2. Mutations

3. Primarily occur after birth

4. Some are inherited, much rarer though

5. Environmental changes/chemical cues and metabolic events

6. P53 has been associated with more than 50% of known cancers

7. P53 can regulates apoptosis and cell senescence

8. P53 is the ‘guardian of the genome’

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. Types of Cancers

11. Carcinomas –

12. epithelial cells = lining of intestines mucosa and skin

13. melanoma = very invasive

14. Sarcomas

15. Leukamias and Lymphomas

16. Nervous System

17. Neuromas

18. Gleiomas

19. Astrocytomas

20. Some cells tend to form secondary tumors in only certain tissues

21. Seed and soil hypothesis

22. Certain cancer cells will embed and metastesize in certain tissues only

23. Unknown why

24. Mechanisms that lead to activation of protooncogene and inactivation of tumor suppressor genes

25. Tumor suppressor genes

26. Normal function is to regulate cell proliferation or shut down if there is DNA damage

27. Inhibits cell mitosis

28. P53

29. Retinoblastoma (Rb) gene and protein

30. In unpi’ed state, binds E2F, a transcription factor

31. When Rb Pi by Ras pathway releases E2f

32. E2F drives gene transcription to make cells for movement into S phase

33. Protooncogenes

34. Proteins that are active that drive cell mitosis

35. Ras, especially in mutated, always on form

36. Binds GTP to be active

37. Functions as a serine/threonine kinase

38. Pi targets like G1-Cdk cyclins

39. Drives entrance into S phase

40. [V] Src – has SH2 domain (V means ‘after viral infection’)

41. Binds RTK

42. Activated

43. Drives cell mitosis

44. Receptor Tyrosine Kinases

45. In mutated forms, can act as oncogenic proteins

46. Upregulate cell mitosis when on

47. Mutational Events that can lead to cancerous cells/oncogenic transformations

48. TSG

49. One allele is mutated – doesn’t matter

50. P53 is able to be made by one functional allele

51. Both alleles

52. KO’s function of TSG

53. Cell can divide in unregulated way

54. Doesn’t respond to DNA damage

55. Will divide in culture unregulated

56. Protooncogenes

57. Gain of functions lead to oncogenic function

58. Only a single mutation is necessary on a single allele

59. Leads to oncogenic transformation

60. Leads to overproduction of a protein that is always on

61. Over production of Ras or RTKs

62. Divides in unregulated way

63. Pathways

64. Growth factors

65. Bind RTKs

66. Activate signaling pathways by autophosphorylation, such as Ras

67. Can lead to gene expression and cell proliferation

68. Pi of cyclins at G1 to move cell to S phase

69. Rb can be Pi’ed > E2F released > drives gene production and cell proliferation

70. Raf> Map Kinase > Erk > gene transcription factor

71. Myc

72. Overexpression

73. Protooncogene

74. Gain of function of myc leads to an increase in cell proliferation

75. Rb

76. Acts as TSG when unPi’ed with E2F

77. If Rb is a TSG, cyclin/CDK Pi Rb > releases E2F > gene transcription > Mitosis

78. Cyclin/Cdk enhances and is a protooncogene

79. Anti Growth Factors

80. Signals from outside of cell that inhibit cell growth

81. Smads

82. Tumor necrosis factor

83. A GF that is secreted by immune cells when they recognize viral or cancerous types of cells

84. Binds to receptor

85. Activates receptor

86. Turns on signaling pathway

87. Can directly inhibit cyclins, shutting down Pi of Rb

88. Upregulate p21 synthesis regulation/activation

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. Can upregulate activity of p21

91. P21 I a tumor suppressor

92. Can directly inhibit roles of cyclins

93. Shut down mitosis, so tumor suppressor

94. P53

95. Activates p21

96. Moves cell to senescence for repair

97. Primary tumor suppressor

98. Can cause cell to apoptose

99. Activates PUMA

100. Inactivates Bcl-2 (which normally keeps mitochondrial membrane stable)

101. Cytochrome c is now released

102. Helps for apotosome

103. Activates caspase 9

104. Activates caspase 3

105. Apoptosis

106. Look at checkpoints for mitosis and understand what’s happening at G2/metaphase-anaphase/G1 checkpoints

107. Oncogenes (Table)

108. PDGF – platelet derived growth factor

109. Mitogen (a very powerful one)

110. Drives mitosis

111. Overexpression leads to rapid proliferation

112. Mutations that encode PDGF and drive unrestricted proliferation

113. V-sis

114. Overproduction of PDGF and binding to receptors of cells that have it

115. Sarcomas (muscle cells)

116. Occurs after viral infection

117. TRK receptor

118. Binds many GFs/family of receptors

119. Nerve GFs

120. Neurotrophins

121. Brain derived neurotrophic factor

122. Mutation leads to activation of TRK receptor

123. RTK

124. Tropomyosin is expressed as part of the TRK receptor, leading to dimerization at all times

125. Leads to, primarily, thyroid cancers

126. ERB2 Receptor

127. Amplification of receptor function b/c EXC domain is deleted

128. Ras

129. Proto-oncogene

130. Can generate lots of types of cancers

131. Ras is always bound to GTP and always active, always Pi Map Kinases

132. Raf

133. Melanomas

134. Src

135. SH2 domain

136. V-src

137. Leads to src kinase activation

138. Responsible for overactive kinase after viral infection

139. Sarcomas

140. DNA rearrangements

141. Myc

142. Upregulates gene transcription

143. Cell Cycle

144. CDK cyclins

145. Bcl2

146. Regulate mitosis and apoptosis

147. Mutation slcan act as oncogenes as well

148. Proto-oncogene

149. Mutations

150. Mutation in a coding sequence

151. point mutation – mutaiton of single nucelotide

152. Deletion

153. Gene amplification

154. Multiple areas that cause a protein to be over expressed

155. Causes an ENHANCED but not ABNORMAL level of protein

156. Chromosomes rearrangement

157. Nearby sequence is put in the promoter sequence of nearby gene

158. Leads to increased amount of protein

159. Fused event

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. Her2 mutaitons

162. Point mutation

163. Dimerization of receptor

164. Breast cancer

165. ERB2

166. Mutaiton takes away EXC binding domain so can’t respond to GFs at all and are active, leading to cell proliferation

167. TRK receptor

168. Normally, a single transmembrane protein with EXC domain, binds to GF, dimerizes, leads to autophosphorylation and activation

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. Linked as if dimerized by receptor and then autophosphorylated and activated all the time

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