Chapter 12 gene regulation and cancer

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Chapter 12 gene regulation and cancer

  1. 1. Introduction to Biology Chapter 12Professor Zaki Sherif, MD., PhD Strayer University
  2. 2. Essentials of Biology Sylvia S. Mader Chapter 12 Lecture OutlineCopyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
  3. 3. 12.1 Control of Gene Expression• Every cell in your body receives a copy of all genes.• Every cell in your body has the potential to become a complete organism.• Cloning uses this potential. 1. Reproductive cloning 2. Therapeutic cloning
  4. 4. • Reproductive cloning • Desired end is an individual exactly like the original. • Plant cloning routine • Cloning of adult animals thought impossible
  5. 5. Figure 12.1 Cloning carrots Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 3 Many like carrot plantlets are cloned from each tissue mass.1 Tiny disks are obtained 2 Each disk produces an from carrot root. undifferentiated tissue mass. (1): © Runk/Schoenberger/Grant Heilman Photography; (2): © Grant Heilman Photography; (3): © E. Webber/Visuals Unlimited
  6. 6. • March 1997 – Dolly, cloned Dorset sheep  Adult nucleus placed in enucleated cell  Donor cells starved causing them to go into G0.  G0 nuclei can be signaled to initiate development.
  7. 7. Figure 12.2 Two types of cloning Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Egg nucleus is removed and discarded. Implant embryo fuse egg culture into nucleus with G0 egg surrogate removed nucleusG0 cells from mother. embryo Clone is born.animal to becloneda. Reproductive cloning
  8. 8. Figure 12.3 Cloned farm animals Farm animals with Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. desirable traits commonly cloned Some endangered animals cloned In US, no federal funds can be used for experiments to clone humans. • Even cloning animals inefficient and may not © AP/Wide World Photos produce healthy animals.
  9. 9. • Therapeutic cloning  Desired end is mature cell types for: • Learning more about cell specialization. • Use in treating human illnesses.  Can be carried out in several ways • Embryonic stem cells  Common but ethical concerns • Adult stem cells  Limited in number of cells they can become  May be able to overcome limitation
  10. 10. Figure 12.2 continued Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. nervous fuse egg culture with G0 blood nucleus egg removed nucleusG0 somatic cells embryo muscleb. Therapeutic cloning Specialized tissue cells are produced.
  11. 11. Figure 12.4 Gene expression in• Levels of gene expression specialized cells control  Body contains many cells that Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Cell type Red blood Muscle Pancreatic differ in structure and function  Only certain genes are active in Gene type cells that perform specialized Housekeeping functions. Hemoglobin Insulin  Housekeeping genes govern Myosin functions common to all cells  Activity of selected genes accounts for specialization.
  12. 12. • Gene expression in prokaryotes  Escherichia coli lives in our intestine and can quickly adjust its enzymes according to what we eat.  If we drink milk, E. coli immediately begins to make 3 enzymes needed to metabolize lactose.  Operon – cluster of bacterial genes along with DNA control sequence • François Jacob and Jacques Monod Nobel Prize 1961 for lac operon
  13. 13. • Lactose is not available most of the time.  E.coli does not normally transcribe the genes of the lac operon.  When lactose is not present, repressor binds to operator and RNA polymerase cannot attach to the promoter.  Inhibits transcription
  14. 14. Figure 12.5 The lac operon Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. no lactose E. coli Operon regulatory gene promoter operator lactose metabolizing genes DNA mRNA RNA polymerase cannot bind to promoter. repressor a. Lactose is absent—operon is turned off. Enzymes needed to metabolize lactose are not produced.
  15. 15. • When lactose is present, it binds to the repressor.  Repressor is inactivated and cannot attach to operator.  RNA polymerase can bind and transcription occurs.• System can also work for genes normally turned on.  Binding of tryptophan (gene for synthesis normally on) causes operator to be turned off.
  16. 16. Figure 12.5 continued Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. lactose RNA polymerase bound to promoter E. coli DNA mRNA mRNA lactose repressor inactive repressor enzymes b. Lactose is present—operon is turned on. Enzymes needed to metabolize lactose are produced.
  17. 17. Please note that due to differingoperating systems, some animationswill not appear until the presentation isviewed in Presentation Mode (SlideShow view). You may see blank slidesin the “Normal” or “Slide Sorter” views.All animations will appear after viewingin Presentation Mode and playing eachanimation. Most animations will requirethe latest version of the Flash Player,which is available athttp://get.adobe.com/flashplayer.
  18. 18. Please note that due to differingoperating systems, some animationswill not appear until the presentation isviewed in Presentation Mode (SlideShow view). You may see blank slidesin the “Normal” or “Slide Sorter” views.All animations will appear after viewingin Presentation Mode and playing eachanimation. Most animations will requirethe latest version of the Flash Player,which is available athttp://get.adobe.com/flashplayer.
  19. 19. • Gene expression in eukaryotes  Each gene has its own promoter.  Employ a variety of mechanisms • Affect whether gene is expressed, speed of expression and length of expression  Some mechanisms occur in nucleus and others in cytoplasm. • Nucleus – chromatin condensation, mRNA transcription, and mRNA processing • Cytoplasm – delay of transcription, length mRNA or protein lasts
  20. 20. Figure 12.6 Control of gene expression in eukaryotic cells Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Cytoplasm signal Nucleus nucleosome chromatin packing Chromatin condensation DNA DNA transcription intron exon primary mRNA mRNA processing mature mRNA
  21. 21. Figure 12.6 continued Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. mature mRNA nuclear envelope nuclear pore mRNA translation polypeptide Protein activity functional protein degraded protein
  22. 22. • Chromatin condensation  Way to keep genes turned off  More tightly compacted = less gene expression  Heterochromatin – dark staining regions of tightly compacted, inactive chromatin  Barr body – second X chromosome in mammalian females • Which X is inactivated? –female tortoiseshell cat
  23. 23. Figure 12.7 X-inactivation in mammalian females Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.Females have two X chromosomes. One X chromosome is inactivated in Coats of calico cats each cell. Which one is by chance. have patches of orange and black. active X chromosome allele for orange color inactive X cell division Barr bodies inactive X allele for black color active X chromosome © Photodisc/Getty RF
  24. 24. • Euchromation  Unpacked heterochromatin  Contains active genes  Nucleosome – portion of DNA wrapped around histones  Transcription activator pushes aside histones so that transcription can begin.
  25. 25. Figure 12.8 DNA unpacking Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Nucleosomes block transcription of gene nucleosome inaccessible promoter chromatin remodeling complex
  26. 26. Figure 12.8 continued Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. accessible promoter Exposed DNA allows gene transcription
  27. 27. • DNA transcription  Same principles as prokaryotic transcription but with more regulatory proteins per gene  Allows for greater control but also a greater chance for malfunction
  28. 28.  Transcription factor – DNA-binding proteins that help RNA polymerase bind to a promoter • Several needed in each case, need all of them • Form complex that helps pull apart helix and help position RNA polymerase • Same ones used in different combinations  If 1 is defective can have serious effect - Huntington disease • Speed up transcription • Bind to enhancer region of DNA
  29. 29. Figure 12.9 Transcription factors and transcription activators Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Transcription RNA polymerase promoterTranscriptionfactors formcomplex. Hairpin loop results transcription Bending of DNA activator enhancer DNA
  30. 30. Please note that due to differingoperating systems, some animationswill not appear until the presentation isviewed in Presentation Mode (SlideShow view). You may see blank slidesin the “Normal” or “Slide Sorter” views.All animations will appear after viewingin Presentation Mode and playing eachanimation. Most animations will requirethe latest version of the Flash Player,which is available athttp://get.adobe.com/flashplayer.
  31. 31. • Possible for a single Figure 12.10 Ey gene Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. transcription factor to have dramatic effect on gene expression  MyoD alone can activate the genes necessary for fibroblasts to become muscle cells. Courtesy Prof. Walter Gehring  Ey can bring about the formation of a complete eye in flies.
  32. 32. • mRNA processing  After transcription, introns must be removed and exons spliced together.  Alternative mRNA processing allows cells to produce multiple proteins from the same gene by changing the way exons are joined.  Fruit fly DScam gene can produce over 38,000 different combinations.
  33. 33. Figure 12.11 Processing of mRNA transcripts Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. intron exon intron exon A B C D E A B C D E cap primary-mRNA poly-A cap primary-mRNApoly-A tail tail RNA splicing RNA splicing A B C DE A B DE mature mRNA mature mRNA protein product 1 protein product 2 a. b.
  34. 34. • mRNA translation  Cytoplasm contains proteins that determine whether translation takes place.  Environmental conditions can delay translation. • Red blood cells do not produce hemoglobin unless heme is available.  The longer mRNA remains in the cytoplasm before it is broken down, the more gene product is produced. • It can be affected by length of poly A tail or presence of hormones.
  35. 35. Figure 12.12 Protein• Protein activity activity  Some proteins are not Copyright © The McGraw-Hill Companies, Inc. active immediately after Permission required for reproduction or display. synthesis. S S S cut S • Insulin must be processed S SS S SS S S before it is an active form.  Allows protein’s activity inactive active polypeptide polypeptide to be delayed until needed
  36. 36. Please note that due to differingoperating systems, some animationswill not appear until the presentation isviewed in Presentation Mode (SlideShow view). You may see blank slidesin the “Normal” or “Slide Sorter” views.All animations will appear after viewingin Presentation Mode and playing eachanimation. Most animations will requirethe latest version of the Flash Player,which is available athttp://get.adobe.com/flashplayer.
  37. 37. • Signaling between cells in eukaryotes  In multicellular organisms, cells are constantly sending out chemical signals that influence the behavior of other cells. • During development determine what a cell becomes • Later help coordinate growth and daily functions  Cell-signaling pathway • Begins when chemical signal binds to receptor on target cell plasma membrane • Initiates signal transduction pathway • End product affects cell (not original signal itself).
  38. 38. Figure 12.13 Cell-signaling pathway Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. plasma membraneSignaling cell chemical signaltissue fluid Translation mRNA cytoplasm transcription factor complex Transcription nuclear envelope DNA Target cell
  39. 39. Figure 12.13 Cell-signaling pathway Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. plasma membraneSignaling cell chemical signal 1 Reception receptortissue fluid Translation mRNA cytoplasm transcription factor complex Transcription nuclear envelope DNA Target cell
  40. 40. Figure 12.13 Cell-signaling pathway Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. plasma membraneSignaling cell chemical signal 1 Reception receptor 2 Transductiontissue fluid signal transduction pathway Translation mRNA cytoplasm transcription factor complex Transcription nuclear envelope DNA Target cell
  41. 41. Figure 12.13 Cell-signaling pathway Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. plasma membraneSignaling cell chemical signal 1 Reception receptor 2 Transduction proteintissue fluid 3 Response signal transduction pathway transcription Translation activator mRNA cytoplasm transcription factor complex Transcription nuclear envelope DNA Target cell
  42. 42. Please note that due to differingoperating systems, some animationswill not appear until the presentation isviewed in Presentation Mode (SlideShow view). You may see blank slidesin the “Normal” or “Slide Sorter” views.All animations will appear after viewingin Presentation Mode and playing eachanimation. Most animations will requirethe latest version of the Flash Player,which is available athttp://get.adobe.com/flashplayer.
  43. 43. 12.2 Cancer: A Failure of Genetic Control• Cancer is a genetic disease.• Requires several mutations to propel cells toward development of a tumor• Several mutations needed to disrupt redundant regulatory pathways that prevent normal cells from becoming cancerous• Takes years for cancer to develop• Likelihood of cancer increases with age.
  44. 44. • Cells that are highly specialized seldom become cancer cells.  In G0 stage• More likely in cells entering new cell cycle• Tumors can grow and spread when accumulating mutations cause cells to gradually lose control.• As additional mutations occur  Angiogenesis – cells produce growth factor to cause blood vessels to branch into cancerous tissue.  Metastasis – produces enzymes to invade neighboring tissue and become motile allowing cancer to spread.
  45. 45. Figure 12.14 Development of cancer Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. epithelial cells 1 mutation a. Cell (red) acquires a mutation for repeated cell division. 2 mutations b. New mutations arise, and one cell (teal) has the ability to start a tumor. tumor 3 mutations c. Cancer in situ. blood The tumor is at vessel its place of origin. lymphatic One cell (purple) vessel mutates further.
  46. 46. Figure 12.14 continued Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. invasive tumord. Cells have gained the ability to invade underlying tissues by producing a proteinase enzyme. malignant tumor distant tumor f. New metastatic tumorse. Cancer cells now are found some distance have the ability to from the original tumor. invade lymphatic lymphatic and blood vessels. vessel
  47. 47. • Proto-oncogenes and tumor suppressor genes  When cancer develops, the cell cycle occurs repeatedly.  Largely due to mutations in 2 types of genes 1. Proto-oncogenes • Code for proteins that promote cell cycle and inhibit apoptosis • Like a gas pedal 2. Tumor suppressor genes • Code for proteins that inhibit cell cycle and promote apoptosis • Like brakes • Normally inhibit cell cycle and prevent cells from dividing inappropriately
  48. 48. • Proto-oncogenes become cancer-causing oncogenes.  Proto-oncogene responds to signal that dampens its activity.  Oncogenes are constantly active because they don’t respond to these signals.  Growth factor is a signal that activates a cell-signaling pathway resulting in cell division.  Ras proto-oncogenes promote mitosis when a growth-factor binds to a receptor.  Ras oncogenes promote mitosis even when growth factors are not present. • Found in 20-30% of human cancers
  49. 49. Figure 12.15 Regulation of the cell cycle through control of gene expression Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. growth factor receptor P P activated P signaling protein signaling protein phosphate a.
  50. 50. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Growth factor Figure 12.15 continued binds to receptor and activates proto-oncogenes through cell-signaling pathway. Activation of proto-oncogene Promotion of cell cycle Expression of Inhibition tumor suppressor of cell cycleProto-oncogenecodes for a protein thatpromotes the cell cycle.If a proto-oncogenemutates, the resultingoncogenes may lead touncontrolled cell division. b. Tumor suppressor gene codes for a protein that inhibits the cell cycle. Mutant tumor suppressor genes can lose this function.
  51. 51. Please note that due to differingoperating systems, some animationswill not appear until the presentation isviewed in Presentation Mode (SlideShow view). You may see blank slidesin the “Normal” or “Slide Sorter” views.All animations will appear after viewingin Presentation Mode and playing eachanimation. Most animations will requirethe latest version of the Flash Player,which is available athttp://get.adobe.com/flashplayer.
  52. 52. • Tumor suppressor genes become inactive  Products no longer inhibit cell cycle nor promote apoptosis.  Retinoblastoma protein (RB) controls activity of E2F transcription factor. • In absence of growth factors, RB binds to E2F and inhibits entry into S stage. • Mutations in RB promote cell cycle inappropriately.
  53. 53. Please note that due to differingoperating systems, some animationswill not appear until the presentation isviewed in Presentation Mode (SlideShow view). You may see blank slidesin the “Normal” or “Slide Sorter” views.All animations will appear after viewingin Presentation Mode and playing eachanimation. Most animations will requirethe latest version of the Flash Player,which is available athttp://get.adobe.com/flashplayer.
  54. 54. • Other genetic changes  Absence of telomere shortening • Repeating DNA sequence at the end of the chromosomes • Promote chromosomal stability • Each time a cell divides the telomeres get shorter. • Telomerase rebuilds telomeres and is turned on in cancer cells. • Cells can divide over and over again.
  55. 55.  Chromosomal rearrangements • Translocation – portion of chromosome may break off and reattach to another chromosome. • May disrupt genes that regulate cell cycle • Philadelphia chromosome – translocation between 9 and 22 • Causes nearly 95% of chronic myelogenous leukemia (CML), a bone marrow cancer
  56. 56. Figure 12.16 A translocation can create the Philadelphia chromosome. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. BCR BCR-ABL Philadelphia 22 chromosomeABL 9
  57. 57. • Cancer-causing alleles  In 1990, DNA studies revealed the first gene allele associated with breast cancer was BRCA1.  Later BRACA2 discovered  Both alleles are mutant tumor suppressor genes that are inherited in an autosomal recessive manner.  If one mutated allele is inherited, a mutation in the other allele is required for the predisposition of cancer to increase.  Because the first mutated allele is inherited, it is present in all body cells.  Cancer is more likely wherever the second mutation happens.
  58. 58. Figure 12.17 Breast cancer can run in families. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. (sisters): © Pam Francis/Time Pix/Getty; (cell): © Steve Gschmeissner/Photo Researchers, Inc.
  59. 59. Figure 12.18 Inherited• RB gene retinoblastoma  Also a tumor suppressor Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. gene  Name from association with eye tumor retinoblastoma  Tumor in one eye most common because it takes mutations in both alleles before cancer can develop  Children who inherit a mutated allele more likely to have tumors in both eyes• RET gene  Proto-oncogene inherited in an autosomal dominant manner  Predisposition to thyroid cancer © Dr. M.A. Ansary/SPL/Photo Researchers, Inc.
  60. 60. • Testing for these and other genes  Genetic are tests available for BRCA genes, RET gene and RB gene.  Genetic tests are also available for other types of mutated genes that help a physician diagnose cancer.  Test for the presence of telomerase

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