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4.26.2010 – Cancer Continued<br /><ul><li>Neoplastic Change (after film/film)
Mutations
Primarily occur after birth
Some are inherited, much rarer though
Environmental changes/chemical cues and metabolic events
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4.26.2010 lecture 2

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4.26.2010 lecture 2

  1. 1. 4.26.2010 – Cancer Continued<br /><ul><li>Neoplastic Change (after film/film)
  2. 2. Mutations
  3. 3. Primarily occur after birth
  4. 4. Some are inherited, much rarer though
  5. 5. Environmental changes/chemical cues and metabolic events
  6. 6. P53 has been associated with more than 50% of known cancers
  7. 7. P53 can regulates apoptosis and cell senescence
  8. 8. P53 is the ‘guardian of the genome’
  9. 9. Senses DNA damage and will send to senescence to be repaired or if it can’t be repaired, will undergo senescence and enter G0
  10. 10. Types of Cancers
  11. 11. Carcinomas –
  12. 12. epithelial cells = lining of intestines mucosa and skin
  13. 13. melanoma = very invasive
  14. 14. Sarcomas
  15. 15. Leukamias and Lymphomas
  16. 16. Nervous System
  17. 17. Neuromas
  18. 18. Gleiomas
  19. 19. Astrocytomas
  20. 20. Some cells tend to form secondary tumors in only certain tissues
  21. 21. Seed and soil hypothesis
  22. 22. Certain cancer cells will embed and metastesize in certain tissues only
  23. 23. Unknown why
  24. 24. Mechanisms that lead to activation of protooncogene and inactivation of tumor suppressor genes
  25. 25. Tumor suppressor genes
  26. 26. Normal function is to regulate cell proliferation or shut down if there is DNA damage
  27. 27. Inhibits cell mitosis
  28. 28. P53
  29. 29. Retinoblastoma (Rb) gene and protein
  30. 30. In unpi’ed state, binds E2F, a transcription factor
  31. 31. When Rb Pi by Ras pathway releases E2f
  32. 32. E2F drives gene transcription to make cells for movement into S phase
  33. 33. Protooncogenes
  34. 34. Proteins that are active that drive cell mitosis
  35. 35. Ras, especially in mutated, always on form
  36. 36. Binds GTP to be active
  37. 37. Functions as a serine/threonine kinase
  38. 38. Pi targets like G1-Cdk cyclins
  39. 39. Drives entrance into S phase
  40. 40. [V] Src – has SH2 domain (V means ‘after viral infection’)
  41. 41. Binds RTK
  42. 42. Activated
  43. 43. Drives cell mitosis
  44. 44. Receptor Tyrosine Kinases
  45. 45. In mutated forms, can act as oncogenic proteins
  46. 46. Upregulate cell mitosis when on
  47. 47. Mutational Events that can lead to cancerous cells/oncogenic transformations
  48. 48. TSG
  49. 49. One allele is mutated – doesn’t matter
  50. 50. P53 is able to be made by one functional allele
  51. 51. Both alleles
  52. 52. KO’s function of TSG
  53. 53. Cell can divide in unregulated way
  54. 54. Doesn’t respond to DNA damage
  55. 55. Will divide in culture unregulated
  56. 56. Protooncogenes
  57. 57. Gain of functions lead to oncogenic function
  58. 58. Only a single mutation is necessary on a single allele
  59. 59. Leads to oncogenic transformation
  60. 60. Leads to overproduction of a protein that is always on
  61. 61. Over production of Ras or RTKs
  62. 62. Divides in unregulated way
  63. 63. Pathways
  64. 64. Growth factors
  65. 65. Bind RTKs
  66. 66. Activate signaling pathways by autophosphorylation, such as Ras
  67. 67. Can lead to gene expression and cell proliferation
  68. 68. Pi of cyclins at G1 to move cell to S phase
  69. 69. Rb can be Pi’ed > E2F released > drives gene production and cell proliferation
  70. 70. Raf> Map Kinase > Erk > gene transcription factor
  71. 71. Myc
  72. 72. Overexpression
  73. 73. Protooncogene
  74. 74. Gain of function of myc leads to an increase in cell proliferation
  75. 75. Rb
  76. 76. Acts as TSG when unPi’ed with E2F
  77. 77. If Rb is a TSG, cyclin/CDK Pi Rb > releases E2F > gene transcription > Mitosis
  78. 78. Cyclin/Cdk enhances and is a protooncogene
  79. 79. Anti Growth Factors
  80. 80. Signals from outside of cell that inhibit cell growth
  81. 81. Smads
  82. 82. Tumor necrosis factor
  83. 83. A GF that is secreted by immune cells when they recognize viral or cancerous types of cells
  84. 84. Binds to receptor
  85. 85. Activates receptor
  86. 86. Turns on signaling pathway
  87. 87. Can directly inhibit cyclins, shutting down Pi of Rb
  88. 88. Upregulate p21 synthesis regulation/activation
  89. 89. P21, a CKI, used in mitosis and checkpoint phases to bind to ATP binding site of CDKs and inhibit ability to phosphorylate targets
  90. 90. Can upregulate activity of p21
  91. 91. P21 I a tumor suppressor
  92. 92. Can directly inhibit roles of cyclins
  93. 93. Shut down mitosis, so tumor suppressor
  94. 94. P53
  95. 95. Activates p21
  96. 96. Moves cell to senescence for repair
  97. 97. Primary tumor suppressor
  98. 98. Can cause cell to apoptose
  99. 99. Activates PUMA
  100. 100. Inactivates Bcl-2 (which normally keeps mitochondrial membrane stable)
  101. 101. Cytochrome c is now released
  102. 102. Helps for apotosome
  103. 103. Activates caspase 9
  104. 104. Activates caspase 3
  105. 105. Apoptosis
  106. 106. Look at checkpoints for mitosis and understand what’s happening at G2/metaphase-anaphase/G1 checkpoints
  107. 107. Oncogenes (Table)
  108. 108. PDGF – platelet derived growth factor
  109. 109. Mitogen (a very powerful one)
  110. 110. Drives mitosis
  111. 111. Overexpression leads to rapid proliferation
  112. 112. Mutations that encode PDGF and drive unrestricted proliferation
  113. 113. V-sis
  114. 114. Overproduction of PDGF and binding to receptors of cells that have it
  115. 115. Sarcomas (muscle cells)
  116. 116. Occurs after viral infection
  117. 117. TRK receptor
  118. 118. Binds many GFs/family of receptors
  119. 119. Nerve GFs
  120. 120. Neurotrophins
  121. 121. Brain derived neurotrophic factor
  122. 122. Mutation leads to activation of TRK receptor
  123. 123. RTK
  124. 124. Tropomyosin is expressed as part of the TRK receptor, leading to dimerization at all times
  125. 125. Leads to, primarily, thyroid cancers
  126. 126. ERB2 Receptor
  127. 127. Amplification of receptor function b/c EXC domain is deleted
  128. 128. Ras
  129. 129. Proto-oncogene
  130. 130. Can generate lots of types of cancers
  131. 131. Ras is always bound to GTP and always active, always Pi Map Kinases
  132. 132. Raf
  133. 133. Melanomas
  134. 134. Src
  135. 135. SH2 domain
  136. 136. V-src
  137. 137. Leads to src kinase activation
  138. 138. Responsible for overactive kinase after viral infection
  139. 139. Sarcomas
  140. 140. DNA rearrangements
  141. 141. Myc
  142. 142. Upregulates gene transcription
  143. 143. Cell Cycle
  144. 144. CDK cyclins
  145. 145. Bcl2
  146. 146. Regulate mitosis and apoptosis
  147. 147. Mutation slcan act as oncogenes as well
  148. 148. Proto-oncogene
  149. 149. Mutations
  150. 150. Mutation in a coding sequence
  151. 151. point mutation – mutaiton of single nucelotide
  152. 152. Deletion
  153. 153. Gene amplification
  154. 154. Multiple areas that cause a protein to be over expressed
  155. 155. Causes an ENHANCED but not ABNORMAL level of protein
  156. 156. Chromosomes rearrangement
  157. 157. Nearby sequence is put in the promoter sequence of nearby gene
  158. 158. Leads to increased amount of protein
  159. 159. Fused event
  160. 160. Piece of one protein is put near coding region of protein of interest so on at all times and can’t be regulated
  161. 161. Her2 mutaitons
  162. 162. Point mutation
  163. 163. Dimerization of receptor
  164. 164. Breast cancer
  165. 165. ERB2
  166. 166. Mutaiton takes away EXC binding domain so can’t respond to GFs at all and are active, leading to cell proliferation
  167. 167. TRK receptor
  168. 168. Normally, a single transmembrane protein with EXC domain, binds to GF, dimerizes, leads to autophosphorylation and activation
  169. 169. In mutated form, muscle tropomysoin dimerizes transmembrane and cytoplasmic domains of the receptor b/c each polypeptide that forms muscle tropomysin binds to the transmembrane or is expressed as the link to a transmembrane domain and cytoplasmic domain.
  170. 170. Linked as if dimerized by receptor and then autophosphorylated and activated all the time
  171. 171. This Trk oncoprotein is the result of this DNA rearrangement event where tropomysoin, which is normally an actin binding protein in muscle, is now linked up with GF receptor, leading to unrestricted cell growth

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