Chapter 11 How Genes Are Controlled

Transcription

1 Chapter 11 How Genes Are Controlled PowerPoint Lectures Campbell Biology: Concepts & Connections, Eighth Edition REECE TAYLOR SIMON DICKEY HOGAN Lecture by Edward J. Zalisko

2 Introduction Well-preserved animals that have been dead for decades may be cloned using closely related animals as surrogates. Scientists have cloned a banteng, an endangered species of cattle native to Indonesia. As of 2013, it remains a healthy inhabitant of the San Diego Zoo. The development of different types of cells depends on turning on and off different genes in different cells the control of gene expression.

3 Figure

4 Figure Chapter 11: Big Ideas Control of Gene Expression Cloning of Plants and Animals The Genetic Basis of Cancer

5 CONTROL OF GENE EXPRESSION

6 11.1 Proteins interacting with DNA turn prokaryotic genes on or off in response to environmental changes Gene regulation is the turning on and off of genes. Gene expression is the overall process of information flow from genes to proteins. The control of gene expression allows cells to produce specific kinds of proteins when and where they are needed. Our earliest understanding of gene control came from the study of E. coli.

7 Figure 11.1a

8 11.1 Proteins interacting with DNA turn prokaryotic genes on or off in response to environmental changes An operon is a cluster of genes with related functions, along with the control sequences. With rare exceptions, operons only exist in prokaryotes.

9 11.1 Proteins interacting with DNA turn prokaryotic genes on or off in response to environmental changes When an E. coli encounters lactose, all the enzymes needed for its metabolism are made at once using the lactose operon. The lactose (lac) operon includes 1. three adjacent lactose-utilization genes, 2. a promoter sequence, a site where RNA polymerase binds and initiates transcription of all three lactose genes, and 3. an operator sequence, where a repressor can bind and block RNA polymerase action.

10 11.1 Proteins interacting with DNA turn prokaryotic genes on or off in response to environmental changes E. coli uses three enzymes to take up and start metabolizing lactose only when lactose is present. The genes coding for these three enzymes are located next to each other and regulated as a single unit.

11 11.1 Proteins interacting with DNA turn prokaryotic genes on or off in response to environmental changes Regulation of the lac operon A regulatory gene, located outside the operon, continually codes for a repressor protein. In the absence of lactose, the repressor binds to the operator and prevents RNA polymerase action. Lactose inactivates the repressor, so the operator is unblocked, RNA polymerase can bind to the promoter, and all three genes of the operon are transcribed.

12 Figure 11.1b-0 Operon turned off (lactose is absent): OPERON Regulatory gene Promoter Operator Lactose-utilization genes DNA mrna RNA polymerase cannot attach to the promoter Protein Active repressor Operon turned on (lactose inactivates the repressor): DNA mrna RNA polymerase is bound to the promoter Translation Protein Lactose Inactive repressor Enzymes for lactose utilization

13 Figure 11.1b-1 Operon turned off (lactose is absent): Regulatory gene Promoter Operator OPERON Lactose-utilization genes DNA mrna RNA polymerase cannot attach to the promoter Protein Active repressor

14 Figure 11.1b-2 Operon turned on (lactose inactivates the repressor): DNA mrna RNA polymerase is bound to the promoter Translation Protein Lactose Inactive repressor Enzymes for lactose utilization

15 11.1 Proteins interacting with DNA turn prokaryotic genes on or off in response to environmental changes There are two types of repressor-controlled operons. The lac operon is an example of an inducible operon that is usually turned off but can be stimulated (induced) by a molecule in this case, by lactose. The trp operon is an example of a repressible operon that is normally turned on but can be inhibited (repressed) when a specific molecule (such as amino acid tryptophan) is present in abundance.

16 Figure 11.1c lac operon (inducible) DNA Promoter Operator Gene trp operon (repressible) Active repressor Active repressor Tryptophan Inactive repressor Lactose Inactive repressor

17 11.1 Proteins interacting with DNA turn prokaryotic genes on or off in response to environmental changes Another type of operon control involves activators, proteins that turn operons on by binding to DNA and stimulating gene transcription. Activators help control a wide variety of operons.

18 11.2 Chromosome structure and chemical modifications can affect gene expression Differentiation involves cell specialization in structure and function and is controlled by turning specific sets of genes on or off. Almost all of the cells in an organism contain an identical genome. The differences between cell types are not due to the presence of different genes but instead due to selective gene expression.

19 11.2 Chromosome structure and chemical modifications can affect gene expression Eukaryotic chromosomes undergo multiple levels of folding and coiling, called DNA packing. Nucleosomes are formed when DNA is wrapped around histone proteins. This packaging gives a beads on a string appearance. Each nucleosome bead includes DNA plus eight histones. Stretches of DNA, called linkers, join consecutive nucleosomes.

20 11.2 Chromosome structure and chemical modifications can affect gene expression Eukaryotic chromosomes undergo multiple levels of folding and coiling, called DNA packing. At the next level of packing, the beaded string is wrapped into a tight helical fiber. This fiber coils further into a thick supercoil. Looping and folding can further compact the DNA.

21 Figure 11.2a-0 DNA double helix (2-nm diameter) Metaphase chromosome Tight helical fiber (30-nm diameter) Linker Beads on a string Nucleosome (10-nm diameter) Histones Supercoil (300-nm diameter) 700 nm

22 Figure 11.2a-1 Linker Beads on a string

23 Figure 11.2a-2 Metaphase chromosome 700 nm

24 11.2 Chromosome structure and chemical modifications can affect gene expression DNA packing tends to prevent gene expression by preventing RNA polymerase and other transcription proteins from contacting the DNA. Higher levels of packing can therefore inactivate genes for the long term. Highly compacted chromatin, found in varying regions of interphase chromosomes, is generally not expressed at all.

25 Animation: DNA Packing

26 11.2 Chromosome structure and chemical modifications can affect gene expression Chemical modification of DNA bases or histone proteins can result in epigenetic inheritance. Certain enzymes can add a methyl group to DNA bases, without changing the sequence of the bases. Individual genes are usually more methylated in cells in which the genes are not expressed. Once methylated, genes usually stay that way through successive cell divisions in an individual.

27 11.2 Chromosome structure and chemical modifications can affect gene expression Removal of the extra methyl groups can turn on some of these genes. Inheritance of traits transmitted by mechanisms not directly involving the nucleotide sequence is called epigenetic inheritance. These modifications can be reversed by processes not yet fully understood.

28 11.2 Chromosome structure and chemical modifications can affect gene expression X chromosome inactivation In female mammals, one of the two X chromosomes is chemically modified and highly compacted. Either the maternal or paternal chromosome is randomly inactivated. Inactivation occurs early in embryonic development, and all cellular descendants have the same inactivated chromosome. An inactivated X chromosome is called a Barr body. Tortoiseshell fur coloration is due to inactivation of X chromosomes in heterozygous female cats.

29 Figure 11.2b-0 Early Embryo Adult X chromosomes Cell division and random X chromosome inactivation Active X Inactive X Two cell populations Orange fur Allele for orange fur Allele for black fur Inactive X Active X Black fur

30 Figure 11.2b-1 Early Embryo Adult X chromosomes Two cell populations Cell division and random X chromosome Active X Orange inactivation Inactive X fur Allele for orange fur Allele for black fur Inactive X Active X Black fur

31 Figure 11.2b-2

32 11.3 Complex assemblies of proteins control eukaryotic transcription Prokaryotes and eukaryotes employ regulatory proteins (activators and repressors) that bind to specific segments of DNA and either promote or block the binding of RNA polymerase, turning the transcription of genes on and off.

33 11.3 Complex assemblies of proteins control eukaryotic transcription In eukaryotes, activator proteins seem to be more important than repressors. Thus, in multicellular eukaryotes, the default state for most genes seems to be off. A typical plant or animal cell needs to turn on and transcribe only a small percentage of its genes.

34 11.3 Complex assemblies of proteins control eukaryotic transcription Eukaryotic RNA polymerase requires the assistance of proteins called transcription factors. Transcription factors include activator proteins, which bind to DNA sequences called enhancers and initiate gene transcription, and other transcription factor proteins that interact with the bound activators, which then collectively bind as a complex at the gene s promoter. RNA polymerase then attaches to the promoter, and transcription begins.

35 Animation: Initiation of Transcription

36 Figure 11.3 Enhancers Promoter Gene DNA Transcription factors Activator proteins Other proteins DNA-bending protein RNA polymerase Bending of DNA Transcription

37 11.3 Complex assemblies of proteins control eukaryotic transcription Coordinated gene expression in eukaryotes often depends on the association of a specific combination of control sequences with every gene of a particular metabolic pathway.

38 11.4 Eukaryotic RNA may be spliced in more than one way Alternative RNA splicing produces different mrnas from the same transcript and results in the production of more than one polypeptide from the same gene. In humans, more than 90% of protein-coding genes appear to undergo alternate splicing.

39 Animation: RNA Processing

40 Figure Exons DNA Introns Introns

41 Figure Exons DNA Introns Introns RNA transcript Cap Tail

42 Figure Exons DNA Introns Introns RNA transcript mrna Cap RNA splicing or Tail

43 11.5 Small RNAs play multiple roles in controlling gene expression Only about 1.5% of the human genome codes for proteins. (This is also true of many other multicellular eukaryotes.) Another small fraction of DNA consists of genes for ribosomal RNA and transfer RNA. A flood of recent data suggests that a significant amount of the remaining genome is transcribed into functioning but non-protein-coding RNAs, including a variety of small RNAs.

44 11.5 Small RNAs play multiple roles in controlling gene expression micrornas (mirnas) can bind to complementary sequences on mrna molecules either degrading the target mrna or blocking its translation. RNA interference (RNAi) is the use of mirna to artificially control gene expression by injecting mirnas into a cell to turn off a specific gene sequence.

45 Animation: Blocking Translation

46 Animation: mrna Degradation

47 Figure mirna 1 Protein

48 Figure mirna 1 Protein 2 mirnaprotein complex Target mrna

49 Figure mirna 1 Protein 2 mirnaprotein complex Target mrna 3 or mrna degraded Translation blocked

50 11.6 Later stages of gene expression are also subject to regulation After a eukaryotic mrna is fully processed and transported to the cytoplasm, gene expression can still be regulated by breakdown of mrna, initiation of translation, protein activation, and protein breakdown.

51 Figure Initial polypeptide (inactive)

52 Figure Folding of the polypeptide and the formation of S S linkages Initial polypeptide (inactive) Folded polypeptide (inactive)

53 Figure Folding of the polypeptide and the formation of S S linkages Cleavage Initial polypeptide (inactive) Folded polypeptide (inactive) Active form of insulin

54 11.7 VISUALIZING THE CONCEPT: Multiple mechanisms regulate gene expression in eukaryotes Multiple control points exist where gene expression in eukaryotes can be turned on or off, speeded up, or slowed down. Although many control points are shown, only a few of them may be important for any particular protein.

55 Animation: Protein Degradation

56 Animation: Protein Processing

57 Figure The flow of genetic information from a chromosome to a protein is controlled at several points, just as the flow of water through pipes is controlled by valves. Chromosome DNA unpacking Gene DNA NUCLEUS CYTOPLASM

58 Figure The flow of genetic information from a chromosome to a protein is controlled at several points, just as the flow of water through pipes is controlled by valves. Chromosome DNA unpacking Gene DNA NUCLEUS Transcription RNA transcript CYTOPLASM

59 Figure The flow of genetic information from a chromosome to a protein is controlled at several points, just as the flow of water through pipes is controlled by valves. Chromosome DNA unpacking Gene DNA NUCLEUS Transcription Exon Splicing Addition of a cap and tail mrna in nucleus Cap Intron RNA transcript Tail CYTOPLASM

60 Figure The flow of genetic information from a chromosome to a protein is controlled at several points, just as the flow of water through pipes is controlled by valves. Chromosome DNA unpacking Gene DNA NUCLEUS Transcription Exon Splicing Addition of a cap and tail Flow through nuclear envelope mrna in nucleus Cap Intron RNA transcript Tail CYTOPLASM mrna in cytoplasm

61 Figure The flow of genetic information from a chromosome to a protein is controlled at several points, just as the flow of water through pipes is controlled by valves. Chromosome DNA unpacking Gene DNA NUCLEUS Transcription Exon Splicing Addition of a cap and tail Flow through nuclear envelope mrna in nucleus Cap Intron RNA transcript Tail CYTOPLASM Breakdown of mrna mrna in cytoplasm Broken-down mrna

62 Figure The flow of genetic information from a chromosome to a protein is controlled at several points, just as the flow of water through pipes is controlled by valves. Chromosome DNA unpacking Gene DNA NUCLEUS Transcription Exon Splicing Addition of a cap and tail Flow through nuclear envelope mrna in nucleus Cap Intron RNA transcript Tail CYTOPLASM Breakdown of mrna Translation mrna in cytoplasm Polypeptide Broken-down mrna

63 Figure The flow of genetic information from a chromosome to a protein is controlled at several points, just as the flow of water through pipes is controlled by valves. Chromosome DNA unpacking Gene DNA NUCLEUS Transcription Exon Splicing Addition of a cap and tail Flow through nuclear envelope mrna in nucleus Cap Intron RNA transcript Tail CYTOPLASM Breakdown of mrna Translation Cleavage, modification, activation mrna in cytoplasm Polypeptide Active protein Broken-down mrna

64 Figure The flow of genetic information from a chromosome to a protein is controlled at several points, just as the flow of water through pipes is controlled by valves. Chromosome DNA unpacking Gene DNA NUCLEUS Transcription Exon Splicing Addition of a cap and tail Flow through nuclear envelope mrna in nucleus Cap Intron RNA transcript Tail CYTOPLASM Breakdown of mrna Translation Cleavage, modification, activation Breakdown of protein Amino acids mrna in cytoplasm Polypeptide Active protein Broken-down mrna

65 11.8 Cell signaling and waves of gene expression direct animal development Early research on gene expression and embryonic development came from studies of a fruit fly. Research on fruit flies and other developmental mutants, such as a mutant fly with two legs where its antennae should be, has led to the identification of many of the genes that program development in the normal fly.

66 Animation: Cell Signaling

67 11.8 Cell signaling and waves of gene expression direct animal development Homeotic genes are master control genes that regulate the batteries of other genes that determine the anatomy of parts of the body and determine which body parts will develop where in the fly.

68 Figure 11.8a-0 Eye Antenna Extra pair of legs

69 Figure 11.8a-1 Eye Antenna

70 Figure 11.8a-2 Extra pair of legs

71 Figure 11.8b-0 Egg cell within ovarian follicle Egg cell Egg cell and follicle 1 cells signaling each other Follicle cells Gene expression Growth of egg cell Localization of head mrna 2 Head mrna Embryo Egg cell Cascades of gene expression Fertilization and mitosis Body segments 3 Adult fly Expression of homeotic genes and cascades of gene expression 4

72 Figure 11.8b-1 Egg cell within ovarian follicle 1 Follicle cells Egg cell Egg cell and follicle cells signaling each other Gene expression Growth of egg cell Localization of head mrna 2 Head mrna Egg cell Cascades of gene expression Fertilization and mitosis

73 Figure 11.8b-2 Embryo Body segments 3 Adult fly Expression of homeotic genes and cascades of gene expression 4

74 11.9 CONNECTION: Scientists use DNA microarrays to test for the transcription of many genes at once Genome-wide expression studies are made possible by DNA microarrays. These consist of a glass or plastic surface with tiny amounts of thousands of different kinds of singlestranded DNA fragments attached to microscopic wells in a tightly spaced array, or grid.

75 11.9 CONNECTION: Scientists use DNA microarrays to test for the transcription of many genes at once A DNA microarray is used to test for transcription in the following way: mrna from a specific cell type is isolated, fluorescent cdna is produced from the mrna, cdna is applied to the microarray, unbound cdna is washed off, and complementary cdna is detected by fluorescence.

76 Figure DNA microarray 1 mrna is isolated. Each well contains DNA from a particular gene. 6,400 genes Reverse transcriptase and fluorescent DNA nucleotides 4 Unbound cdna is rinsed away. 3 cdna is applied to the wells. Fluorescent spot Nonfluorescent spot 2 cdna is made from mrna. cdna DNA of an expressed gene DNA of an unexpressed gene

77 Figure mrna is isolated. Reverse transcriptase and fluorescent DNA nucleotides 2 cdna is made from mrna.

78 Figure DNA microarray Each well contains DNA from a particular gene. 6,400 genes 4 Unbound cdna is rinsed away. 3 cdna is applied to the wells. Fluorescent spot Nonfluorescent spot cdna DNA of an expressed gene DNA of an unexpressed gene

79 11.9 CONNECTION: Scientists use DNA microarrays to test for the transcription of many genes at once DNA microarrays are a potential boon to medical research. A study showed that DNA microarray data can classify different types of leukemia, helping to identify which chemotherapies will be most effective. Some oncologists predict that DNA microarrays will usher in a new era in which medical treatment is personalized to each patient DNA microarrays also reveal general profiles of gene expression over the lifetime of an organism.

80 11.10 Signal transduction pathways convert messages received at the cell surface to responses within the cell A signal transduction pathway is a series of molecular changes that convert a signal on the target cell s surface to a specific response within the cell. Signal transduction pathways are crucial to many cellular functions.

81 Animation: Overview of Cell Signaling

82 Animation: Signal Transduction Pathways

83 Figure Signaling cell 1 2 EXTRACELLULAR FLUID Signaling molecule Receptor protein Plasma membrane Target cell Relay proteins 3 Signal transduction pathway Transcription factor (activated) 4 NUCLEUS DNA 5 mrna Transcription 6 New protein CYTOPLASM Translation

84 Figure Signaling cell 1 2 EXTRACELLULAR FLUID Signaling molecule Receptor protein Plasma membrane Target cell Relay proteins 3 Signal transduction pathway

85 Figure Transcription factor (activated) 4 NUCLEUS DNA 5 mrna Transcription 6 New protein CYTOPLASM Translation

86 11.11 EVOLUTION CONNECTION: Cellsignaling systems appeared early in the evolution of life In the yeast used to make bread, beer, and wine, mating is controlled by a signal transduction pathway. These yeast cells identify their mates by chemical signaling.

87 11.11 EVOLUTION CONNECTION: Cellsignaling systems appeared early in the evolution of life Yeast (Saccharomyces cerevisiae) have two mating types: a and α. Each produces a chemical factor that binds to receptors on cells of the opposite mating type. Binding to receptors triggers growth toward the other cell and fusion. Early versions of the cell-signaling mechanisms used today evolved well before the first multicellular creatures appeared on Earth.

88 Figure Receptor a α factor α Yeast cell, mating type a a factor Yeast cell, mating type α a α a/α

89 CLONING OF PLANTS AND ANIMALS

90 11.12 Plant cloning shows that differentiated cells may retain all of their genetic potential Most cells express only a small percentage of their genes. If all genes are still present but some are turned off, have the unexpressed genes become permanently disabled? Or do all genes (even the unexpressed ones) retain the potential to be expressed?

91 11.12 Plant cloning shows that differentiated cells may retain all of their genetic potential One way to approach these questions is to determine if a differentiated cell can be stimulated to generate a whole new organism. In plants, this ability is common. A differentiated plant cell can undergo cell division and give rise to all the tissues of an adult plant.

92 11.12 Plant cloning shows that differentiated cells may retain all of their genetic potential On a larger scale, the technique described in Figure can be used to produce hundreds or thousands of genetically identical plants from the cells of a single plant. Such an organism, produced through asexual reproduction from a single parent, is called a clone. The term clone refers to an individual created by asexual reproduction.

93 Figure Root of carrot plant Single cell Root cells cultured in growth medium Cell division in culture Plantlet Adult plant

94 11.12 Plant cloning shows that differentiated cells may retain all of their genetic potential In animals, a good indication that differentiation need not impair a cell s genetic potential is the natural process of regeneration, the regrowth of lost body parts. When a salamander loses a leg, for example, certain cells in the leg stump dedifferentiate, divide, and then redifferentiate, giving rise to a new leg. Many animals, especially among the invertebrates (sea stars, for example), can regenerate lost parts.

95 11.13 SCIENTIFIC THINKING: Biologists can clone animals via nuclear transplantation Animal cloning can be achieved using nuclear transplantation. In this process, the nucleus of an egg cell or zygote is replaced with a nucleus from an adult somatic cell. About 5 days after transplantation, repeated cell divisions form a blastocyst, a hollow ball of about 100 cells. If the animal being cloned is a mammal, the blastocyst is then implanted into the uterus of a surrogate mother. This type of cloning is called reproductive cloning because it results in the birth of a new living individual.

96 Figure The nucleus is removed from an egg cell.

97 Figure Donor cell 1 2 The nucleus is removed from an egg cell. A somatic cell from an adult donor is added.

98 Figure Donor cell Nucleus from the donor cell Blastocyst The nucleus is removed from an egg cell. A somatic cell from an adult donor is added. The cell grows in culture to produce a blastocyst (early embryo).

99 Figure Donor cell Nucleus from the donor cell Blastocyst The nucleus is removed from an egg cell. A somatic cell from an adult donor is added. The cell grows in culture to produce a blastocyst (early embryo). The blastocyst is implanted in a surrogate mother.

100 Figure Donor cell Nucleus from the donor cell Blastocyst The nucleus is removed from an egg cell. A somatic cell from an adult donor is added. The cell grows in culture to produce a blastocyst (early embryo). The blastocyst is implanted in a surrogate mother. A clone of the donor is born.

101 11.13 SCIENTIFIC THINKING: Biologists can clone animals via nuclear transplantation Nuclear transplantation was first performed in the 1950s using cells from frog embryos. It was first used in mammals in 1996 to produce the sheep Dolly. Dolly demonstrated that the differentiation of animal cells is achieved by changes in gene expression, rather than by permanent changes in the genes themselves. Researchers have since cloned many other mammals, including mice, cats, horses, cows, mules, pigs, rabbits, ferrets, and dogs.

102 11.13 SCIENTIFIC THINKING: Biologists can clone animals via nuclear transplantation Conservation biologists hope that reproductive cloning can be used to restock the populations of endangered animals. However, an increasing body of evidence suggests that cloned animals may be less healthy than those arising from a fertilized egg. Recent research suggests that the methylation of chromatin may be responsible for health problems in cloned animals. Researchers are investigating whether chromatin in a donor nucleus can be artificially rejuvenated to resemble that of a newly fertilized egg.

103 11.14 CONNECTION: Therapeutic cloning can produce stem cells with great medical potential A blastocyst can provide embryonic stem cells (ES cells), which can differentiate in an embryo to give rise to all the specialized cell types of the body or divide indefinitely when grown in laboratory culture. When the goal is to produce embryonic stem cells to use in therapeutic treatments, this process is called therapeutic cloning.

104 Figure Embryonic stem cells removed from blastocyst Adult stem cells in bone marrow Cultured embryonic stem cells Different culture conditions Blood cells Nerve cells Heart muscle cells Different types of differentiated cells

105 11.14 CONNECTION: Therapeutic cloning can produce stem cells with great medical potential The adult body also has stem cells, which serve to replace nonreproducing specialized cells as needed. Because adult stem cells are farther along the road to differentiation than ES cells, they can give rise to only a few related types of cells.

106 THE GENETIC BASIS OF CANCER

107 11.15 Cancer results from mutations in genes that control cell division Cancer is a set of diseases in which the control mechanisms that normally limit cellular growth have malfunctioned. Scientists have learned that such malfunction is often due to changes in gene expression.

108 11.15 Cancer results from mutations in genes that control cell division The genes that a cancer-causing virus inserts into a host cell can make the cell cancerous. Such a gene is called an oncogene (from the Greek onco, tumor). Over the last century, researchers have identified a number of viruses that harbor cancer-causing genes. One example is the human papillomavirus (HPV), which can be transmitted through sexual contact and is associated with several types of cancer, most frequently cervical cancer.

109 11.15 Cancer results from mutations in genes that control cell division Mutations in two types of genes can cause cancer. 1. Oncogenes Proto-oncogenes are normal genes that promote cell division. Mutations to proto-oncogenes create cancer-causing oncogenes that often stimulate cell division. 2. Tumor-suppressor genes Tumor-suppressor genes normally inhibit cell division or function in the repair of DNA damage. Mutations inactivate the genes and allow uncontrolled division to occur.

110 Figure 11.15a Proto-oncogene (for a protein that stimulates cell division) DNA A mutation within the gene Multiple copies of the gene The gene is moved to a new DNA locus, under new controls Oncogene New promoter Hyperactive growthstimulating protein in a normal amount Normal growthstimulating protein in excess Normal growthstimulating protein in excess

111 Figure 11.15b Tumor-suppressor gene Mutated tumorsuppressor gene Normal growthinhibiting protein Cell division under control Defective, nonfunctioning protein Cell division not under control

112 11.16 Multiple genetic changes underlie the development of cancer More than 100,000 Americans will be stricken by cancer of the colon this year. Colon cancer is one of the best-understood types of human cancer and illustrates an important principle about how cancer develops.

113 11.16 Multiple genetic changes underlie the development of cancer Colon cancer illustrates the gradual progression from somatic mutation to cancer. 1. An oncogene arises or is activated, resulting in increased cell division in apparently normal cells in the colon lining. 2. Additional DNA mutations cause the growth of a small benign tumor (polyp) in the colon wall. 3. Additional mutations lead to a malignant tumor with the potential to metastasize.

114 Figure 11.16a-1 DNA changes: An oncogene is activated Cellular changes: Increased cell division 1 Colon wall

115 Figure 11.16a-2 DNA changes: An oncogene is activated A tumor-suppressor gene is inactivated Cellular changes: Increased cell division 1 Growth of a polyp (benign tumor) 2 Colon wall

116 Figure 11.16a-3 DNA changes: An oncogene is activated A tumor-suppressor gene is inactivated A second tumorsuppressor gene is inactivated Cellular changes: Increased cell division Growth of a polyp (benign tumor) Growth of a malignant tumor Colon wall

117 Figure 11.16b Chromosomes 1 mutation 2 mutations 3 mutations 4 mutations Normal cell Malignant cell

118 11.17 Faulty proteins can interfere with normal signal transduction pathways Proto-oncogenes and tumor-suppressor genes often code for proteins involved in signal transduction pathways leading to gene expression. Two main types of signal transduction pathways lead to the synthesis of proteins that influence cell division. 1. One pathway produces a product that stimulates cell division. 2. A second pathway produces a product that inhibits cell division.

119 Figure 11.17a-0 Normal Growth factor Target cell Mutant No growth factor Normal product of ras gene CYTOPLASM Relay proteins Transcription factor (activated) Normal product of ras gene Hyperactive relay protein (product of ras oncogene) even in absence of growth factor DNA DNA Transcription NUCLEUS Protein that stimulates cell division Normal cell division Translation NUCLEUS Transcription Overexpression of stimulating protein Increased cell division

120 Figure 11.17a-1 Normal Growth factor Target cell Normal product of ras gene Relay proteins CYTOPLASM Transcription factor (activated) DNA Transcription NUCLEUS Protein that stimulates cell division Translation Normal cell division

121 Figure 11.17a-2 Mutant No growth factor Normal product of ras gene Relay proteins Transcription factor (activated) Hyperactive relay protein (product of ras oncogene) even in absence of growth factor DNA Transcription NUCLEUS Overexpression of stimulating protein Increased cell division

122 Figure 11.17b-0 Normal Mutant Growthinhibiting factor Receptor Normal product of p53 gene Protein that inhibits cell division No cell division Relay proteins Transcription factor (activated) Transcription Translation Transcription and translation do not occur Nonfunctional transcription factor (product of faulty p53 tumorsuppressor gene) cannot trigger transcription Protein absent (cell division not inhibited) Increased cell division

123 Figure 11.17b-1 Normal Growthinhibiting factor Receptor Relay proteins Normal product of p53 gene Transcription factor (activated) Transcription Protein that inhibits cell division Translation No cell division

124 Figure 11.17b-2 Mutant Relay proteins Nonfunctional transcription factor (product of faulty p53 tumorsuppressor gene) cannot trigger transcription Transcription and translation do not occur Protein absent (cell division not inhibited) Increased cell division

125 11.18 CONNECTION: Lifestyle choices can reduce the risk of cancer After heart disease, cancer is the second-leading cause of death in most industrialized nations. Cancer can run in families if an individual inherits an oncogene or a mutant allele of a tumorsuppressor gene that makes cancer one step closer. But most cancers cannot be associated with an inherited mutation.

126 11.18 CONNECTION: Lifestyle choices can reduce the risk of cancer Carcinogens are cancer-causing agents that alter DNA. Most mutagens (substances that promote mutations) are carcinogens. Two of the most potent carcinogens (mutagens) are X-rays and ultraviolet radiation in sunlight.

127 11.18 CONNECTION: Lifestyle choices can reduce the risk of cancer The one substance known to cause more cases and types of cancer than any other single agent is tobacco. More people die of lung cancer than any other form of cancer. Although most tobacco-related cancers come from smoking, passive inhalation of second-hand smoke is also a risk. Tobacco use, sometimes in combination with alcohol consumption, causes cancers in addition to lung cancer.

128 Table

129 Table

130 Table

131 11.18 CONNECTION: Lifestyle choices can reduce the risk of cancer Healthy lifestyles that reduce the risks of cancer include avoiding carcinogens, including the sun and tobacco products, exercising adequately, regular medical checks for common types of cancer, and a healthy high-fiber, low-fat diet including plenty of fruits and vegetables.

132 You should now be able to 1. Describe and compare the regulatory mechanisms of the lac operon, trp operon, and operons using activators. 2. Explain how selective gene expression yields a variety of cell types in multicellular eukaryotes. 3. Explain how DNA is packaged into chromosomes. 4. Explain how a cat s tortoiseshell coat pattern is formed and why this pattern is only seen in female cats.

133 You should now be able to 5. Explain how eukaryotic gene expression is controlled. 6. Describe the process and significance of alternative DNA splicing. 7. Describe the significance of mirna molecules. 8. Explain how mrna breakdown, initiation of translation, protein activation, and protein breakdown regulate gene expression.

134 You should now be able to 9. Describe the roles of homeotic genes in development. 10. Explain how DNA microarrays can be used to study gene activity and treat disease. 11. Explain how a signal transduction pathway triggers a specific response inside a target cell. 12. Compare the cell-signaling systems of yeast and animal cells.

135 You should now be able to 13. Explain how nuclear transplantation can be used to clone animals. 14. Describe some of the practical applications of reproductive cloning and the process and goals of therapeutic cloning. 15. Explain how viruses, proto-oncogenes, and tumor-suppressor genes can each contribute to cancer. 16. Explain why the development of most cancers is a slow and gradual process.

136 You should now be able to 17. Explain how mutations in ras or p53 proteins can lead to cancer. 18. Describe factors that can increase or decrease the risks of developing cancer.

137 Figure 11.UN01 DNA A typical operon Regulatory gene Promoter Operator Gene 1 Gene 2 Gene 3 Encodes a repressor that in active form attaches to an operator RNA polymerase binding site Switches the operon on or off Code for proteins

138 Figure 11.UN02 Egg cell or zygote with nucleus removed Nucleus from a donor cell An early embryo resulting from nuclear transplantation Surrogate mother Clone of the donor

139 Figure 11.UN03 Egg cell or zygote with nucleus removed Nucleus from a donor cell An early embryo resulting from nuclear transplantation Embryonic stem cells in culture Specialized cells

140 Figure 11.UN04 controlled by a protein called (b) in active form binds to prokaryotic genes are often grouped into operons are switched on/off by Gene regulation in eukaryotes may involve (a) is a normal gene that can be mutated to an when abnormal oncogene may lead to can cause (c) (d) (e) (f) (g) occurs in female mammals are proteins that promote transcription can produce multiple kinds of mrna per gene