4.12.2010<br /><ul><li>Types of Pathways for Cell death
Extrinsic
Fas/Fas Ligand Pathway aka “Death Receptor”
Links procaspases to Fas/FasL receptor complex by FADD
Activated caspase 8 cleaves caspase 3
Apoptosis activated
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4.12.2010

  1. 1. 4.12.2010<br /><ul><li>Types of Pathways for Cell death
  2. 2. Extrinsic
  3. 3. Fas/Fas Ligand Pathway aka “Death Receptor”
  4. 4. Links procaspases to Fas/FasL receptor complex by FADD
  5. 5. Activated caspase 8 cleaves caspase 3
  6. 6. Apoptosis activated
  7. 7. Activates endonucleases
  8. 8. Enzymes that cut DNA in between nucleosomes (internucleosomal cleavage – a sign of apoptosis)
  9. 9. Organization of apoptotis is why endonucleases are used in a specific way to cleave the DNA
  10. 10. Activates proteases
  11. 11. Cleaves nuclear and cytoplasmic/skeletal proteins
  12. 12. Drives assembly/formation of apoptotic body
  13. 13. Allows phagocytic cells to come in and engulf the dying cell without inducing inflammation
  14. 14. Perforin and Granzyme – used primarily in the immune system.
  15. 15. Cytotoxic cells, which are immune cells, target a cell for death by releasing perforin through exocytosis
  16. 16. Perforin perforates membrane and forms a pore
  17. 17. Allows for granzyme to be inserted through pore
  18. 18. Activates caspase 3
  19. 19. Work like endonucleases too to cleave DNA directly
  20. 20. Perferin has hydrophobic/hydrophilic region, ampipathic, inserts in membrane, conof change and cell death ensues through granzyme
  21. 21. Cytotoxic cells sense viral infections, bacterial infections, and neoplastic change, or becoming oncogenic
  22. 22. Surivial Mode
  23. 23. Bcl2 is more prominent as well as anti-apoptotic proteins
  24. 24. Caspase 12 comes from ER
  25. 25. Turned on by stress sensors
  26. 26. Enzymes that can cleave procaspase 12 in ER and release to activate caspase 3
  27. 27. These stress proteins (IREs) are activated that sense the cell has a buildup of misfolded proteins (IREs sense the buildup of misfolded proteins – they sense the stress of the misfolded proteins building up in the ER, the family of proteins then activates caspase 12)
  28. 28. Cleave caspase 12, activating it, from procaspase (pro section cleaved off by IREs)
  29. 29. Activates caspase 3
  30. 30. Apoptosis
  31. 31. Way for tissue to eliminate cell that don’t produce the right proteins that aren’t making a good cell
  32. 32. ER stress sensors – IRE’s that activate caspase 12
  33. 33. IAP – inhibitors of apoptosis
  34. 34. We used to think that apoptosis was an all or nothing thing, but the identification of IAPs provided an understanding of ways the cell can regulate apoptosis
  35. 35. Can stop apoptosis at any stage because they directly interact with activated caspases anywhere along the way.
  36. 36. 70 amino acid sequence Baculovirus Sequence.
  37. 37. A BIR
  38. 38. Bacular Virus Internal Repeat
  39. 39. Common to all inhibitors of apoptosis
  40. 40. Highly conserved
  41. 41. Identified in baculoviruses first
  42. 42. Conservative – so very important
  43. 43. Allows interacting area with caspases
  44. 44. Allows to interact directly with caspases or complexes that lead to caspase 3 activation.
  45. 45. Suppress apoptosis
  46. 46. Protein complexes from the mitochondria breaking down inhibit IAPs
  47. 47. Intrinsic Signals
  48. 48. Withdrawal of trophic factors
  49. 49. P53
  50. 50. Bax destabilizes cell membrane and releases cytochrome c
  51. 51. Apf-1 and cytochrome c come together to cleave procaspase 9, makes an apotosome
  52. 52. Activates caspase 3 from procaspase 3
  53. 53. Activates endonuclease activity, which cleave DNA, for apoptosis between nucleosomes
  54. 54. Proteases are activated, which degrade nuclear and cytoskeletal proteins
  55. 55. Cytoskeleton remodeling
  56. 56. Responsible for formation of apoptotic bodies/ “blebs”
  57. 57. Phagocytose, chew up, some spit out and used by endocytosis or pinocytosis and used to remake organelles etc or other components
  58. 58. Other forms of Cell Death
  59. 59. Aponecrosis
  60. 60. A combination of apoptosis and necrosis
  61. 61. Cell death induced by injury, much like necrosis
  62. 62. Has a phenotype of necrosis
  63. 63. But involves protein synthesis like apoptosis
  64. 64. We don’t know why
  65. 65. Requires gene transcription like apoptosis
  66. 66. Autophagy
  67. 67. Removes dead or dying organelles to the lysosomes and uses them for metabolic purposes
  68. 68. Can involve formation of an autophagosome
  69. 69. ER membrane surrounds organelles to make autophagosomes
  70. 70. fuses with lysosomes to make an autophagolysosome
  71. 71. breakdown entire cell substituent
  72. 72. Cell may want to replace and use the components for ATP or generation of other things
  73. 73. If the environment is not sufficient, not enough nutrients or GFs, the cell may breakdown organelle membranes inside the cell and use that for ATP
  74. 74. Not enough oxygen, then may break down – oxidative stress
  75. 75. Some type of cell death
  76. 76. Radiation
  77. 77. Chemotherapy
  78. 78. Trigger autophagy where all internal contents are degraded.
  79. 79. Intracellular pathogens
  80. 80. Cells infected, without increasing chance of infecting neighbors, eliminates intracellular infection internally
  81. 81. TB
  82. 82. Viral infection
  83. 83. Lack of growth factors or nutrients in environment
  84. 84. Other cells need materials to make glucose or ATP
  85. 85. Use substituents of other cells to make ATP such as phospholipids etc.
  86. 86. Cannibalism is in our nature!
  87. 87. Characteristics
  88. 88. Autophagian vacuoles form
  89. 89. Nucleus is left fairly in tact
  90. 90. Chromsomes will not undergo condensation/cleave such as in apoptosis
  91. 91. Can be used to provide a source of materials for neighboring cells
  92. 92. Huntington’s/Alzheimers Disease
  93. 93. Benefits
  94. 94. Removal of damaged organelles
  95. 95. Limitation of infection
  96. 96. Use components of organelles for metabolic substrates
  97. 97. How it works
  98. 98. Membrane surround Organelle from ER to form autophagosome
  99. 99. Fuses with lysosome to make autophagolysosome
  100. 100. Parapoptosis
  101. 101. Apoptotic-like form of cell death, but uses an alternate form of caspase 9, cytochrome c
  102. 102. Alternative form of cell death driven by formation of apotosome like structure
  103. 103. Cytochrome c release + activation of caspase 9
  104. 104. This alternate form does NOT use APAF-1
  105. 105. Many inhibitors that block apotosomes do not affect this form of cell death (first identified this way)
  106. 106. Can be induced by internal or external factors
  107. 107. External, lack of GF’s outside of cell
  108. 108. Seen in Huntington’s Disease/Alzheimer’s Disease/ALS (Amyotrophic lateral sclerosis aka Lou Gehrig’s Disease)
  109. 109. Involved in activation of caspase 9 but no formation of apotosomes
  110. 110. It is not inhibited by the caspase 3 inhibitor, so we can’t block it like we could in normal apoptosis
  111. 111. Involves cytoplasmic indulution
  112. 112. Vacuoles form
  113. 113. Degrade contents of the cytoplasm
  114. 114. Mediated by MAP kinase pathway
  115. 115. Leads to activation of caspase 9 and cell death
  116. 116. Triggered by immune cell death signaling molecules that target cells for death
  117. 117. Tumor necrosis factor
  118. 118. Bound by TNF receptor
  119. 119. Triggers cells death
  120. 120. Usually mediated by caspase 9
  121. 121. Primarily activates other signaling molecules aside from MAP kinase
  122. 122. Caspase 3 independent
  123. 123. If cell is released and into the lumen, two types of cell death can occur
  124. 124. Used primarily for metastatic cells
  125. 125. Anoikis
  126. 126. Form of apoptosis that ensues after cell is detached from ECM
  127. 127. Activation of caspases
  128. 128. Release of cytochrome c
  129. 129. Death when cells become detached from ECM
  130. 130. ECM is a substrate to which cells adhere to organize and form tissue
  131. 131. If a cell, like epithelial, becomes detached
  132. 132. ‘loss of home’
  133. 133. TJ and AJ – adherin junction and tight junctions
  134. 134. Hold cells to one another
  135. 135. Integrin attachments hold cell to ECM
  136. 136. All attachments have been degraded
  137. 137. When cells detach, they are unhealthy of neoplastic, tumoregenic
  138. 138. Released from normal environment
  139. 139. Entosis
  140. 140. Not a type of cell death that involves apoptotic mechanisms
  141. 141. 2 cells detach from ECM and go to lumen of tissue, but remain attached to one another at only one site
  142. 142. one sucks up the other and brings it into the cytoplasm to form into a vacuole called an entocyte
  143. 143. can spit out…
  144. 144. autophagic-like mechanism begins to degrade the entocyte
  145. 145. Identified in mammals/ breast cancer tissue
  146. 146. May be a way to degrade neoplastic cells in cancer
  147. 147. Cells that are lucent, become sucked up by neighboring cells
  148. 148. Engulfed like phagocytosis
  149. 149. The loosening of the cell
  150. 150. Degrades entire cell
  151. 151. Think It is a likely way of preventing oncogenic cells
  152. 152. Neoplastic
  153. 153. A cell is demonstrating features of cancer, or being cancerous.
  154. 154. End Lecture----------------------------------------------------------------------------------------
  155. 155. --------------------------------The Extracellular Matrix------------------------------------------------
  156. 156. Disease linked to abnormalities in the ECM
  157. 157. Cancer
  158. 158. Osteoporosis
  159. 159. Osteoarthritis
  160. 160. Inflammatory Diseases
  161. 161. Periodontal Disease
  162. 162. Neurodegenerative Diseases
  163. 163. Tissues
  164. 164. Muscular tissues
  165. 165. ECM is usually between cells, a thin layer surrounding plasma cell membrane (basal lamina refers to thin ECM material that surrounds plasma membrane, instead of ECX. Epithelial, thin layer below ECM directly below skin)
  166. 166. Smooth
  167. 167. Cardiac
  168. 168. skeletal
  169. 169. Nervous tissue
  170. 170. Central NS
  171. 171. Peripheral NS
  172. 172. ***Connective tissue (focus of time in this section)
  173. 173. Bone
  174. 174. Osteocytes sit in bone and secrete calcified ECM that makes bone tissue or have blood run through
  175. 175. Cartilage
  176. 176. Less dense than bone
  177. 177. Cells secrete components of cartilage and ECM components of it
  178. 178. Loose connective tissue
  179. 179. Under epithelial cells
  180. 180. Less dense than cartilage
  181. 181. Form strands in gel like substance
  182. 182. Immune cells move through
  183. 183. Blood vessels penetrate
  184. 184. Under skin or intestinal lining
  185. 185. ***Blood
  186. 186. osteocytes secrete ECM molecules
  187. 187. Immune cells
  188. 188. ***Lymphoid tissue
  189. 189. Basal Lamina
  190. 190. The area attached to ECM
  191. 191. Epithelial Cells
  192. 192. Packed tightly to one another, held by TJ and AJ, linked up by integrins at the basal side of the cell and attach TO the basal lamina
  193. 193. Lumen of Gut
  194. 194. Epithelial cells
  195. 195. Attached to basal lamina of ECM
  196. 196. Adhere to loose connective tissue
  197. 197. LCT
  198. 198. Strand like
  199. 199. Endothelial cells of lumen of blood vssesl
  200. 200. Blood vessels allow immune cell transportation
  201. 201. GAG’s
  202. 202. Glycosylamino glycoproteins
  203. 203. Allows for gel like substance to form
  204. 204. Fibroblasts can stop making things to adhesion
  205. 205. Endothelial cells of blood vessels, surrounded by smooth muscle cells.

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