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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 Chapter 18 Regulation of Gene Expression Lectures by Erin Barley Kathleen Fitzpatrick © 2011 Pearson Education, Inc. 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. 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 © 2011 Pearson Education, Inc. Figure 18.2 Precursor Feedback inhibition trpE gene Enzyme 1 trpD gene Enzyme 2 Regulation of gene expression trpC gene trpB gene Enzyme 3 trpA gene Tryptophan (a) Regulation of enzyme activity (b) Regulation of enzyme production 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. • By default the trp operon is on and the genes for tryptophan synthesis are transcribed • When tryptophan is present, it binds to the trp repressor protein, which turns the operon off • The repressor is active only in the presence of its corepressor tryptophan; thus the trp operon is turned off (repressed) if tryptophan levels are high © 2011 Pearson Education, Inc. Figure 18.3 trp operon Promoter Promoter Genes of operon DNA trpE trpR trpD trpC trpB trpA C B A Operator Regulatory gene 3 RNA polymerase Start codon Stop codon mRNA 5 mRNA 5 E Protein Inactive repressor D Polypeptide subunits that make up enzymes for tryptophan synthesis (a) Tryptophan absent, repressor inactive, operon on DNA No RNA made mRNA Protein Active repressor Tryptophan (corepressor) (b) Tryptophan present, repressor active, operon off Figure 18.3a trp operon Promoter Promoter Genes of operon DNA trpR Regulatory gene mRNA trpE 3 Operator RNA Start codon polymerase mRNA 5 trpD trpC trpB trpA C B A Stop codon 5 E Protein Inactive repressor D Polypeptide subunits that make up enzymes for tryptophan synthesis (a) Tryptophan absent, repressor inactive, operon on Figure 18.3b-1 DNA mRNA Protein Active repressor Tryptophan (corepressor) (b) Tryptophan present, repressor active, operon off Figure 18.3b-2 DNA No RNA made mRNA Protein Active repressor Tryptophan (corepressor) (b) Tryptophan present, repressor active, operon off 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. Figure 18.4 Regulatory Promoter gene DNA Operator lacI lacZ No RNA made 3 mRNA RNA polymerase 5 Active repressor Protein (a) Lactose absent, repressor active, operon off lac operon DNA lacI lacZ lacY lacA RNA polymerase 3 mRNA 5 mRNA 5 -Galactosidase Protein Allolactose (inducer) Inactive repressor (b) Lactose present, repressor inactive, operon on Permease Transacetylase Figure 18.4a Regulatory gene DNA Promoter Operator lacI lacZ No RNA made 3 mRNA 5 Protein RNA polymerase Active repressor (a) Lactose absent, repressor active, operon off Figure 18.4b lac operon lacI DNA lacZ lacY lacA Permease Transacetylase RNA polymerase 3 mRNA 5 mRNA 5 -Galactosidase Protein Allolactose (inducer) Inactive repressor (b) Lactose present, repressor inactive, operon on • 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 lacI lacZ CAP-binding site cAMP Operator RNA polymerase Active binds and transcribes CAP Inactive CAP Allolactose Inactive lac repressor (a) Lactose present, glucose scarce (cAMP level high): abundant lac mRNA synthesized Promoter DNA lacI CAP-binding site lacZ Operator RNA polymerase less likely to bind Inactive CAP Inactive lac repressor (b) Lactose present, glucose present (cAMP level low): little lac mRNA synthesized Figure 18.5a Promoter DNA lacI lacZ CAP-binding site cAMP Operator RNA polymerase Active binds and transcribes CAP Inactive CAP Allolactose Inactive lac repressor (a) Lactose present, glucose scarce (cAMP level high): abundant lac mRNA synthesized Figure 18.5b Promoter DNA lacI CAP-binding site lacZ Operator RNA polymerase less likely to bind Inactive CAP Inactive lac repressor (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 DNA Chromatin modification: DNA unpacking involving histone acetylation and DNA demethylation Gene available for transcription Gene Transcription RNA Exon Primary transcript Intron RNA processing Cap Tail mRNA in nucleus Transport to cytoplasm CYTOPLASM mRNA in cytoplasm Degradation of mRNA Translation Polypeptide Protein processing, such as cleavage and chemical modification Degradation of protein Active protein Transport to cellular destination Cellular function (such as enzymatic activity, structural support) Figure 18.6a Signal NUCLEUS Chromatin DNA Chromatin modification: DNA unpacking involving histone acetylation and DNA demethylation Gene available for transcription Gene Transcription RNA Exon Primary transcript Intron RNA processing Cap Tail mRNA in nucleus Transport to cytoplasm CYTOPLASM Figure 18.6b CYTOPLASM mRNA in cytoplasm Degradation of mRNA Translation Polypeptide Protein processing, such as cleavage and chemical modification Degradation of protein Active protein Transport to cellular destination Cellular function (such as enzymatic activity, structural support) Regulation of Chromatin Structure • Genes within highly packed heterochromatin are usually not expressed • Chemical modifications to histones and DNA of chromatin influence both chromatin structure and gene expression © 2011 Pearson Education, Inc. 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 Animation: DNA Packing © 2011 Pearson Education, Inc. Figure 18.7 Histone tails Amino acids available for chemical modification DNA double helix Nucleosome (end view) (a) Histone tails protrude outward from a nucleosome Acetylated histones Unacetylated 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 Proximal control elements Transcription start site Exon Promoter Intron Exon Poly-A signal Transcription sequence termination region Intron Exon Downstream Figure 18.8-2 Enhancer (distal control elements) DNA Upstream Proximal control elements Transcription start site Exon Intron Promoter Primary RNA transcript 5 (pre-mRNA) Exon Poly-A signal Transcription sequence termination region Intron Exon Downstream Poly-A signal Intron Exon Cleaved 3 end of primary transcript Transcription Exon Intron Exon Figure 18.8-3 Enhancer (distal control elements) Proximal control elements Transcription start site Exon DNA Upstream Intron Exon Intron Downstream Poly-A signal Intron Exon Exon Cleaved 3 end of primary RNA processing transcript Promoter Transcription Exon Primary RNA transcript 5 (pre-mRNA) Poly-A signal Transcription sequence termination region Intron Exon Intron RNA Coding segment mRNA G P AAA AAA P P 5 Cap 5 UTR Start Stop codon codon 3 UTR Poly-A tail 3 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. Enhancers and Specific Transcription 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 © 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 proteinprotein interactions that result in transcription of a given gene Animation: Initiation of Transcription © 2011 Pearson Education, Inc. Figure 18.9 Activation domain DNA-binding domain DNA • 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. Figure 18.10-1 Activators Promoter DNA Enhancer Distal control element TATA box Gene Figure 18.10-2 Promoter Activators DNA Enhancer Distal control element Gene TATA box General transcription factors DNAbending protein Group of mediator proteins Figure 18.10-3 Promoter Activators DNA Enhancer Distal control element Gene TATA box General transcription factors DNAbending protein Group of mediator proteins RNA polymerase II RNA polymerase II Transcription initiation complex RNA synthesis Figure 18.11 Enhancer Control elements Promoter Albumin gene Crystallin gene LENS CELL NUCLEUS LIVER CELL NUCLEUS Available activators Available activators Albumin gene not expressed Albumin gene expressed Crystallin gene not expressed (a) Liver cell Crystallin gene expressed (b) Lens cell Figure 18.11a Enhancer Control elements Promoter LIVER CELL NUCLEUS Albumin gene Crystallin gene Available activators Albumin gene expressed Crystallin gene not expressed (a) Liver cell Figure 18.11b Enhancer Control elements Promoter LENS CELL NUCLEUS Albumin gene Crystallin gene Available activators Albumin gene not expressed Crystallin gene expressed (b) Lens cell 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 © 2011 Pearson Education, Inc. 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 RNA polymerases • These may be areas specialized for a common function © 2011 Pearson Education, Inc. Figure 18.12 Chromosomes in the interphase nucleus Chromosome territory 10 m Chromatin loop Transcription factory Figure 18.12a Chromosomes in the interphase nucleus 10 m 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 Animation: RNA Processing © 2011 Pearson Education, Inc. Figure 18.13 Exons DNA 1 3 2 4 5 Troponin T gene Primary RNA transcript 3 2 1 5 4 RNA splicing mRNA 1 2 3 5 or 1 2 4 5 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 Animation: mRNA Degradation © 2011 Pearson Education, Inc. 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 Animation: Blocking Translation © 2011 Pearson Education, Inc. 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 Animation: Protein Processing Animation: Protein Degradation © 2011 Pearson Education, Inc. Figure 18.14 Ubiquitin Proteasome Protein to be degraded Ubiquitinated protein Proteasome and ubiquitin to be recycled Protein entering a proteasome 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 © 2011 Pearson Education, Inc. Figure 18.15 Hairpin Hydrogen bond miRNA Dicer 5 3 (a) Primary miRNA transcript miRNA miRNAprotein complex mRNA degraded Translation blocked (b) Generation and function of miRNAs • 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. Chromatin Remodeling and Effects on Transcription by ncRNAs • In some yeasts siRNAs play a role in heterochromatin formation and can block large regions of the chromosome • Small ncRNAs called piwi-associated RNAs (piRNAs) induce heterochromatin, blocking the expression of parasitic DNA elements in the genome, known as transposons • RNA-based mechanisms may also block transcription of single genes © 2011 Pearson Education, Inc. 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. A Genetic Program for Embryonic Development • The transformation from zygote to adult results from cell division, cell differentiation, and morphogenesis © 2011 Pearson Education, Inc. Figure 18.16 1 mm (a) Fertilized eggs of a frog 2 mm (b) Newly hatched tadpole Figure 18.16a 1 mm (a) Fertilized eggs of a frog Figure 18.16b 2 mm (b) Newly hatched tadpole • 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. 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 Early embryo (32 cells) Nucleus Molecules of two different cytoplasmic determinants NUCLEUS Zygote (fertilized egg) Mitotic cell division Two-celled embryo Signal transduction pathway Signal receptor Signaling molecule (inducer) Figure 18.17a (a) Cytoplasmic determinants in the egg Unfertilized egg Sperm Fertilization Zygote (fertilized egg) Mitotic cell division Two-celled embryo Nucleus Molecules of two different cytoplasmic determinants • 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 © 2011 Pearson Education, Inc. 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. • 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 © 2011 Pearson Education, Inc. Figure 18.18-1 Nucleus Embryonic precursor cell Master regulatory gene myoD Other muscle-specific genes DNA OFF OFF Figure 18.18-2 Nucleus Embryonic precursor cell Myoblast (determined) Master regulatory gene myoD Other muscle-specific genes DNA OFF OFF mRNA OFF MyoD protein (transcription factor) Figure 18.18-3 Nucleus Embryonic precursor cell Master regulatory gene myoD Other muscle-specific genes DNA Myoblast (determined) OFF OFF mRNA OFF MyoD protein (transcription factor) mRNA MyoD Part of a muscle fiber (fully differentiated cell) mRNA Another transcription factor mRNA mRNA Myosin, other muscle proteins, and cell cycle– blocking proteins 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. • 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 © 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. Figure 18.19 Head Thorax Abdomen 1 Egg developing within ovarian follicle Follicle cell Nucleus Egg 0.5 mm Nurse cell Dorsal BODY AXES Anterior Left Right Posterior 2 Unfertilized egg Depleted nurse cells Ventral (a) Adult Egg shell Fertilization Laying of egg 3 Fertilized egg Embryonic development 4 Segmented embryo 0.1 mm Body segments 5 Larval stage (b) Development from egg to larva Hatching Figure 18.19a Head Thorax Abdomen 0.5 mm Dorsal BODY AXES Anterior Left Ventral (a) Adult Right Posterior Figure 18.19b Follicle cell 1 Egg Nucleus developing within ovarian follicle Egg Nurse cell 2 Unfertilized egg Depleted nurse cells Egg shell Fertilization Laying of egg 3 Fertilized egg Embryonic development 4 Segmented embryo Body segments 0.1 mm Hatching 5 Larval stage (b) Development from egg to larva Genetic Analysis of Early Development: Scientific Inquiry • Edward B. Lewis, Christiane Nüsslein-Volhard, and Eric Wieschaus won a Nobel 1995 Prize 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 Eye Leg Antenna Wild type Mutant Figure 18.20a Eye Antenna Wild type Figure 18.20b Leg Mutant • 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 eggpolarity genes because they control orientation of the egg and consequently the fly Animation: Development of Head-Tail Axis in Fruit Flies © 2011 Pearson Education, Inc. 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 © 2011 Pearson Education, Inc. Figure 18.21 Head Tail A8 T1 T2 T3 A1 A2 A3 A4 A5 A6 Wild-type larva A7 250 m Tail Tail A8 A8 A7 A6 A7 Mutant larva (bicoid) Figure 18.21a Head Tail A8 T1 T2 T3 A1 A2 A3 A4 A5 Wild-type larva A6 A7 250 m Figure 18.21b Tail Tail A8 A8 A7 A6 A7 Mutant larva (bicoid) • 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 18.22 100 m RESULTS Anterior end Fertilization, translation of bicoid mRNA Bicoid mRNA in mature unfertilized egg Bicoid mRNA in mature unfertilized egg Bicoid protein in early embryo Bicoid protein in early embryo Figure 18.22a Bicoid mRNA in mature unfertilized egg Figure 18.22b 100 m Anterior end Bicoid protein in early embryo • 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 growthstimulating protein in excess Point mutation: within a control within element the gene Oncogene Normal growth-stimulating protein in excess Normal growthstimulating protein in excess Oncogene Hyperactive or degradationresistant 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 tumorsuppressor 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 MUTATION 1 Growth factor Ras 3 G protein GTP Ras P P P P P P 2 Protein kinases Hyperactive Ras protein (product of oncogene) issues signals on its own. GTP MUTATION 3 Active form of p53 UV light 2 Receptor 4 Protein kinases (phosphorylation cascade) 1 DNA damage in genome Defective or missing transcription factor, such as p53, cannot activate transcription. DNA NUCLEUS 5 Transcription factor (activator) Protein that inhibits the cell cycle DNA Gene expression (b) Cell cycle–inhibiting pathway Protein that stimulates the cell cycle EFFECTS OF MUTATIONS Protein overexpressed Protein absent (a) Cell cycle–stimulating pathway Cell cycle overstimulated (c) Effects of mutations Increased cell division Cell cycle not inhibited Figure 18.24a MUTATION 1 Growth factor Ras 3 G protein GTP Ras P P P 2 Receptor P P P Hyperactive Ras protein (product of oncogene) issues signals on its own. GTP 4 Protein kinases (phosphorylation cascade) NUCLEUS 5 Transcription factor (activator) DNA Gene expression Protein that stimulates the cell cycle (a) Cell cycle–stimulating pathway Figure 18.24b 2 Protein kinases 3 Active form of p53 UV light 1 DNA damage in genome DNA Protein that inhibits the cell cycle (b) Cell cycle–inhibiting pathway MUTATION Defective or missing transcription factor, such as p53, cannot activate transcription. • 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 Protein overexpressed Cell cycle overstimulated (c) Effects of mutations Protein absent Increased cell division Cell cycle not inhibited The Multistep Model of Cancer Development • Multiple mutations are generally needed for fullfledged 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 1 Loss of tumorsuppressor gene APC (or other) 2 Activation of ras oncogene 4 Loss of tumorsuppressor gene p53 3 Loss 5 Additional Colon wall mutations of tumorSmall benign suppressor Larger Normal colon Malignant growth epithelial cells tumor gene DCC benign growth (polyp) (adenoma) (carcinoma) Figure 18.25a Colon Colon wall Normal colon epithelial cells Figure 18.25b 1 Loss of tumorsuppressor gene APC (or other) Small benign growth (polyp) Figure 18.25c 2 Activation of ras oncogene 3 Loss of tumor-suppressor gene DCC Larger benign growth (adenoma) Figure 18.25d 4 Loss of tumor-suppressor gene p53 5 Additional mutations Malignant tumor (carcinoma) 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. Figure 18.26 Figure 18.UN01 Operon Promoter Genes A B C Operator RNA polymerase A B C Polypeptides Figure 18.UN02 Genes expressed Genes not expressed Promoter Genes Operator Inactive repressor: no corepressor present Active repressor: corepressor bound Corepressor Figure 18.UN03 Genes not expressed Promoter Operator Genes expressed Genes Active repressor: no inducer present Inactive repressor: inducer bound Figure 18.UN04 Transcription Chromatin modification • Genes in highly compacted chromatin are generally not transcribed. • Histone acetylation seems to loosen chromatin structure, enhancing transcription. • DNA methylation generally reduces transcription. • Regulation of transcription initiation: DNA control elements in enhancers bind specific transcription factors. Bending of the DNA enables activators to contact proteins at the promoter, initiating transcription. • Coordinate regulation: Enhancer for Enhancer for liver-specific genes lens-specific genes Chromatin modification Transcription RNA processing RNA processing • Alternative RNA splicing: Primary RNA transcript mRNA degradation Translation Protein processing and degradation mRNA or Translation • Initiation of translation can be controlled via regulation of initiation factors. mRNA degradation • Each mRNA has a characteristic life span, determined in part by sequences in the 5 and 3 UTRs. Protein processing and degradation • Protein processing and degradation by proteasomes are subject to regulation. Figure 18.UN04a Chromatin modification • Genes in highly compacted chromatin are generally not transcribed. • Histone acetylation seems to loosen chromatin structure, enhancing transcription. • DNA methylation generally reduces transcription. Transcription • Regulation of transcription initiation: DNA control elements in enhancers bind specific transcription factors. Bending of the DNA enables activators to contact proteins at the promoter, initiating transcription. • Coordinate regulation: Enhancer for Enhancer for lens-specific genes liver-specific genes Chromatin modification Transcription RNA processing RNA processing • Alternative RNA splicing: Primary RNA transcript mRNA degradation Translation Protein processing and degradation mRNA or Figure 18.UN04b Chromatin modification Transcription RNA processing mRNA degradation Translation Protein processing and degradation Translation • Initiation of translation can be controlled via regulation of initiation factors. mRNA degradation • Each mRNA has a characteristic life span, determined in part by sequences in the 5 and 3 UTRs. Protein processing and degradation • Protein processing and degradation by proteasomes are subject to regulation. Figure 18.UN05 Chromatin modification Chromatin modification • Small or large noncoding RNAs can promote the formation of heterochromatin in certain regions, blocking transcription. Transcription RNA processing mRNA degradation Translation • miRNA or siRNA can block the translation of specific mRNAs. Translation Protein processing and degradation mRNA degradation • miRNA or siRNA can target specific mRNAs for destruction. Figure 18.UN06 Enhancer Promoter Gene 1 Gene 2 Gene 3 Gene 4 Gene 5 Figure 18.UN07 Enhancer Promoter Gene 1 Gene 2 Gene 3 Gene 4 Gene 5 Figure 18.UN08 Enhancer Promoter Gene 1 Gene 2 Gene 3 Gene 4 Gene 5