Genetics: From genes to genomes - Chapter 17: How genes are regulated

PowerPoint to accompanyGenetics: From Genes to GenomesFourth EditionLeland H. Hartwell, Leroy Hood, Michael L. Goldberg, Ann E. Reynolds, and Lee M. SilverPrepared by Mary A. BedellUniversity of Georgia*Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th editionHow Genes Are Regulated*PART VCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 17Somatic Mutation and the Genetics of Cancer17.1 Overview: Initiation of Division17.2 Cancer: A Failure of Control over Cell Division17.3 The Normal Control of Cell DivisionCHAPTER OUTLINECHAPTERThe relative percentages of new cancers in the United States that occur at different sitesCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 17*Fig. 17.1Two unifying themes about cancer geneticsCancer is a disease of genesMultiple cancer phenotypes arise from mutations in genes that regulate cell growth and divisionEnvironmental chemicals increase mutation rates and increase chances of cancerCancer has a different inheritance pattern than other genetic disordersInherited mutations can predispose to cancer, but the mutations causing cancer occur in somatic cellsMutations accumulate in clonal descendants of a single cellCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 17*Overview of the initiation of cell divisionTwo basic types of signals that tell cells whether to divide, metabolize, or dieExtracellular signals – act over long or short distances Collectively known as hormonesSteroids, peptides, or proteinsCell-bound signals – require direct contact between cells Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 17*An example of an extracellular signal that acts over large distancesThyroid-stimulating hormone (TSH) produced in pituitary glandMoves through blood to thyroid gland, which expresses thyroxineCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 17*Fig. 17.2aAn example of an extracellular signal that is mediated by cell-to-cell contactCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 17*Fig. 17.2bEach signaling system has four componentsGrowth factors Extracellular hormones or cell-bound signals that stimulate or inhibit cell proliferationReceptorsComprised of a signal-binding site outside the cell, a transmembrane segment, and an intracellular domainSignal transducersLocated in cytoplasmTranscription factorsActivate expression of specific genes to either promote or inhibit cell proliferationCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 17*Hormones transmit signals into cells through receptors that span the cellular membraneCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 17*Fig. 17.3aSignaling systems can stimulate or inhibit growthSignal transduction - activation or inhibition of intracellular targets after binding of growth factor to its receptorCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 17*Fig. 17.3b&cRAS is an intracellular signaling moleculeCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 17*Fig. 17.3dCancer phenotypes result from the accumulation of mutationsMutations are in genes controlling proliferation as well as other processesResult in a clone of cells that overgrows normal cellsCancer phenotypes include:Uncontrolled cell growthGenomic and karyotypic instabilityPotential for immortalityAbility to invade and disrupt local and distant tissuesCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 17* Phenotypic changes that produce uncontrolled cell growthCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 17*Autocrine stimulation:Cancer cells can make their own stimulatory signalsLoss of contact inhibition:Growth of cancer cells doesn't stop when the cells contact each othera.1a.2Most normal cellsMany cancer cellsMost normal cellsMany cancer cellsFig. 17.4 Phenotypic changes that produce uncontrolled cell growth (cont)Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 17*Loss of cell death: Cancer cells are more resistant to programmed cell death (apoptosis)Loss of gap junctions:Cancer cells lose channels for communicating with adjacent cellsa.3a.4Most normal cellsMany cancer cellsMost normal cellsMany cancer cellsFig. 17.4Phenotypic changes that produce genomic and karyotypic instabilityDefects in DNA replication machinery:Cancer cells have lost the ability to replicate their DNA accuratelyIncreased mutation rates can occur because of defects in DNA replication machineryCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 17*Fig. 17.4b.1 Phenotypic changes that produce genomic and karyotypic instability (cont)Increased rate of chromosomal aberrations:Cancer cells often have chromosome rearrangements (translocations, deletions, aneuploidy, etc)Some rearrangements appear regularly in specific tumor types Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 17*Fig. 17.4b.2Fig. 17.4b.2Phenotypic changes that produce a potential for immortality Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 17*Loss of limitations on the number of cell divisions:Tumor cells can divide indefinitely in culture (below) and express telomerase (not shown)c.1c.2Most normal cellsMany cancer cellsFig. 17.4ImmortalityGrowth in soft agar Phenotypic changes that enable a tumor to disrupt local tissue and invade distant tissuesCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 17*Fig. 17.4Ability to metastasize:Tumor cells can invade the surrounding tissue and travel through the bloodstreamAngiogenesis:Tumor cells can secrete substances that promote growth of blood vesselsd.1d.2Evidence from mouse models that cancer is caused by several mutationsTransgenic mice with dominant mutations in the myc gene and in the ras gene Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 17*Fig. 17.5a(b)(a)Mice with recessive mutations in the p53 geneFig. 17.5Evidence that cancer cells are clonal descendants of a single somatic cellAnalysis of polymorphic enzymes encoded by the X chromosome in femalesSample from normal tissues has mixture of both allelesClones of normal cells has only one alleleSample from tumor has only one allele Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 17*Fig. 17.6The incidence of some common cancers varies between countriesCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 17*Table 17.1The role of environmental mutagens in cancerConcordance for the same type of cancer in first degree relatives (i.e. siblings) is low for most forms of cancerThe incidence of some cancers varies between countries (see Table 17.2)When a population migrates to a new location, the cancer profile becomes like that of the indigenous populationNumerous environmental agents are mutagens and increase the likelihood of cancerSome viruses, cigarette smokeCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 17*Cancer development over timeLung cancer death rates and incidence of cancer with ageCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 17*Fig. 17.7Some families have a genetic predisposition to certain types of cancerExample: retinoblastoma caused by mutations in RB geneIndividuals who inherit one copy of the RB− allele are prone to cancer of the retinaDuring proliferation of retinal cells, the RB+ allele is lost or mutatedTumors develop as a clone of RB−/RB− cellsCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 17*Fig. 17.8Cancer is thought to arise by successive mutations in a clone of proliferating cellsCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 17*Fig. 17.9Cancer-producing mutations are of two general typesCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 17*Fig. 17.10Oncogenes act dominantly and cause increased proliferationOncogenes are produced when mutations cause improper activation a geneTwo approaches to identifying oncogenes:Tumor-causing viruses (Fig 17.11a)Many tumor viruses in animals are retrovirusesSome DNA viruses carry oncogenes [e.g. Human papillomavirus (HPV)]Tumor DNA (Fig. 17.11b)Transform normal mouse cells in culture with human tumor DNACopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 17*Cancer-causing retroviruses carry a mutant or overexpressed copy of a cellular geneAfter infection, retroviral genome integrates into host genomeIf the retrovirus integrates near a proto-oncogene, the proto-oncogene can be packaged with the viral genomeCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 17*Fig. 17.11aRetroviruses and their associated oncogenesCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 17*Table 17.2DNA from human tumor cells is able to transform normal mouse cells into tumor cellsHuman gene that is oncogenic can be identified and cloned from transformed mouse cellsCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 17*Fig. 17.11bThe RAS oncogene is the mutant form of the RAS proto-oncogeneNormal RAS is inactive until it becomes activated by binding of growth factors to their receptorsOncogenic forms of RAS are constitutively activatedCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 17*Fig. 17.11cOncogenes are members of signal transduction systemsCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 17*Table 17.3Cancer can be caused by mutations that improperly inactivate tumor suppressor genesFunction of normal allele of tumor suppressor genes is to control cell proliferationMutant tumor suppressor alleles act recessively and cause increased cell proliferationTumor suppressor genes identified through genetic analysis of families with inherited predisposition to cancerInheritance of a mutant tumor suppressor alleleOne normal allele sufficient for normal cell proliferation in heterozygotesWild-type allele in somatic cells of heterozygote can be lost or mutated  abnormal cell proliferationCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 17*The retinoblastoma tumor-suppressor geneCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 17*Fig. 17.12Mutant alleles of these tumor-suppressor genes decrease the accuracy of cell reproductionCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 17*Table 17.4The normal control of cell divisionFour phases of the cell cycle:G1, S, G2, and MCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 17*Fig. 17.13Experiments with yeast helped identify genes that control cell divisionTwo kinds of used: Saccharomyces cerevisiae (budding yeast) and Schizosaccharomyces pombe (fission yeast)Usefulness of yeast for studies of the cell cycleBoth grow as haploids or diploidsCan identify recessive mutations in haploidsCan do complementation analysis in diploidsS. cerevisiae – size of buds serves as a marker of progress through the cell cycleDaughter cells arise as small buds on mother cell at end of G1 and grow during mitosisStage of cell cycle can be determined by relative appearance of buds (see Fig 17.14)Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 17*The isolation of temperature-sensitive mutants of yeastMutants grow normally at permissive temperature (22°)At restrictive temperature (36°), mutants lose gene functionAfter replica plating, colonies that grow at 22° but not at 36° have temperature-sensitive mutationCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 17*Fig. 17.15A temperature-sensitive cell-cycle mutant in S. cerevesiaeCells grown at permissive temperature display buds of all sizes (asynchronous division)Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 17*Fig. 17.14bFig. 17.14aGrowth of the same cells at restrictive temperature – all have large budsSome important cell-cycle and DNA repair genesCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 17*Table 17.5CDKs interact with cyclins and control the cell cycle by phosphorylating other proteinsCyclin-dependent kinases (CDKs) – family of kinases that regulate the transition from G1 to S and from G2 to MCyclin specifies the protein targets for CDKPhosphorylation by CDKs can activate or inactive a proteinCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 17*Fig. 17.16aCDKs control the dissolution of the nuclear membrane at mitosisLamins – provide structural support to the nucleusForm an insoluble matrix during most of the cell cycleAt mitosis, lamins are phosphorylated by CDKs and become solubleCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 17*Fig. 17.16Mutant yeast permit the cloning of a human CDK geneHuman CDKs and cyclins can function in yeast and replace the corresponding yeast proteins Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 17*Fig. 17.17CDKs mediate the transition from the G1 to the S phase of the cell cycleCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 17*Fig. 17.18CDK activity in yeast is controlled by phosphorylation and dephosphorylationCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 17*Fig. 17.19Cell-cycle checkpoints ensure genomic stabilityCheckpoints monitor the genome and cell-cycle machinery before allowing progression to the next stage of cell cycleG1-to-S checkpointDNA synthesis can be delayed to allow time for repair of DNA that was damaged during G1 The G2-to-M checkpointMitosis can be delayed to allow time for repair of DNA that was damaged during G2Spindle checkpointMonitors formation of mitotic spindle and engagement of all pairs of sister chromatidsCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 17*The G1-to-S checkpoint is activated by DNA damageCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 17*Fig. 17.20aDisruption of the G1-to-S checkpoint in p53-deficient cells can lead to amplified DNA Tumor cells often have homogenously staining regions (HSRs) or small, extrachromosomal pieces of DNA (double minutes)Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 17*Fig. 17.20bDisruption of the G1-to-S checkpoint in p53-deficient cells can lead to many types of chromosome rearrangementsCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 17*Fig. 17.20cCheckpoints acting at the G2-to-M cell-cycle transition or during M phaseCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 17*Fig. 17.21The necessity of checkpointsCheckpoints are not essential for cell divisionCells with defective checkpoints are viable and divide at normal ratesBut, they are much more vulnerable to DNA damage than normal cellsCheckpoints help prevent transmission of three kinds of genomic instability (Fig 17.22)Chromosome aberrationsChanges in ploidyAneuploidyCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 17*Three classes of error lead to aneuploidy in tumor cellsCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 17*Fig. 17.22aChromosome painting can be used to detect chromosome rearrangementsChromosomes from normal cellsCopyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 17*Fig. 17.22Chromosomes from tumor cells