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