Lecture9BIO155BB - BIO155 How Genes are Controlled Jessica...

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Unformatted text preview: BIO155 How Genes are Controlled Jessica Pamment Overview • • • • • Cellular differentiation is possible due to regulation of gene expression Bacteria as a model organism Eukaryotic gene expression can be regulated at several stages Reproductive and therapeutic cloning Cancer arises when the gene regulatory system goes wrong Why are genes regulated? Why are genes regulated? • Each cell type has structure suited to its function • Every cell carries the same genes • Different genes are expressed in different cell types • This regulation of gene expression results in cellular differentiation Differentiated Cells Differentiated Cells • A gene that is ‘on’ is being transcribed to mRNA • A gene that is ‘off’ is not accessible to transcribing enzyme • The process by which genetic information flows from gene to proteins is called gene expression Patterns of Gene Expression Expression Regulation of Eukaryotic Gene Expression Regulation of Eukaryotic Gene Expression • Typical human cell expresses 20% of its genes at any one time • Differential gene expression allows cell specificity • In humans only 1.5% of genome encodes for proteins • When gene expression goes wrong serious diseases can arise Control Points in Gene Expression Control Points in Gene Expression • Chromatin structure • Transcription • Transport to cytoplasm • Translation • Protein processing • Protein targeting Potential Points of Gene Regulation Regulation Signal NUCLEUS Chromatin Chromatin modification Gene available for transcription Gene Transcription RNA Exon Primary transcript Intron RNA processing Tail Cap mRNA in nucleus Transport to cytoplasm CYTOPLASM Potential Points of Gene Regulation CYTOPLASM mRNA in cytoplasm Translation Degradation of mRNA Polypeptide Protein processing Degradation of protein Active protein Transport to cellular destination Cellular function Regulation of DNA Packaging Regulation of DNA Packaging • State of chromatin will affect whether genes are accessible to transcription factors (TFs) • Genes within tightly packed chromatin usually not expressed • Genes within loosely packed chromatin usually active • Chromatin state regulated by histone modifications • Long term inactivation can be achieved by tight packaging of DNA, e.g. tortoiseshell pattern on cat X Chromosome inactivation: the tortoiseshell pattern on a cat pattern Another example of chromosome inactivation, Calico cat Another Initiation of Transcription Initiation of Transcription • Most important stage for regulation in both prokaryotes and eukaryotes • Eukaryotic genes mainly have individual promoters (START) and control sequences transcription factors; Can’t start until initiation complex complete eukaryotes is ‘off’ • Complex process in eukaryotes involving many • Default state for most genes in multicellular Regulation of Translation Regulation of Translation • Occurs mainly at point of initiation • Many factors needed, such as regulatory proteins • Example: protein in red blood cells prevents translation of hemoglobin unless heme is present Protein Processing and Breakdown Protein Processing and Breakdown • Most polypeptides have to be processed before they become functional • Selective degradation of proteins allows cell to respond to changes in the environment The Formation of an Active Insulin Molecule The Cell Signaling Cell Signaling • Key mechanism in development of multicellular organism other • Allows neighboring cells to ‘talk’ to each • Proteins or hormones carry messages from signaling cells to receiving cells A cell-signaling pathway that turns on a gene turns A cell-signaling pathway that turns on a gene A cell-signaling pathway that turns on a gene A cell-signaling pathway that turns on a gene Review Control of Gene Expression Review Control of Gene Expression • Different cell types exist because different combinations of genes are expressed in different cells • Gene regulation is responsible for genes being on or off • Simple model of gene regulation in bacteria • More complex in eukaryotes: more points of control • Most important control point in both prokaryotes and eukaryotes is gene transcription Organismal Cloning Organismal Cloning • Distinct from gene and cell cloning • Method for cloning whole organisms from a single cell • The interest in this technique is the potential to generate stem cells • Stem cells can generate many different tissues Test-tube Cloning of a Carrot Plant Test-tube EXPERIMENT Frog embryo UV Frog egg cell Frog tadpole Less differentiated cell Enucleated egg cell Egg with donor nucleus activated to begin development Fully differentiated (intestinal) cell RESULTS Most develop into tadpoles Most stop developing before tadpole stage Animal Cloning Animal Cloning • Trickier than plant cloning as differentiated cells do not divide in culture • First experiments involved nuclear transplantation: replacing nucleus of an egg with differentiated nucleus direct normal development related to age and differentiation of donor cell • The ability of transplanted nucleus to Cloning a mammal using a nucleus from differentiated cell differentiated TECHNIQUE Mammary cell donor 1 Egg cell donor 2 3 Cells fused Cultured mammary cells 3 Nucleus removed 4 Grown in Nucleus from mammary cell Early embryo culture 5 Implanted in uterus of a third sheep Surrogate mother Lamb (“Dolly”) genetically identical to mammary cell donor 6 Embryonic development RESULTS 2 Main types of Cloning 2 Main types of Cloning • Reproductive cloning­ aim is to make new individuals • Therapeutic cloning­ aim is to harvest embryonic stem cells for medical treatments Cloning by Nuclear Transplantation Cloning Reproductive Cloning of Mammals Reproductive Stem Cell Stem Cell • Relatively unspecialized cell • Can reproduce itself indefinitely • Can differentiate into specialized cells • Isolated from embryos at blastula stage • Embryonic vs. adult stem cells Embryonic Stem Cells Embryonic Stem Cells Derived from blastocyst, before implantation into uterus • ES can divide indefinitely in lab • Can induce the cell to divide into any cell type with right conditions • Controversial Adult Stem Cells Adult Stem Cells • These are cells in adult tissues that generate • They are already partly differentiated • Usually give rise to only a few cell types • Harder to grow in culture • Not controversial replacements for nondividing differentiated cells Umbilical Cord Blood Stem Cells Umbilical Cord Blood Stem Cells • Stem cells are collected from the blood in placenta and umbilical cord at birth • These stem cells are less differentiated than AS but more than ES cells • Some success stories • Most cord blood therapies unsuccessful so far Umbilical Blood Cord Banking Umbilical Embryonic stem cells Adult stem cells From bone marrow in this example Stem Cells Cells Early human embryo at blastocyst stage (mammalian equivalent of blastula) Cells generating all embryonic cell types Cultured stem cells Cells generating some cell types Different culture conditions Different types of differentiated cells Liver cells Nerve cells Blood cells Embryonic vs. Adult Stem Cells Embryonic vs. Adult Stem Cells • ES cells are pluripotent • AS cells differentiate into limited cell types • Harvesting of ES controversial, currently derived from donated embryos use as source of ES avoid rejection • Aim is to clone embryos to blastocyst stage to • Will allow designer clones using DNA of patient, Induced Pluripotent Cells (iPS) Induced Pluripotent Cells (iPS) • 2007 first iPS made • iPS is a stem cell that has been derived from a fully differentiated adult cell • iPS can do everything ES can do • Current research working on directing iPS to differentiate to specific cell types eggs or embryos • iPS may in the future avoid use of any human Summary for Cloning Summary for Cloning • The genetic potential of cells • Reproductive cloning of animals to make identical copies of animals stem cells • Therapeutic cloning for the purpose of making • Controversy over stem cells: embryonic, adult and umbilical cord stem cells Cancer Cancer • i. ii. iii. A group of diseases in which the cells display: Uncontrolled growth Invasion Sometimes metastasis This differentiates them from benign tumors The Molecular Basis of Cancer The Molecular Basis of Cancer • Oncogenes and Proto­oncogenes: Proto­oncogenes encode for proteins that promote cell growth and division. Oncogenes arises from proto­oncogenes due to abnormal expression of proto­oncogene • Tumor Suppressors Encode for proteins that inhibit cell division Ways to turn a proto-oncogene into an oncogene Ways Tumor-Suppressor Genes Tumor-Suppressor Defective Cell­Signaling Defective Cell­Signaling Pathways can result in cancer • Proto­oncogene products involved in cell cycle­stimulating pathway • Tumor suppressor products involved in cell cycle­inhibiting pathway EFFECTS OF MUTATIONS Protein overexpressed Protein absent Cell cycle overstimulated Increased cell division Cell cycle not inhibited Multistep model of Cancer Development Multistep model of Cancer Development • Cancer results from the accumulation of mutations • Colorectal cancer as a model of multistep path to cancer • About 6 DNA changes must occur before cell becomes cancerous Inherited Predisposition Inherited Predisposition • Inheritance of oncogene or TS gene increases the chances an individual will develop cancer alleles • 15% colorectal cancers involve inherited cancer • 5­10% breast cancers involve inheritance of cancer alleles • 50% of inherited breast cancers have mutations in BRCA1 or BRCA2 Cancer Risk and Prevention Cancer Risk and Prevention • Overall cancer death rate is on the rise, increasing at 1% per decade • Preventative measures include: • Avoiding carcinogens, cancer­causing agents • Smart food choices Figure 11.00d Figure Summary Summary • Cancer results from genetic changes that affect cell cycle control • Types of genes associated with cancer include proto­oncogenes and tumor suppressors • Many cancer genes code for components of signaling pathways that either stimulate or inhibit cell growth • Multistep model for cancer development • Inherited predisposition to cancer Biology and Society Biology and Society • There are genetic tests available for several types of inherited cancer • They indicate only an increased risk • For many there are no life style changes that can decrease the risk of getting cancer • Is the test useless? • Would you want to get screened? • Testing positive for a predisposition to cancer could be used by health insurance companies to deny insurance to people who are more likely to develop cancer Biology and Society Biology and Society • The goal of gene therapy is to correct flawed genes so that they no longer express defective proteins, which cause the symptoms of genetic disease. • This has been attempted on a limited basis for a few genetic diseases but the ultimate goal is to correct the genes in the embryo. • Another option for attempting to deal with • • genetic diseases is to use genetic drugs to block faulty genes so that they can no longer express defective proteins. In limited cases this has the potential to at least alleviate the symptoms of a genetic disease. Do you agree with research that promotes gene therapy in embryos? What about research into genetic drugs? “I think I’m a Clone Now” • • • Very cool song by Weird Al Yankovic :) http://videos.howstuffworks.com/science­ channel/29246­kapow­superhero­science­ limb­regeneration­video.htm http://www.youtube.com/watch?v=yRHuiJeKg6 ...
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This note was uploaded on 04/25/2011 for the course BIO 155 taught by Professor Skoubis during the Fall '10 term at DePaul.

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