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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. Figure 18.1 Concept 18.1: Bacteria often respond to environmental change by regulating transcription • 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 is the product of a separate regulatory gene • 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 © 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 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 © 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 • 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 © 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 Differential Gene Expression (Eukaryotes) • Almost all the cells in an organism are genetically identical • Differences between cell types result from ? • differential gene expression • Gene expression is regulated at many stages © 2011 Pearson Education, Inc. 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) DNA Methylation • DNA methylation, • is associated with reduced transcription • can cause long-term inactivation of genes in cellular differentiation • Can regulate expression of either the maternal or paternal alleles (genomic imprinting) © 2011 Pearson Education, Inc. Epigenetic Inheritance • The inheritance of traits transmitted by mechanisms not directly involving the nucleotide sequence is called • epigenetic inheritance © 2011 Pearson Education, Inc. 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 RNA Processing • In alternative RNA splicing, different mRNA molecules are produced from the same primary transcript © 2011 Pearson Education, Inc. Animation: RNA Processing Right-click slide / select “Play” © 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 Animation: mRNA Degradation Right-click slide / select “Play” © 2011 Pearson Education, Inc. Animation: Blocking Translation Right-click slide / select “Play” © 2011 Pearson Education, Inc. Animation: Protein Processing Right-click slide / select “Play” © 2011 Pearson Education, Inc. Animation: Protein Degradation Right-click slide / select “Play” © 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) Small noncoding RNAs • Small ncRNAs can regulate gene expression at multiple steps • miRNAs - microRNAs • siRNAs – small intefering RNAs © 2011 Pearson Education, Inc. Figure 18.16 1 mm (a) Fertilized eggs of a frog 2 mm (b) Newly hatched tadpole Animation: Cell Signaling Right-click slide / select “Play” © 2011 Pearson Education, Inc. 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 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 © 2011 Pearson Education, Inc. Animation: Development of Head-Tail Axis in Fruit Flies Right-click slide / select “Play” © 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