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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 © 2011 Pearson Education, Inc. Lectures by Erin Barley Kathleen Fitzpatrick Regulation of Gene Expression Chapter 18
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 • RNA molecules play many roles in regulating gene expression in eukaryotes © 2011 Pearson Education, Inc.
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 © 2011 Pearson Education, Inc.
Precursor Feedback inhibition Enzyme 1 Enzyme 2 Enzyme 3 Tryptophan (a) (b) Regulation of enzyme activity Regulation of enzyme production Regulation of gene expression   trpE gene trpD gene trpC gene trpB gene trpA gene Figure 18.2
Operons: The Basic Concept • A cluster of functionally related genes can be under coordinated control by a single “on-off switch” • The regulatory “switch” is a segment of DNA called an operator usually positioned within the promoter • An operon is the entire stretch of DNA that includes the operator, the promoter, and the genes that they control © 2011 Pearson Education, Inc.
• The operon can be switched off by a protein repressor • The repressor prevents gene transcription by binding to the operator and blocking RNA polymerase • The repressor is the product of a separate regulatory gene © 2011 Pearson Education, Inc.
• The repressor can be in an active or inactive form, depending on the presence of other molecules • A corepressor is a molecule that cooperates with a repressor protein to switch an operon off • For example, E. coli can synthesize the amino acid tryptophan © 2011 Pearson Education, Inc.
Promoter DNA Regulatory gene mRNA trpR 5 3 Protein Inactive repressor RNA polymerase Promoter trp operon Genes of operon Operator mRNA 5 Start codon Stop codon trpE trpD trpC trpB trpA E D C B A Polypeptide subunits that make up enzymes for tryptophan synthesis (a) Tryptophan absent, repressor inactive, operon on (b) Tryptophan present, repressor active, operon off DNA mRNA Protein Tryptophan (corepressor) Active repressor No RNA made Figure 18.3
Repressible and Inducible Operons: Two Types of Negative Gene Regulation • A repressible operon is one that is usually on; binding of a repressor 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 repressor and turns on transcription © 2011 Pearson Education, Inc.
• 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 repressor is active and switches the lac operon off • A molecule called an inducer inactivates the repressor to turn the lac operon on © 2011 Pearson Education, Inc.
(a) Lactose absent, repressor active, operon off (b) Lactose present, repressor inactive, operon on Regulatory gene Promoter Operator DNA lacZ lacI lacI DNA mRNA 5 3 No RNA made RNA polymerase Active repressor Protein lac operon lacZ lacY lacA DNA mRNA 5 3 Protein mRNA 5 Inactive repressor RNA polymerase Allolactose (inducer) -Galactosidase Permease Transacetylase Figure 18.4
• 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 repressor © 2011 Pearson Education, Inc.
Positive Gene Regulation • 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 RNA polymerase, thus accelerating transcription © 2011 Pearson Education, Inc.
• 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 © 2011 Pearson Education, Inc.
Figure 18.5 Promoter DNA CAP-binding site lacZ lacI RNA polymerase binds and transcribes Operator cAMP Active CAP Inactive CAP Allolactose Inactive lac repressor (a) Lactose present, glucose scarce (cAMP level high): abundant lac mRNA synthesized Promoter DNA CAP-binding site lacZ lacI Operator RNA polymerase less likely to bind Inactive lac repressor Inactive CAP (b) Lactose present, glucose present (cAMP level low): little lac mRNA synthesized
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 © 2011 Pearson Education, Inc.
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 © 2011 Pearson Education, Inc.
Figure 18.6 Signal NUCLEUS Chromatin Chromatin modification: DNA unpacking involving histone acetylation and DNA demethylation DNA Gene Gene available for transcription RNA Exon Primary transcript Transcription Intron RNA processing Cap Tail mRNA in nucleus Transport to cytoplasm CYTOPLASM mRNA in cytoplasm Translation Degradation of mRNA Polypeptide Protein processing, such as cleavage and chemical modification Active protein Degradation of protein Transport to cellular destination Cellular function (such as enzymatic activity, structural support)
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 © 2011 Pearson Education, Inc.
© 2011 Pearson Education, Inc. Animation: DNA Packing Right-click slide / select “Play”
Figure 18.7 Amino acids available for chemical modification Histone tails DNA double helix Nucleosome (end view) (a) Histone tails protrude outward from a nucleosome Unacetylated histones Acetylated histones (b) Acetylation of histone tails promotes loose chromatin structure that permits transcription
• 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 © 2011 Pearson Education, Inc.
DNA Methylation • DNA methylation, the addition of methyl groups to certain bases in DNA, is associated with reduced transcription in some species • DNA 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 © 2011 Pearson Education, Inc.
Epigenetic Inheritance • Although the chromatin modifications just discussed do not alter DNA 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 © 2011 Pearson Education, Inc.
Regulation of Transcription Initiation • Chromatin-modifying enzymes provide initial control of gene expression by making a region of DNA either more or less able to bind the transcription machinery © 2011 Pearson Education, Inc.
Organization of a Typical Eukaryotic Gene • Associated with most eukaryotic genes are multiple control elements, segments of noncoding DNA 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 © 2011 Pearson Education, Inc.
Figure 18.8-1 Enhancer (distal control elements) DNA Upstream Promoter Proximal control elements Transcription start site Exon Intron Exon Exon Intron Poly-A signal sequence Transcription termination region Downstream
Figure 18.8-2 Enhancer (distal control elements) DNA Upstream Promoter Proximal control elements Transcription start site Exon Intron Exon Exon Intron Poly-A signal sequence Transcription termination region Downstream Poly-A signal Exon Intron Exon Exon Intron Transcription Cleaved 3 end of primary transcript 5 Primary RNA transcript (pre-mRNA)
Figure 18.8-3 Enhancer (distal control elements) DNA Upstream Promoter Proximal control elements Transcription start site Exon Intron Exon Exon Intron Poly-A signal sequence Transcription termination region Downstream Poly-A signal Exon Intron Exon Exon Intron Transcription Cleaved 3 end of primary transcript 5 Primary RNA transcript (pre-mRNA) Intron RNA RNA processing mRNA Coding segment 5 Cap 5 UTR Start codon Stop codon 3 UTR 3 Poly-A tail P P P G AAA AAA
The Roles of Transcription Factors • To initiate transcription, eukaryotic RNA 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 © 2011 Pearson Education, Inc.
• 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 Enhancers and Specific Transcription Factors © 2011 Pearson Education, Inc.
• An activator is a protein that binds to an enhancer and stimulates transcription of a gene • Activators have two domains, one that binds DNA and a second that activates transcription • Bound activators facilitate a sequence of protein- protein interactions that result in transcription of a given gene © 2011 Pearson Education, Inc.
© 2011 Pearson Education, Inc. Animation: Initiation of Transcription Right-click slide / select “Play”
Figure 18.9 DNA Activation domain DNA-binding domain
• Some transcription factors function as repressors, inhibiting expression of a particular gene by a variety of methods • Some activators and repressors act indirectly by influencing chromatin structure to promote or silence transcription © 2011 Pearson Education, Inc.
Activators DNA Enhancer Distal control element Promoter Gene TATA box Figure 18.10-1
Activators DNA Enhancer Distal control element Promoter Gene TATA box General transcription factors DNA- bending protein Group of mediator proteins Figure 18.10-2
Activators DNA Enhancer Distal control element Promoter Gene TATA box General transcription factors DNA- bending protein Group of mediator proteins RNA polymerase II RNA polymerase II RNA synthesis Transcription initiation complex Figure 18.10-3
Figure 18.11 Control elements Enhancer Promoter Albumin gene Crystallin gene LIVER CELL NUCLEUS Available activators Albumin gene expressed Crystallin gene not expressed (a) Liver cell LENS CELL NUCLEUS Available activators Albumin gene not expressed Crystallin gene expressed (b) Lens cell
Mechanisms of Post-Transcriptional Regulation • Transcription 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 © 2011 Pearson Education, Inc.
RNA Processing • In alternative RNA splicing, different mRNA molecules are produced from the same primary transcript, depending on which RNA segments are treated as exons and which as introns © 2011 Pearson Education, Inc.
© 2011 Pearson Education, Inc. Animation: RNA Processing Right-click slide / select “Play”
Exons DNA Troponin T gene Primary RNA transcript RNA splicing or mRNA 1 1 1 1 2 2 2 2 3 3 3 4 4 4 5 5 5 5 Figure 18.13
mRNA Degradation • The life span of mRNA molecules in the cytoplasm is a key to determining protein synthesis • Eukaryotic mRNA is more long lived than prokaryotic mRNA • Nucleotide sequences that influence the lifespan of mRNA in eukaryotes reside in the untranslated region (UTR) at the 3 end of the molecule © 2011 Pearson Education, Inc.
© 2011 Pearson Education, Inc. Animation: mRNA Degradation Right-click slide / select “Play”
Initiation of Translation • The initiation of translation of selected mRNAs can be blocked by regulatory proteins that bind to sequences or structures of the mRNA • Alternatively, translation of all mRNAs in a cell may be regulated simultaneously • For example, translation initiation factors are simultaneously activated in an egg following fertilization © 2011 Pearson Education, Inc.
© 2011 Pearson Education, Inc. Animation: Blocking Translation Right-click slide / select “Play”
Protein 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 © 2011 Pearson Education, Inc.
© 2011 Pearson Education, Inc. Animation: Protein Processing Right-click slide / select “Play”
© 2011 Pearson Education, Inc. Animation: Protein Degradation Right-click slide / select “Play”
Figure 18.14 Protein to be degraded Ubiquitin Ubiquitinated protein Proteasome Protein entering a proteasome Proteasome and ubiquitin to be recycled Protein fragments (peptides)
Concept 18.3: Noncoding RNAs play multiple roles in controlling gene expression • Only a small fraction of DNA codes for proteins, and a very small fraction of the non-protein-coding DNA consists of genes for RNA such as rRNA and tRNA • A significant amount of the genome may be transcribed into noncoding RNAs (ncRNAs) • Noncoding RNAs regulate gene expression at two points: mRNA translation and chromatin configuration © 2011 Pearson Education, Inc.
Effects on mRNAs by MicroRNAs and Small Interfering RNAs • MicroRNAs (miRNAs) are small single-stranded RNA molecules that can bind to mRNA • These can degrade mRNA or block its translation • The phenomenon of inhibition of gene expression by RNA molecules is called RNA interference (RNAi) • RNAi is caused by small interfering RNAs (siRNAs) • siRNAs and miRNAs are similar but form from different RNA precursors © 2011 Pearson Education, Inc.
(a) Primary miRNA transcript Hairpin miRNA miRNA Hydrogen bond Dicer miRNA- protein complex mRNA degraded Translation blocked (b) Generation and function of miRNAs 5 3 Figure 18.15
The Evolutionary Significance of Small ncRNAs • Small ncRNAs can regulate gene expression at multiple steps • An increase in the number of miRNAs in a species may have allowed morphological complexity to increase over evolutionary time • siRNAs may have evolved first, followed by miRNAs and later piRNAs © 2011 Pearson Education, Inc.
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 © 2011 Pearson Education, Inc.
Figure 18.16 (a) Fertilized eggs of a frog (b) Newly hatched tadpole 1 mm 2 mm
• 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 © 2011 Pearson Education, Inc. A Genetic Program for EmbryonicDevelopment
Cytoplasmic Determinants and Inductive Signals • An egg’s cytoplasm contains RNA, 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 © 2011 Pearson Education, Inc.
Figure 18.17 (a) Cytoplasmic determinants in the egg (b) Induction by nearby cells Unfertilized egg Sperm Fertilization Zygote (fertilized egg) Mitotic cell division Two-celled embryo Nucleus Molecules of two different cytoplasmic determinants Early embryo (32 cells) NUCLEUS Signal transduction pathway Signal receptor Signaling molecule (inducer)
• 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 © 2011 Pearson Education, Inc.
© 2011 Pearson Education, Inc. Animation: Cell Signaling Right-click slide / select “Play”
Figure 18.17b (b) Induction by nearby cells Early embryo (32 cells) NUCLEUS Signal transduction pathway Signal receptor Signaling molecule (inducer)
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 © 2011 Pearson Education, Inc.
Nucleus Embryonic precursor cell DNA Master regulatory gene myoD OFF OFF Other muscle-specific genes Figure 18.18-1
Nucleus Embryonic precursor cell Myoblast (determined) DNA Master regulatory gene myoD OFF OFF OFF mRNA Other muscle-specific genes MyoD protein (transcription factor) Figure 18.18-2
Nucleus Embryonic precursor cell Myoblast (determined) Part of a muscle fiber (fully differentiated cell) DNA Master regulatory gene myoD OFF OFF OFF mRNA Other muscle-specific genes MyoD protein (transcription factor) mRNA mRNA mRNA mRNA MyoD Another transcription factor Myosin, other muscle proteins, and cell cycle– blocking proteins Figure 18.18-3
Pattern Formation: Setting Up the Body Plan • 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 © 2011 Pearson Education, Inc.
The Life Cycle of Drosophila • 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 © 2011 Pearson Education, Inc.
Head Thorax Abdomen 0.5 mm BODY AXES Anterior Left Ventral Dorsal Right Posterior (a) Adult Egg developing within ovarian follicle Follicle cell Nucleus Nurse cell Egg Unfertilized egg Depleted nurse cells Egg shell Fertilization Laying of egg Fertilized egg Embryonic development Segmented embryo Body segments Hatching 0.1 mm Larval stage (b) Development from egg to larva 2 1 3 4 5 Figure 18.19
Genetic Analysis of Early Development: Scientific Inquiry • 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 © 2011 Pearson Education, Inc.
Figure 18.20 Wild type Mutant Eye Antenna 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 © 2011 Pearson Education, Inc.
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 egg- polarity genes because they control orientation of the egg and consequently the fly © 2011 Pearson Education, Inc.
© 2011 Pearson Education, Inc. Animation: Development of Head-Tail Axis in Fruit Flies Right-click slide / select “Play”
• 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 Bicoid: A Morphogen Determining Head Structures © 2011 Pearson Education, Inc.
Figure 18.21 Head Tail Tail Tail Wild-type larva Mutant larva (bicoid) 250 m T1 T2 T3 A1 A2 A3 A4 A5 A6 A7 A8 A8 A7 A6 A7 A8
• 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 © 2011 Pearson Education, Inc.
Figure 18.22 Bicoid mRNA in mature unfertilized egg Bicoid mRNA in mature unfertilized egg Fertilization, translation of bicoid mRNA Anterior end 100 m Bicoid protein in early embryo Bicoid protein in early embryo RESULTS
• 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 © 2011 Pearson Education, Inc.
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 © 2011 Pearson Education, Inc.
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 © 2011 Pearson Education, Inc.
• 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 © 2011 Pearson Education, Inc.
Figure 18.23 Proto-oncogene DNA Translocation or transposition: gene moved to new locus, under new controls Gene amplification: multiple copies of the gene New promoter Normal growth- stimulating protein in excess Normal growth-stimulating protein in excess Point mutation: within a control element within the gene Oncogene Oncogene Normal growth- stimulating protein in excess Hyperactive or degradation- resistant protein
• Proto-oncogenes can be converted to oncogenes by – Movement of DNA 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 © 2011 Pearson Education, Inc.
Tumor-Suppressor Genes • Tumor-suppressor genes help prevent uncontrolled cell growth • Mutations that decrease protein products of tumor- suppressor genes may contribute to cancer onset • Tumor-suppressor proteins – Repair damaged DNA – Control cell adhesion – Inhibit the cell cycle in the cell-signaling pathway © 2011 Pearson Education, Inc.
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 © 2011 Pearson Education, Inc.
Figure 18.24 Growth factor 1 2 3 4 5 1 2 Receptor G protein Protein kinases (phosphorylation cascade) NUCLEUS Transcription factor (activator) DNA Gene expression Protein that stimulates the cell cycle Hyperactive Ras protein (product of oncogene) issues signals on its own. (a) Cell cycle–stimulating pathway MUTATION Ras Ras GTP GTP P P P P P P (b) Cell cycle–inhibiting pathway Protein kinases UV light DNA damage in genome Active form of p53 DNA Protein that inhibits the cell cycle Defective or missing transcription factor, such as p53, cannot activate transcription. MUTATION EFFECTS OF MUTATIONS (c) Effects of mutations Protein overexpressed Cell cycle overstimulated Increased cell division Protein absent Cell cycle not inhibited 3
• Suppression of the cell cycle can be important in the case of damage to a cell’s DNA; p53 prevents a cell from passing on mutations due to DNA damage • Mutations in the p53 gene prevent suppression of the cell cycle © 2011 Pearson Education, Inc.
Figure 18.24c EFFECTS OF MUTATIONS (c) Effects of mutations Protein overexpressed Cell cycle overstimulated Increased cell division Protein absent Cell cycle not inhibited
The Multistep Model of Cancer Development • Multiple mutations are generally needed for full- fledged cancer; thus the incidence increases with age • At the DNA level, a cancerous cell is usually characterized by at least one active oncogene and the mutation of several tumor-suppressor genes © 2011 Pearson Education, Inc.
Figure 18.25 Colon Normal colon epithelial cells Loss of tumor- suppressor gene APC (or other) 1 2 3 4 5 Colon wall Small benign growth (polyp) Activation of ras oncogene Loss of tumor- suppressor gene DCC Loss of tumor- suppressor gene p53 Additional mutations Malignant tumor (carcinoma) Larger benign growth (adenoma)
Inherited Predisposition and Other Factors Contributing to Cancer • 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 DNA sequencing can detect these mutations © 2011 Pearson Education, Inc.

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  • 1. 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 © 2011 Pearson Education, Inc. Lectures by Erin Barley Kathleen Fitzpatrick Regulation of Gene Expression Chapter 18
  • 2. 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 • RNA molecules play many roles in regulating gene expression in eukaryotes © 2011 Pearson Education, Inc.
  • 3. 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 © 2011 Pearson Education, Inc.
  • 4. Precursor Feedback inhibition Enzyme 1 Enzyme 2 Enzyme 3 Tryptophan (a) (b) Regulation of enzyme activity Regulation of enzyme production Regulation of gene expression   trpE gene trpD gene trpC gene trpB gene trpA gene Figure 18.2
  • 5. Operons: The Basic Concept • A cluster of functionally related genes can be under coordinated control by a single “on-off switch” • The regulatory “switch” is a segment of DNA called an operator usually positioned within the promoter • An operon is the entire stretch of DNA that includes the operator, the promoter, and the genes that they control © 2011 Pearson Education, Inc.
  • 6. • The operon can be switched off by a protein repressor • The repressor prevents gene transcription by binding to the operator and blocking RNA polymerase • The repressor is the product of a separate regulatory gene © 2011 Pearson Education, Inc.
  • 7. • The repressor can be in an active or inactive form, depending on the presence of other molecules • A corepressor is a molecule that cooperates with a repressor protein to switch an operon off • For example, E. coli can synthesize the amino acid tryptophan © 2011 Pearson Education, Inc.
  • 8. Promoter DNA Regulatory gene mRNA trpR 5 3 Protein Inactive repressor RNA polymerase Promoter trp operon Genes of operon Operator mRNA 5 Start codon Stop codon trpE trpD trpC trpB trpA E D C B A Polypeptide subunits that make up enzymes for tryptophan synthesis (a) Tryptophan absent, repressor inactive, operon on (b) Tryptophan present, repressor active, operon off DNA mRNA Protein Tryptophan (corepressor) Active repressor No RNA made Figure 18.3
  • 9. Repressible and Inducible Operons: Two Types of Negative Gene Regulation • A repressible operon is one that is usually on; binding of a repressor 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 repressor and turns on transcription © 2011 Pearson Education, Inc.
  • 10. • 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 repressor is active and switches the lac operon off • A molecule called an inducer inactivates the repressor to turn the lac operon on © 2011 Pearson Education, Inc.
  • 11. (a) Lactose absent, repressor active, operon off (b) Lactose present, repressor inactive, operon on Regulatory gene Promoter Operator DNA lacZ lacI lacI DNA mRNA 5 3 No RNA made RNA polymerase Active repressor Protein lac operon lacZ lacY lacA DNA mRNA 5 3 Protein mRNA 5 Inactive repressor RNA polymerase Allolactose (inducer) -Galactosidase Permease Transacetylase Figure 18.4
  • 12. • 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 repressor © 2011 Pearson Education, Inc.
  • 13. Positive Gene Regulation • 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 RNA polymerase, thus accelerating transcription © 2011 Pearson Education, Inc.
  • 14. • 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 © 2011 Pearson Education, Inc.
  • 15. Figure 18.5 Promoter DNA CAP-binding site lacZ lacI RNA polymerase binds and transcribes Operator cAMP Active CAP Inactive CAP Allolactose Inactive lac repressor (a) Lactose present, glucose scarce (cAMP level high): abundant lac mRNA synthesized Promoter DNA CAP-binding site lacZ lacI Operator RNA polymerase less likely to bind Inactive lac repressor Inactive CAP (b) Lactose present, glucose present (cAMP level low): little lac mRNA synthesized
  • 16. 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 © 2011 Pearson Education, Inc.
  • 17. 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 © 2011 Pearson Education, Inc.
  • 18. Figure 18.6 Signal NUCLEUS Chromatin Chromatin modification: DNA unpacking involving histone acetylation and DNA demethylation DNA Gene Gene available for transcription RNA Exon Primary transcript Transcription Intron RNA processing Cap Tail mRNA in nucleus Transport to cytoplasm CYTOPLASM mRNA in cytoplasm Translation Degradation of mRNA Polypeptide Protein processing, such as cleavage and chemical modification Active protein Degradation of protein Transport to cellular destination Cellular function (such as enzymatic activity, structural support)
  • 19. 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 © 2011 Pearson Education, Inc.
  • 20. © 2011 Pearson Education, Inc. Animation: DNA Packing Right-click slide / select “Play”
  • 21. Figure 18.7 Amino acids available for chemical modification Histone tails DNA double helix Nucleosome (end view) (a) Histone tails protrude outward from a nucleosome Unacetylated histones Acetylated histones (b) Acetylation of histone tails promotes loose chromatin structure that permits transcription
  • 22. • 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 © 2011 Pearson Education, Inc.
  • 23. DNA Methylation • DNA methylation, the addition of methyl groups to certain bases in DNA, is associated with reduced transcription in some species • DNA 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 © 2011 Pearson Education, Inc.
  • 24. Epigenetic Inheritance • Although the chromatin modifications just discussed do not alter DNA 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 © 2011 Pearson Education, Inc.
  • 25. Regulation of Transcription Initiation • Chromatin-modifying enzymes provide initial control of gene expression by making a region of DNA either more or less able to bind the transcription machinery © 2011 Pearson Education, Inc.
  • 26. Organization of a Typical Eukaryotic Gene • Associated with most eukaryotic genes are multiple control elements, segments of noncoding DNA 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 © 2011 Pearson Education, Inc.
  • 27. Figure 18.8-1 Enhancer (distal control elements) DNA Upstream Promoter Proximal control elements Transcription start site Exon Intron Exon Exon Intron Poly-A signal sequence Transcription termination region Downstream
  • 28. Figure 18.8-2 Enhancer (distal control elements) DNA Upstream Promoter Proximal control elements Transcription start site Exon Intron Exon Exon Intron Poly-A signal sequence Transcription termination region Downstream Poly-A signal Exon Intron Exon Exon Intron Transcription Cleaved 3 end of primary transcript 5 Primary RNA transcript (pre-mRNA)
  • 29. Figure 18.8-3 Enhancer (distal control elements) DNA Upstream Promoter Proximal control elements Transcription start site Exon Intron Exon Exon Intron Poly-A signal sequence Transcription termination region Downstream Poly-A signal Exon Intron Exon Exon Intron Transcription Cleaved 3 end of primary transcript 5 Primary RNA transcript (pre-mRNA) Intron RNA RNA processing mRNA Coding segment 5 Cap 5 UTR Start codon Stop codon 3 UTR 3 Poly-A tail P P P G AAA AAA
  • 30. The Roles of Transcription Factors • To initiate transcription, eukaryotic RNA 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 © 2011 Pearson Education, Inc.
  • 31. • 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 Enhancers and Specific Transcription Factors © 2011 Pearson Education, Inc.
  • 32. • An activator is a protein that binds to an enhancer and stimulates transcription of a gene • Activators have two domains, one that binds DNA and a second that activates transcription • Bound activators facilitate a sequence of protein- protein interactions that result in transcription of a given gene © 2011 Pearson Education, Inc.
  • 33. © 2011 Pearson Education, Inc. Animation: Initiation of Transcription Right-click slide / select “Play”
  • 35. • Some transcription factors function as repressors, inhibiting expression of a particular gene by a variety of methods • Some activators and repressors act indirectly by influencing chromatin structure to promote or silence transcription © 2011 Pearson Education, Inc.
  • 38. Activators DNA Enhancer Distal control element Promoter Gene TATA box General transcription factors DNA- bending protein Group of mediator proteins RNA polymerase II RNA polymerase II RNA synthesis Transcription initiation complex Figure 18.10-3
  • 39. Figure 18.11 Control elements Enhancer Promoter Albumin gene Crystallin gene LIVER CELL NUCLEUS Available activators Albumin gene expressed Crystallin gene not expressed (a) Liver cell LENS CELL NUCLEUS Available activators Albumin gene not expressed Crystallin gene expressed (b) Lens cell
  • 40. Mechanisms of Post-Transcriptional Regulation • Transcription 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 © 2011 Pearson Education, Inc.
  • 41. RNA Processing • In alternative RNA splicing, different mRNA molecules are produced from the same primary transcript, depending on which RNA segments are treated as exons and which as introns © 2011 Pearson Education, Inc.
  • 42. © 2011 Pearson Education, Inc. Animation: RNA Processing Right-click slide / select “Play”
  • 43. Exons DNA Troponin T gene Primary RNA transcript RNA splicing or mRNA 1 1 1 1 2 2 2 2 3 3 3 4 4 4 5 5 5 5 Figure 18.13
  • 44. mRNA Degradation • The life span of mRNA molecules in the cytoplasm is a key to determining protein synthesis • Eukaryotic mRNA is more long lived than prokaryotic mRNA • Nucleotide sequences that influence the lifespan of mRNA in eukaryotes reside in the untranslated region (UTR) at the 3 end of the molecule © 2011 Pearson Education, Inc.
  • 45. © 2011 Pearson Education, Inc. Animation: mRNA Degradation Right-click slide / select “Play”
  • 46. Initiation of Translation • The initiation of translation of selected mRNAs can be blocked by regulatory proteins that bind to sequences or structures of the mRNA • Alternatively, translation of all mRNAs in a cell may be regulated simultaneously • For example, translation initiation factors are simultaneously activated in an egg following fertilization © 2011 Pearson Education, Inc.
  • 47. © 2011 Pearson Education, Inc. Animation: Blocking Translation Right-click slide / select “Play”
  • 48. Protein 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 © 2011 Pearson Education, Inc.
  • 49. © 2011 Pearson Education, Inc. Animation: Protein Processing Right-click slide / select “Play”
  • 50. © 2011 Pearson Education, Inc. Animation: Protein Degradation Right-click slide / select “Play”
  • 51. Figure 18.14 Protein to be degraded Ubiquitin Ubiquitinated protein Proteasome Protein entering a proteasome Proteasome and ubiquitin to be recycled Protein fragments (peptides)
  • 52. Concept 18.3: Noncoding RNAs play multiple roles in controlling gene expression • Only a small fraction of DNA codes for proteins, and a very small fraction of the non-protein-coding DNA consists of genes for RNA such as rRNA and tRNA • A significant amount of the genome may be transcribed into noncoding RNAs (ncRNAs) • Noncoding RNAs regulate gene expression at two points: mRNA translation and chromatin configuration © 2011 Pearson Education, Inc.
  • 53. Effects on mRNAs by MicroRNAs and Small Interfering RNAs • MicroRNAs (miRNAs) are small single-stranded RNA molecules that can bind to mRNA • These can degrade mRNA or block its translation • The phenomenon of inhibition of gene expression by RNA molecules is called RNA interference (RNAi) • RNAi is caused by small interfering RNAs (siRNAs) • siRNAs and miRNAs are similar but form from different RNA precursors © 2011 Pearson Education, Inc.
  • 54. (a) Primary miRNA transcript Hairpin miRNA miRNA Hydrogen bond Dicer miRNA- protein complex mRNA degraded Translation blocked (b) Generation and function of miRNAs 5 3 Figure 18.15
  • 55. The Evolutionary Significance of Small ncRNAs • Small ncRNAs can regulate gene expression at multiple steps • An increase in the number of miRNAs in a species may have allowed morphological complexity to increase over evolutionary time • siRNAs may have evolved first, followed by miRNAs and later piRNAs © 2011 Pearson Education, Inc.
  • 56. 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 © 2011 Pearson Education, Inc.
  • 57. Figure 18.16 (a) Fertilized eggs of a frog (b) Newly hatched tadpole 1 mm 2 mm
  • 58. • 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 © 2011 Pearson Education, Inc. A Genetic Program for EmbryonicDevelopment
  • 59. Cytoplasmic Determinants and Inductive Signals • An egg’s cytoplasm contains RNA, 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 © 2011 Pearson Education, Inc.
  • 60. Figure 18.17 (a) Cytoplasmic determinants in the egg (b) Induction by nearby cells Unfertilized egg Sperm Fertilization Zygote (fertilized egg) Mitotic cell division Two-celled embryo Nucleus Molecules of two different cytoplasmic determinants Early embryo (32 cells) NUCLEUS Signal transduction pathway Signal receptor Signaling molecule (inducer)
  • 61. • 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 © 2011 Pearson Education, Inc.
  • 62. © 2011 Pearson Education, Inc. Animation: Cell Signaling Right-click slide / select “Play”
  • 63. Figure 18.17b (b) Induction by nearby cells Early embryo (32 cells) NUCLEUS Signal transduction pathway Signal receptor Signaling molecule (inducer)
  • 64. 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 © 2011 Pearson Education, Inc.
  • 65. Nucleus Embryonic precursor cell DNA Master regulatory gene myoD OFF OFF Other muscle-specific genes Figure 18.18-1
  • 66. Nucleus Embryonic precursor cell Myoblast (determined) DNA Master regulatory gene myoD OFF OFF OFF mRNA Other muscle-specific genes MyoD protein (transcription factor) Figure 18.18-2
  • 67. Nucleus Embryonic precursor cell Myoblast (determined) Part of a muscle fiber (fully differentiated cell) DNA Master regulatory gene myoD OFF OFF OFF mRNA Other muscle-specific genes MyoD protein (transcription factor) mRNA mRNA mRNA mRNA MyoD Another transcription factor Myosin, other muscle proteins, and cell cycle– blocking proteins Figure 18.18-3
  • 68. Pattern Formation: Setting Up the Body Plan • 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 © 2011 Pearson Education, Inc.
  • 69. The Life Cycle of Drosophila • 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 © 2011 Pearson Education, Inc.
  • 70. Head Thorax Abdomen 0.5 mm BODY AXES Anterior Left Ventral Dorsal Right Posterior (a) Adult Egg developing within ovarian follicle Follicle cell Nucleus Nurse cell Egg Unfertilized egg Depleted nurse cells Egg shell Fertilization Laying of egg Fertilized egg Embryonic development Segmented embryo Body segments Hatching 0.1 mm Larval stage (b) Development from egg to larva 2 1 3 4 5 Figure 18.19
  • 71. Genetic Analysis of Early Development: Scientific Inquiry • 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 © 2011 Pearson Education, Inc.
  • 72. Figure 18.20 Wild type Mutant Eye Antenna Leg
  • 73. • 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 © 2011 Pearson Education, Inc.
  • 74. 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 egg- polarity genes because they control orientation of the egg and consequently the fly © 2011 Pearson Education, Inc.
  • 75. © 2011 Pearson Education, Inc. Animation: Development of Head-Tail Axis in Fruit Flies Right-click slide / select “Play”
  • 76. • 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 Bicoid: A Morphogen Determining Head Structures © 2011 Pearson Education, Inc.
  • 77. Figure 18.21 Head Tail Tail Tail Wild-type larva Mutant larva (bicoid) 250 m T1 T2 T3 A1 A2 A3 A4 A5 A6 A7 A8 A8 A7 A6 A7 A8
  • 78. • 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 © 2011 Pearson Education, Inc.
  • 79. Figure 18.22 Bicoid mRNA in mature unfertilized egg Bicoid mRNA in mature unfertilized egg Fertilization, translation of bicoid mRNA Anterior end 100 m Bicoid protein in early embryo Bicoid protein in early embryo RESULTS
  • 80. • 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 © 2011 Pearson Education, Inc.
  • 81. 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 © 2011 Pearson Education, Inc.
  • 82. 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 © 2011 Pearson Education, Inc.
  • 83. • 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 © 2011 Pearson Education, Inc.
  • 84. Figure 18.23 Proto-oncogene DNA Translocation or transposition: gene moved to new locus, under new controls Gene amplification: multiple copies of the gene New promoter Normal growth- stimulating protein in excess Normal growth-stimulating protein in excess Point mutation: within a control element within the gene Oncogene Oncogene Normal growth- stimulating protein in excess Hyperactive or degradation- resistant protein
  • 85. • Proto-oncogenes can be converted to oncogenes by – Movement of DNA 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 © 2011 Pearson Education, Inc.
  • 86. Tumor-Suppressor Genes • Tumor-suppressor genes help prevent uncontrolled cell growth • Mutations that decrease protein products of tumor- suppressor genes may contribute to cancer onset • Tumor-suppressor proteins – Repair damaged DNA – Control cell adhesion – Inhibit the cell cycle in the cell-signaling pathway © 2011 Pearson Education, Inc.
  • 87. 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 © 2011 Pearson Education, Inc.
  • 88. Figure 18.24 Growth factor 1 2 3 4 5 1 2 Receptor G protein Protein kinases (phosphorylation cascade) NUCLEUS Transcription factor (activator) DNA Gene expression Protein that stimulates the cell cycle Hyperactive Ras protein (product of oncogene) issues signals on its own. (a) Cell cycle–stimulating pathway MUTATION Ras Ras GTP GTP P P P P P P (b) Cell cycle–inhibiting pathway Protein kinases UV light DNA damage in genome Active form of p53 DNA Protein that inhibits the cell cycle Defective or missing transcription factor, such as p53, cannot activate transcription. MUTATION EFFECTS OF MUTATIONS (c) Effects of mutations Protein overexpressed Cell cycle overstimulated Increased cell division Protein absent Cell cycle not inhibited 3
  • 89. • Suppression of the cell cycle can be important in the case of damage to a cell’s DNA; p53 prevents a cell from passing on mutations due to DNA damage • Mutations in the p53 gene prevent suppression of the cell cycle © 2011 Pearson Education, Inc.
  • 90. Figure 18.24c EFFECTS OF MUTATIONS (c) Effects of mutations Protein overexpressed Cell cycle overstimulated Increased cell division Protein absent Cell cycle not inhibited
  • 91. The Multistep Model of Cancer Development • Multiple mutations are generally needed for full- fledged cancer; thus the incidence increases with age • At the DNA level, a cancerous cell is usually characterized by at least one active oncogene and the mutation of several tumor-suppressor genes © 2011 Pearson Education, Inc.
  • 92. Figure 18.25 Colon Normal colon epithelial cells Loss of tumor- suppressor gene APC (or other) 1 2 3 4 5 Colon wall Small benign growth (polyp) Activation of ras oncogene Loss of tumor- suppressor gene DCC Loss of tumor- suppressor gene p53 Additional mutations Malignant tumor (carcinoma) Larger benign growth (adenoma)
  • 93. Inherited Predisposition and Other Factors Contributing to Cancer • 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 DNA sequencing can detect these mutations © 2011 Pearson Education, Inc.