4.28.2010<br /><ul><li>TRK
Muscle tropomyosin
Normally binds to actin filaments
Functions in a dimerized form, forming a polypeptide where each of two peptides is wound around one another and Ns and Cs ...
Interacts with actin for muscle contraction
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4.28.2010 lecture 2

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4.28.2010 lecture 2

  1. 1. 4.28.2010<br /><ul><li>TRK
  2. 2. Muscle tropomyosin
  3. 3. Normally binds to actin filaments
  4. 4. Functions in a dimerized form, forming a polypeptide where each of two peptides is wound around one another and Ns and Cs are aligned
  5. 5. Interacts with actin for muscle contraction
  6. 6. In gene rearrangement, MusTrop is exchanged for EXC domain of TRK receptor
  7. 7. TRK normally binds to GFs like nerve GFs, BDNF, Neurotrophins
  8. 8. Single polypeptide of Trk receptor interacts with one region of that GF while the other interacts with another region of GF, dimerizing to make a functioning Trk receptor
  9. 9. In this example, a single polypeptide of MusTro is expressed with or instead of the EXC domain of a single Trk receptor
  10. 10. When MusTrop dimerizes, it dimerizes the receptor and bring two polypeptides together so that the cytoplasmic regions are juxtaposed
  11. 11. Autophosphorylate one another acting as if always bound by GFs
  12. 12. Oncoprotein now is continually active, activating Ras signaling and driving cell mitosis
  13. 13. PDGF receptor
  14. 14. Platelet derived growth factor
  15. 15. GF that binds to Trk receptor under normal circumstances, turning on kinase signaling
  16. 16. In the oncoprotein form: (driving cell mitosis)
  17. 17. Tel, a transcription factor, is coded and expressed as EXC domain of the PDGF receptor
  18. 18. Due to its structure, helix loop helix, it interacts to dimerize receptors and always on
  19. 19. Rb Protein
  20. 20. Tumor suppressor
  21. 21. Rb normally functions in absence of GF to bind E2F and restrict it from promoting gene transcription
  22. 22. GFs can activate Ras pathway
  23. 23. Stimulates signaling cascade that Pi G1 Cdk-cyclin
  24. 24. Pi Rb
  25. 25. Releasing E2F
  26. 26. Drive gene transcription
  27. 27. Proteins for S phase required are synthesized
  28. 28. Heritable mutations
  29. 29. Lead to one hit on a TSGene
  30. 30. In sperm, allele is mutated
  31. 31. Now have a single copy with functioning Rb and non-functioning Rb
  32. 32. Each cell of the body has one hit on normally functioning allele
  33. 33. Required for TSG
  34. 34. TSG regulate mitotic ability and not enhance it (must have two hits for TSG)
  35. 35. Mutations from external signals
  36. 36. Cells divide normally until individuals cells are mutated twice on the particular gene after fertilization in somatic cells
  37. 37. Ras Mutation
  38. 38. If on always
  39. 39. Continually Pi Rb to keep cell in mitotic state
  40. 40. Point mutations of Ras and Raf lead to always on
  41. 41. Mutations don’t mean that cell will divide uncontrollably
  42. 42. P53 – guardian of cell
  43. 43. Shut cell down by upregulating ihibitors of the Cdk-cyclin proteins, going to G0
  44. 44. P21 is the Cdk inhibitor
  45. 45. Inhibits function of G1 Cdk-cyclins by taking up the ATP binding site of the G1 Cdk cyclin so it can’t Pi Rb
  46. 46. Upregulates PUMA
  47. 47. Binds to Bcl2
  48. 48. Leads cell to apoptosis
  49. 49. Mechanisms to recognize DNA damage
  50. 50. Tumors are loss of ability to recognize DNA damage
  51. 51. Cell Stress
  52. 52. Responses of cells to stress that can be recognized by cell and lead to cell cycle arrest or death
  53. 53. Treatment induced stress can lead to mutations that can lead to cell death
  54. 54. Can induce so much damage that the cell will die instead of mitosis
  55. 55. Sometimes the treatment for cancers is to also induce mutations so much that it will die instead of go through mitosis
  56. 56. Can cause mitotic failure
  57. 57. Instable MTs and can’t polymerize/associate with chromosomes and detach at anaphase
  58. 58. Can drive autophagy or necrosis
  59. 59. Radiation or chemotherapy
  60. 60. Tumoregenic Stress
  61. 61. Harms cell way toooooo much
  62. 62. Limitation to GFs, oxygen and nutrients
  63. 63. Angiogenesis can deal with this lack of nutrients
  64. 64. Immune responses
  65. 65. Though to fight tumoregenic cells
  66. 66. DNA damage
  67. 67. There’s a limit though
  68. 68. Oncogene activation
  69. 69. Telomere shortening
  70. 70. Related to aging
  71. 71. Progeria disease (premature aging)
  72. 72. Regulate mitosis (Hayflick limit)
  73. 73. Telomere shortening causes cells to reach the Hayflick limit before senescence
  74. 74. Telomerases shorten ends of telomeres until too short to replicate cell
  75. 75. In cancer cells, telomeres don’t shorten
  76. 76. In normal cells
  77. 77. EXC signal leads to DNA damage
  78. 78. Repaired by p53 or other mechanisms
  79. 79. Or undergoes Apoptosis
  80. 80. In cancer cells
  81. 81. Ionizing radiation causes DNA damage
  82. 82. No cell cycle arrest if that mutation is not recognized because p53 is not functional and cell divides to become cancerous
  83. 83. Cell can die if damage is severe
  84. 84. Used for radiation therapy
  85. 85. P53
  86. 86. Functioning p53 genes
  87. 87. Treating cells with chemo drugs
  88. 88. Undegoe apoptosis
  89. 89. Heterozygous mutation
  90. 90. Treat with chemo
  91. 91. Some cells don’t divide
  92. 92. Both alleles are knocked out, no functioning p53
  93. 93. Treat cells with chemo
  94. 94. Look just like normal cells (in these particular chemo agents 5-fluorouracil, etoposide, adriamycin)
  95. 95. Moral:
  96. 96. May cause secondary side effects with chemo drugs and not reducing cancer cells and may not affect tumor cells, so which treatments are best then?
  97. 97. Mutations
  98. 98. Normal cell undergoes cell division and divide to reach hayflick limit
  99. 99. Successive mutations
  100. 100. Lead to oncogenic transofmraiton and then malignancy
  101. 101. Cell divides with properties passed down to progeny
  102. 102. Can mutate more
  103. 103. Cancer Smart Bombs
  104. 104. Try to target delivery mechanisms to cancer cells
  105. 105. There are two types of therapies of these
  106. 106. Nanoparticles
  107. 107. Coated with chemo drugs (anti-cancer drugs) Docetaxel
  108. 108. Also coated with proteins that act as homing receptors for these chemo packets
  109. 109. These homing receptors will target these nanonparticle packaged with chemo drugs to specific cells of interest
  110. 110. Work like immune cells
  111. 111. Homing receprots on immune cells will target specific types of immune cells to inflamed tissue, but to particular sites of tissue where the receptor recognizes a particular protein on surface of that cell
  112. 112. Coated with aptomers (homing receptors)
  113. 113. Short RNA sequences that bind to proteins
  114. 114. Put on surface of packages/cancer drugs
  115. 115. Target drug to receptors on cancer cells
  116. 116. Study: prostate cancer cells
  117. 117. Receptor: PSMA protein
  118. 118. Mucosal adresin protein that has globular domains
  119. 119. RNA binds to it and delivers drug to prostate cancer cell
  120. 120. Endocytosed so drug comes in and hopefully kills prostate cell
  121. 121. Docetaxel nanoparticle (np aptomer)
  122. 122. Targets prostate cells
  123. 123. Can just target cancer cells
  124. 124. Manipulates a person’s immune system
  125. 125. Took melanoma patients
  126. 126. Took out immune cells
  127. 127. Virally infected immune cells with a virus that would express a protein that would target them to the melanoma cancer cells
  128. 128. While generating ‘super immune cells’ outside, they irradiated the person to destroy the immune system and replaced with super immune system designed through viral infection (and cytokine activation for reproducing normal immune cells)
  129. 129. Two of 17 showed a sustained decrease in melanoma
  130. 130. Considered successful and worked!
  131. 131. Benefits
  132. 132. Don’t have rejection because it’s the person’s own immune system
  133. 133. Hallmarks of Cancer
  134. 134. Characteristics of tumor cells
  135. 135. Tumor cell recruits blood vessels (increased angiogenesis as well)
  136. 136. Cells less dependent on GFs
  137. 137. Enhanced signaling (such as kinase signaling)
  138. 138. Unregulated cell mitosis
  139. 139. May become invasive to become malignant
  140. 140. Immune function contributes to tumor progression (Kim et al)
  141. 141. Study showed that they have the ability to recruit immune cells, called macrophages, that are activated in such a way that they do two things to promote tumor formation:
  142. 142. Increase in cytokine production
  143. 143. Change in ECM proteins (Versican)
  144. 144. This protein (Versican) is secreted by macrophages in high concentrations and also upregulate production of cytokines
  145. 145. These characteristics favor tumor cell growth where the cells are healthier

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