4.28.2010<br /><ul><li>Mutations
Oncoprotein
Trk
Upcoming SlideShare
Loading in …5
×

4.28.2010 2

197 views

Published on

0 Comments
0 Likes
Statistics
Notes
  • Be the first to comment

  • Be the first to like this

No Downloads
Views
Total views
197
On SlideShare
0
From Embeds
0
Number of Embeds
2
Actions
Shares
0
Downloads
3
Comments
0
Likes
0
Embeds 0
No embeds

No notes for slide

4.28.2010 2

  1. 1. 4.28.2010<br /><ul><li>Mutations
  2. 2. Oncoprotein
  3. 3. Trk
  4. 4. Increase in activity leads to increase in cell mitosis
  5. 5. Muscle topomyosin protein, the gene that controls that is inadvertently
  6. 6. Trk usually dimerizes and autophosphorylates, but in this case doesn’t depend on growth factors
  7. 7. Each tropomysoin protein is linked with a Trk receptor peptide
  8. 8. PDGF receptor and PDGF ligand – platelet derived growth factor
  9. 9. We have a coding region for a transcription factor that forms a helix shape
  10. 10. Tel and PDGF recepts bind and
  11. 11. Dimerized transcription factor and due to helix shape, keeps
  12. 12. Tel acts as an oncogene and drives cell mitosis
  13. 13. Causes to be always on
  14. 14. RB mutations
  15. 15. Rb in unPi state will ind to E2F and restrict gene transcription required for S phase
  16. 16. When Pi, ras signaling is turned on, leading to activation of G1 cyclin
  17. 17. Cdk Pi Rb
  18. 18. E2F regulates gene transcription and translation for enzymes and other S phase proteins
  19. 19. Seen in children
  20. 20. Tumors in retinas
  21. 21. If inherited
  22. 22. Will be a single mutation in those gene cells
  23. 23. If there is another hit on the healthy allele that produces Rb, there will be hereditary retinoblastoma
  24. 24. If not inherited
  25. 25. At some point, environmental stress can lead to mutaion on RB gene and take a second hit after that to lead to an RB oncogenic transformation
  26. 26. Methods to help restrict cell growth
  27. 27. P53 pi, turns on two mechanisms for regulating cells that have mutations
  28. 28. Upregulated CKI – p21
  29. 29. Activate PUMA – inhibit Bcl2, driving apoptosis
  30. 30. P53 is the guardian of the gene
  31. 31. Cell Stress that can be recognized by p53
  32. 32. Treatment induced
  33. 33. Chemicals used to try to eliminate tumors
  34. 34. Intraceullular stress
  35. 35. Can lead to cell death or arrest
  36. 36. Telomere shortening
  37. 37. Haflick limit
  38. 38. Another round of cell mitosis just can’t take place
  39. 39. telomere shortening doesn’t occur at the same rate
  40. 40. telomere shortenining doesn’t happen in cancer cells
  41. 41. Cell death isn’t just mitosis
  42. 42. Mitotic catastrophe drives deploy of microtubules required to pull apart sister chromatids
  43. 43. Autophagy helps eliminate cancer cells
  44. 44. Necrosis and entosis can contribute to help remove cancer cells
  45. 45. Trating cancer
  46. 46. Ioninzing radiation exposed to cell
  47. 47. Results in DNA damage
  48. 48. p53 recognizes damage and do its duty of arrest/repair or death
  49. 49. even if p53 is not working, the cell will recognize damage, arrest, mitotic failure, catastrophe, and the tumor will regress in size.
  50. 50. If you don’t make a severe mutation to allow cell death, the cell will continue to divide and go through mitosis
  51. 51. KO studies of p53 and treated with chemotherapy drugs
  52. 52. 5-flurouracil, etoposide, adriamycin, are all cancer drugs
  53. 53. DKO = no p53
  54. 54. As if chemo has not even been done
  55. 55. +/- = one mutated gene
  56. 56. control
  57. 57. Cell division
  58. 58. Will top dividing after Haflick limit
  59. 59. With optimum genetic instability, there will be a change in the cells that will make them more likely to become oncogenic with a second hit.
  60. 60. These do not need to be malignant generally
  61. 61. May end up with cell that is neoplastic and malignant and form metastasis in other parts of the body.
  62. 62. Therapies for cancer
  63. 63. If you can’t mutate the dna with treatment, cancer smart bombs are an option
  64. 64. Nanoparticles – filled with chemotherapy drugs
  65. 65. Package a concentrated amount of chemo drugs into or on the nanoparticles and develop a way to give to a specific cancer cell
  66. 66. Whats on the surface that we can target there?
  67. 67. Cells are targeted to particular tissues because thy have receptors that recognze addressins
  68. 68. often integrin type receptors or cell adhesion (CAMs) that bind specific tissues and target to particular site.
  69. 69. Prostate Cancer
  70. 70. Docetaxel on the NPs and recognize aptomers, or short strands of RNA
  71. 71. We can target aptomers to specific proteins
  72. 72. PSMA – prostate receptor mucosal addressing
  73. 73. Endocytosis and a mechanism for killing of prostate cancer cells
  74. 74. A problem with chemo is specificity of the drug
  75. 75. Take immune cells from individuals, aggressive mealnoma patients, and virally infect the cells with constructs that target them to epithelial cells, or melanoma cancer cells.
  76. 76. Irradiate and kill off the rest of the person’s functional immune system
  77. 77. Hope to only have these virally infected immune cells active for treatment
  78. 78. Inject super active immune cells into individual, targeting cancer cells more effectively.
  79. 79. 2/17 people have shown continual remission. So not very successful.
  80. 80. Because using own immune system, don’t have to worry about rejection
  81. 81. Hallmarks of Cancer/tumoregenic cells
  82. 82. Avoidance of apoptosis
  83. 83. Sustained angiogenesis, where they can recruit endothelial cells to enhance blood vesicles around tumors
  84. 84. Lack of growth factor dependeance
  85. 85. Loss of contact inhibition as well
  86. 86. Unlimited mitotic potential
  87. 87. Increased cell signaling, which supports iunlimited mitotic potential
  88. 88. Tissue invasion/metastasis
  89. 89. Inflammation
  90. 90. Kime et all 2009 - Nature
  91. 91. Macrophages, usually phagocytic cells, can contribute to tumor progression because cytokines secreted help drive cell mitosis of cancer cells
  92. 92. Change ECM protein expression, supporting tumor survival/growth

×