasmic Determinants and Inductive Signals
Egg’s Cytoplasm: RNA, proteins, other substances Distributed unevenly in unfertilized egg Cytoplasmic Determinants: Maternal substances in egg Influence early development Zygote Divides by Mitosis Cells contain different cytoplasmic determinants  different gene expression

Environmental Affect on Development
Environment Surrounding the Cell Signals from nearby embryonic cells Induction: Signal molecules from embryonic cells cause transcriptional changes in nearby target cells Induce differentiation of specialized cell types

Figure 18.17 (a) Cytoplasmic determinants in the egg (b) Induction by nearby cells Molecules of two different cytoplasmic determinants Early embryo (32 cells) Nucleus NUCLEUS Fertilization Mitotic cell division Unfertilized egg Signal transduction pathway Sperm Zygote (fertilized egg) Signal receptor Two-celled embryo Figure Sources of developmental information for the early embryo Signaling molecule Unit5: Molecular Basis of Inheritance

Animation: Cell Signaling

Sequential Regulation of Gene Expression During Cellular Differentiation
Determination precedes differentiation Irreversibly commits cell to final fate Cell differentiation marked by the production of tissue-specific proteins Myoblasts: Cells determined to produce muscle cells and begin producing muscle-specific proteins MyoD: “Master regulatory gene” Encodes transcription factor  commits cell to becoming skeletal muscle MyoD protein can turn some kinds of differentiated cells—fat cells and liver cells—into muscle cells

Figure Nucleus Master regulatory gene myoD Other muscle-specific genes DNA Embryonic precursor cell OFF OFF mRNA OFF MyoD protein (transcription factor) Myoblast (determined) Figure Determination and differentiation of muscle cells (step 3) mRNA mRNA mRNA mRNA Myosin, other muscle proteins, and cell cycle– blocking proteins MyoD Another transcription factor Part of a muscle fiber (fully differentiated cell) Unit5: Molecular Basis of Inheritance

Pattern Formation: Setting Up the Body Plan
Pattern Formation: Development of spatial organization of tissues and organs Animals: Begins with establishment of major axes Studied extensively in Drosophila melanogaster Combining anatomical, genetic, and biochemical approaches, researchers have discovered developmental principles common to many other species, including humans Positional Information: Molecular cues control pattern formation Tells cell its location relative to body axes and neighboring cells

Figure 18.19 Follicle cell Cytoplasmic determinants in unfertilized egg determine the axes before fertilization After fertilization, embryo develops into segmented larva with 3 larval stages 1 Developing egg within ovarian follicle Nucleus Egg Nurse cell 2 Mature, unfertilized egg Egg shell Depleted nurse cells Fertilization Laying of egg 3 Fertilized egg Head Thorax Abdomen Embryonic development Figure Key developmental events in the life cycle of Drosophila 4 0.5 mm Segmented embryo 0.1 mm Body segments Hatching Dorsal Right BODY AXES Anterior Posterior Left 5 Larva Ventral (a) Adult (b) Development from egg to larva Unit5: Molecular Basis of Inheritance

Genetic Analysis of Early Development: Scientific Inquiry
Edward B. Lewis, Christiane Nüsslein-Volhard, and Eric Wieschaus Won 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 Nüsslein-Volhard and Wieschaus studied segment formation Created mutants for breeding experiments and looked for corresponding genes Many identified mutations were embryonic lethals Cause death during embryogenesis Found 120 genes essential for normal segmentation

Axis Establishment Maternal Effect Genes (Egg-polarity Genes):
Encode cytoplasmic determinants Control orientation of the egg  Fly Establish the axes of the body of Drosophila Example: Bicoid gene Affects front half of the body

Animation: Development of Head-Tail Axis in Fruit Flies

Figure 18.21 Head Tail A8 T1 T2 T3 A7 A6 A1 A5 A2 A3 A4 Wild-type larva 250 µm Tail Tail Figure Effect of the bicoid gene on Drosophila development A8 A8 A7 A7 A6 Mutant larva (bicoid ) Unit5: Molecular Basis of Inheritance

Bicoid: A Morphogen That Determines Head Structures
Mother lacks functional bicoid gene  Embryo lacks front half of its body  Duplicate posterior structures at both ends Phenotype suggests product of mother’s bicoid gene is essential for setting up the anterior end of the embryo Morphogen Gradient Hypothesis Gradients of substances called morphogens establish an embryo’s axes and other features of its form Experimental Results: Bicoid protein is distributed in an anterior to posterior gradient in the early embryo

Figure 18.22 Results 100 µm Anterior end Fertilization, translation of bicoid mRNA Bicoid mRNA in mature unfertilized egg Bicoid protein in early embryo Figure Inquiry: Could Bicoid be a morphogen that determines the anterior end of a fruit fly? Unit5: Molecular Basis of Inheritance

The bicoid research was ground breaking 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 concept that a gradient of molecules can determine polarity and position in the embryo

Evolutionary Developmental Biology (“Evo-Devo”)
The fly with legs emerging from its head in Figure is the result of a single mutation in one gene Scientists considered if these mutations could contribute to evolution by generating novel body shapes This line of inquiry gave rise to the field of evolutionary developmental biology, “evo-devo”

Concept 18.5: Cancer results from genetic changes that affect cell cycle control
Cancer: Gene regulation systems go wrong Same systems involved in embryonic development EFFECTS OF MUTATIONS Protein overexpressed Cell cycle overstimulated Increased cell division Protein absent Cell cycle not inhibited

Types of Genes Associated with Cancer
Cancer caused by mutations to genes regulating cell growth and division Spontaneous mutation Environmental influences Chemicals, radiation, and some viruses Oncogenes: Cancer-causing genes found in some types of viruses

Proto-oncogenes Corresponding normal cellular genes responsible for normal cell growth and division Proto-oncogenes can be converted to an oncogene Causes: Movement of DNA within the genome Near active promoter  Transcription may increase Amplification of a proto-oncogene Increases # copies of gene Point mutations in proto-oncogene or control elements Increase in gene expression Can lead to abnormal stimulation of cell cycle

Genetic Changes: Proto-oncogene  Oncogene
Chapter 18 Regulation Gene Expression Genetic Changes: Proto-oncogene  Oncogene Proto-oncogene Proto-oncogene Proto-oncogene Translocation or transposition: gene moved to new locus, under new controls Gene amplification: multiple copies of the gene Point mutation: within a control element New promoter within the gene Oncogene Oncogene Oncogene Figure Genetic changes that can turn proto-oncogenes into oncogenes Normal growth- stimulating protein in excess Normal growth-stimulating protein in excess Normal growth- stimulating protein in excess Hyperactive or degradation- resistant protein Unit5: Molecular Basis of Inheritance

Tumor-Suppressor Genes
Normally help prevent uncontrolled cell growth Mutations can decrease protein products of tumor- suppressor genes  Contribute to cancer onset Tumor-suppressor protein functions: Repair damaged DNA Control cell adhesion Act in cell-signaling pathways that inhibit the cell cycle

Interference with Normal Cell-Signaling Pathways
Mutations in the ras proto-oncogene and p53 tumor-suppressor gene are common in human cancers Suppression of cell cycle can be important if cell’s DNA is damaged p53 gene Mutation: Prevents cell cycle suppression p53 prevents cell from passing on these mutations ras gene Mutation  Produce hyperactive Ras protein  increased cell division

Figure 18.24 1 Growth factor 3 G protein NUCLEUS P P 5 6 Protein that stimulates the cell cycle P P Ras P P Transcription factor (activator) GTP 2 Receptor 4 Protein kinases MUTATION Overexpression of protein Figure Normal and mutant cell cycle–stimulating pathway Ras NUCLEUS GTP Transcription factor (activator) Ras protein active with or without growth factor. Unit5: Molecular Basis of Inheritance

Figure 18.25 2 Protein kinases 5 Protein that inhibits the cell cycle NUCLEUS UV light 1 DNA damage in genome 3 Active form of p53 4 Transcription Inhibitory protein absent Figure Normal and mutant cell cycle–inhibiting pathway UV light MUTATION Defective or missing transcription factor. DNA damage in genome Unit5: Molecular Basis of Inheritance

The Multistep Model of Cancer Development
Full-fledged cancer usually requires multiple mutations Incidence increases with age (mutations more likely) DNA Level: Cancerous cell characterized by at least one active oncogene and multiple mutations of tumor-suppressor genes Cancer Screening: Colorectal cancer: Routine screening for suspicious polyps to be removed before cancer progresses Breast Cancer: Heterogeneous disease Most common form of cancer in women in US DNA profiling of breast tumors identified 4 major types

Figure 18.26a 1 Loss of tumor- suppressor gene APC (or other) Colon wall Normal colon epithelial cells Small benign growth (polyp) 2 Activation of ras oncogene 4 Loss of tumor-suppressor gene p53 Figure 18.26a A multistep model for the development of colorectal cancer (part 1: detail) 3 Loss of tumor- suppressor gene SMAD4 5 Additional mutations Larger benign growth (adenoma) Malignant tumor (carcinoma) Unit5: Molecular Basis of Inheritance

Figure 18.27a MAKE CONNECTIONS: Genomics, Cell Signaling, and Cancer Normal Breast Cells in a Milk Duct • ERα+ • PR+ • HER2+ Duct interior Estrogen receptor alpha (ERα) Progesterone receptor (PR) HER2 (a receptor tyrosine kinase) Figure 18.27a Make connections: genomics, cell signaling, and cancer (part 1: normal breast cells) Support cell Extracellular matrix Unit5: Molecular Basis of Inheritance

Figure 18.27b MAKE CONNECTIONS: Genomics, Cell Signaling, and Cancer Breast Cancer Subtypes Luminal A Luminal B Figure 18.27b Make connections: genomics, cell signaling, and cancer (part 2: breast cancer subtypes, luminal A and luminal B) • ERα+++ • PR++ • HER2− • 40% of breast cancers • Best prognosis • ERα++ • PR++ • HER2− (shown); some HER2++ • 15–20% of breast cancers • Poorer prognosis than luminal A subtype Unit5: Molecular Basis of Inheritance

Figure 18.27c MAKE CONNECTIONS: Genomics, Cell Signaling, and Cancer Breast Cancer Subtypes HER2 Basal-like Figure 18.27c Make connections: genomics, cell signaling, and cancer (part 3: breast cancer subtypes, HER2 and Basal-like) • ERα− • PR− • HER2++ • 10–15% of breast cancers • Poorer prognosis than luminal A subtype • ERα− • PR− • HER2− • 15–20% of breast cancers • More aggressive; poorer prognosis than other subtypes Unit5: Molecular Basis of Inheritance

Inherited Predisposition and Environmental Factors Contributing to Cancer
Inherited Mutations Individuals can inherit oncogenes or mutant alleles of tumor-suppressor genes Detected by DNA sequencing tests Tumor-suppressor gene adenomatous polyposis coli Common in individuals with colorectal cancer BRCA1 or BRCA2 gene Found in ~1/2 of inherited breast cancers

The Role of Viruses in Cancer
Viruses are powerful biological agents Some tumor viruses can cause cancer in humans and animals Viruses integrate into the DNA of a cell Interfere with normal gene regulation

Chapter 18 Regulation Gene Expression Regulation of Gene Expression

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Chapter 18 Regulation Gene Expression Regulation of Gene Expression

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