2. Extrinsic

3. Fas/Fas Ligand Pathway aka “Death Receptor”

4. Links procaspases to Fas/FasL receptor complex by FADD

5. Activated caspase 8 cleaves caspase 3

6. Apoptosis activated

7. Activates endonucleases

8. Enzymes that cut DNA in between nucleosomes (internucleosomal cleavage – a sign of apoptosis)

9. Organization of apoptotis is why endonucleases are used in a specific way to cleave the DNA

10. Activates proteases

11. Cleaves nuclear and cytoplasmic/skeletal proteins

12. Drives assembly/formation of apoptotic body

13. Allows phagocytic cells to come in and engulf the dying cell without inducing inflammation

14. Perforin and Granzyme – used primarily in the immune system.

15. Cytotoxic cells, which are immune cells, target a cell for death by releasing perforin through exocytosis

16. Perforin perforates membrane and forms a pore

17. Allows for granzyme to be inserted through pore

18. Activates caspase 3

19. Work like endonucleases too to cleave DNA directly

20. Perferin has hydrophobic/hydrophilic region, ampipathic, inserts in membrane, conof change and cell death ensues through granzyme

21. Cytotoxic cells sense viral infections, bacterial infections, and neoplastic change, or becoming oncogenic

22. Surivial Mode

23. Bcl2 is more prominent as well as anti-apoptotic proteins

24. Caspase 12 comes from ER

25. Turned on by stress sensors

26. Enzymes that can cleave procaspase 12 in ER and release to activate caspase 3

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. Cleave caspase 12, activating it, from procaspase (pro section cleaved off by IREs)

29. Activates caspase 3

30. Apoptosis

31. Way for tissue to eliminate cell that don’t produce the right proteins that aren’t making a good cell

32. ER stress sensors – IRE’s that activate caspase 12

33. IAP – inhibitors of apoptosis

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. Can stop apoptosis at any stage because they directly interact with activated caspases anywhere along the way.

36. 70 amino acid sequence Baculovirus Sequence.

37. A BIR

38. Bacular Virus Internal Repeat

39. Common to all inhibitors of apoptosis

40. Highly conserved

41. Identified in baculoviruses first

42. Conservative – so very important

43. Allows interacting area with caspases

44. Allows to interact directly with caspases or complexes that lead to caspase 3 activation.

45. Suppress apoptosis

46. Protein complexes from the mitochondria breaking down inhibit IAPs

47. Intrinsic Signals

48. Withdrawal of trophic factors

49. P53

50. Bax destabilizes cell membrane and releases cytochrome c

51. Apf-1 and cytochrome c come together to cleave procaspase 9, makes an apotosome

52. Activates caspase 3 from procaspase 3

53. Activates endonuclease activity, which cleave DNA, for apoptosis between nucleosomes

54. Proteases are activated, which degrade nuclear and cytoskeletal proteins

55. Cytoskeleton remodeling

56. Responsible for formation of apoptotic bodies/ “blebs”

57. Phagocytose, chew up, some spit out and used by endocytosis or pinocytosis and used to remake organelles etc or other components

58. Other forms of Cell Death

59. Aponecrosis

60. A combination of apoptosis and necrosis

61. Cell death induced by injury, much like necrosis

62. Has a phenotype of necrosis

63. But involves protein synthesis like apoptosis

64. We don’t know why

65. Requires gene transcription like apoptosis

66. Autophagy

67. Removes dead or dying organelles to the lysosomes and uses them for metabolic purposes

68. Can involve formation of an autophagosome

69. ER membrane surrounds organelles to make autophagosomes

70. fuses with lysosomes to make an autophagolysosome

71. breakdown entire cell substituent

72. Cell may want to replace and use the components for ATP or generation of other things

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. Not enough oxygen, then may break down – oxidative stress

75. Some type of cell death

76. Radiation

77. Chemotherapy

78. Trigger autophagy where all internal contents are degraded.

79. Intracellular pathogens

80. Cells infected, without increasing chance of infecting neighbors, eliminates intracellular infection internally

81. TB

82. Viral infection

83. Lack of growth factors or nutrients in environment

84. Other cells need materials to make glucose or ATP

85. Use substituents of other cells to make ATP such as phospholipids etc.

86. Cannibalism is in our nature!

87. Characteristics

88. Autophagian vacuoles form

89. Nucleus is left fairly in tact

90. Chromsomes will not undergo condensation/cleave such as in apoptosis

91. Can be used to provide a source of materials for neighboring cells

92. Huntington’s/Alzheimers Disease

93. Benefits

94. Removal of damaged organelles

95. Limitation of infection

96. Use components of organelles for metabolic substrates

97. How it works

98. Membrane surround Organelle from ER to form autophagosome

99. Fuses with lysosome to make autophagolysosome

100. Parapoptosis

101. Apoptotic-like form of cell death, but uses an alternate form of caspase 9, cytochrome c

102. Alternative form of cell death driven by formation of apotosome like structure

103. Cytochrome c release + activation of caspase 9

104. This alternate form does NOT use APAF-1

105. Many inhibitors that block apotosomes do not affect this form of cell death (first identified this way)

106. Can be induced by internal or external factors

107. External, lack of GF’s outside of cell

108. Seen in Huntington’s Disease/Alzheimer’s Disease/ALS (Amyotrophic lateral sclerosis aka Lou Gehrig’s Disease)

109. Involved in activation of caspase 9 but no formation of apotosomes

110. It is not inhibited by the caspase 3 inhibitor, so we can’t block it like we could in normal apoptosis

111. Involves cytoplasmic indulution

112. Vacuoles form

113. Degrade contents of the cytoplasm

114. Mediated by MAP kinase pathway

115. Leads to activation of caspase 9 and cell death

116. Triggered by immune cell death signaling molecules that target cells for death

117. Tumor necrosis factor

118. Bound by TNF receptor

119. Triggers cells death

120. Usually mediated by caspase 9

121. Primarily activates other signaling molecules aside from MAP kinase

122. Caspase 3 independent

123. If cell is released and into the lumen, two types of cell death can occur

124. Used primarily for metastatic cells

125. Anoikis

126. Form of apoptosis that ensues after cell is detached from ECM

127. Activation of caspases

128. Release of cytochrome c

129. Death when cells become detached from ECM

130. ECM is a substrate to which cells adhere to organize and form tissue

131. If a cell, like epithelial, becomes detached

132. ‘loss of home’

133. TJ and AJ – adherin junction and tight junctions

134. Hold cells to one another

135. Integrin attachments hold cell to ECM

136. All attachments have been degraded

137. When cells detach, they are unhealthy of neoplastic, tumoregenic

138. Released from normal environment

139. Entosis

140. Not a type of cell death that involves apoptotic mechanisms

141. 2 cells detach from ECM and go to lumen of tissue, but remain attached to one another at only one site

142. one sucks up the other and brings it into the cytoplasm to form into a vacuole called an entocyte

143. can spit out…

144. autophagic-like mechanism begins to degrade the entocyte

145. Identified in mammals/ breast cancer tissue

146. May be a way to degrade neoplastic cells in cancer

147. Cells that are lucent, become sucked up by neighboring cells

148. Engulfed like phagocytosis

149. The loosening of the cell

150. Degrades entire cell

151. Think It is a likely way of preventing oncogenic cells

152. Neoplastic

153. A cell is demonstrating features of cancer, or being cancerous.

154. End Lecture----------------------------------------------------------------------------------------

155. --------------------------------The Extracellular Matrix------------------------------------------------

156. Disease linked to abnormalities in the ECM

157. Cancer

158. Osteoporosis

159. Osteoarthritis

160. Inflammatory Diseases

161. Periodontal Disease

162. Neurodegenerative Diseases

163. Tissues

164. Muscular tissues

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. Smooth

167. Cardiac

168. skeletal

169. Nervous tissue

170. Central NS

171. Peripheral NS

172. ***Connective tissue (focus of time in this section)

173. Bone

174. Osteocytes sit in bone and secrete calcified ECM that makes bone tissue or have blood run through

175. Cartilage

176. Less dense than bone

177. Cells secrete components of cartilage and ECM components of it

178. Loose connective tissue

179. Under epithelial cells

180. Less dense than cartilage

181. Form strands in gel like substance

182. Immune cells move through

183. Blood vessels penetrate

184. Under skin or intestinal lining

185. ***Blood

186. osteocytes secrete ECM molecules

187. Immune cells

188. ***Lymphoid tissue

189. Basal Lamina

190. The area attached to ECM

191. Epithelial Cells

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. Lumen of Gut

194. Epithelial cells

195. Attached to basal lamina of ECM

196. Adhere to loose connective tissue

197. LCT

198. Strand like

199. Endothelial cells of lumen of blood vssesl

200. Blood vessels allow immune cell transportation

201. GAG’s

202. Glycosylamino glycoproteins

203. Allows for gel like substance to form

204. Fibroblasts can stop making things to adhesion

205. Endothelial cells of blood vessels, surrounded by smooth muscle cells.