2. Most mutations occur after birth

3. Environmental mutations

4. P53 – prevents DNA damage or drives apoposis

5. No safeguards now to recognize damage and shut cell proliferation down

6. Benzoapyrene from smoking

7. Deamination

8. Replace for thymine –

9. Andogenous process – liver metabolism

10. About 50% of cancers are from a mutation in the p53 gene

11. P53

12. Tumor suppressor gene (not a protooncogene)

13. Helps suppress cell proliferation that is abnormal

14. Retinoblastoma – RB

15. Holds on to and inhibits transcription factors that drive production of cyclins that move past G1 until phosphorylated by Ras pathway for gene transcription regulation

16. Restricts mitosis and regulates cell growth in unaltered state

17. Proto-oncogenes

18. APC

19. Ras (ras pathway)

20. In an overexpressed state, will drive

21. Src – SH2 domains

22. Kinase, has SH2 domain, activated in response to RTK

23. If there is is single allel in a protooncogene that is mutated, it will cause that cell to divide uncontrollably and unregulated

24. If there is a normal copy on the other allele, a normal cell will divide correctly. However, if both alleles are mutated, that single cell may divide uncontrollably.

25. Pathways

26. Ras

27. GFs activated RTK

28. Recruit SH2 to activate Ras

29. Ras activates gene transcription pathways

30. Myc, when Pi, will lead to enhanced gene expression and enhance cell mitosis

31. Protonocogene – leads to favored gene expression and poliferation

32. P16, like p21, inhibits cyclin that binds to cyclin and keeps it from Pi Rb

33. P16 is a tumor suppressor, restricts cell mitosis

34. Anti growth factors

35. TNS – tumor necrosis factor

36. Growth factor that regulates growth – restricting it

37. Activates a pathway that turns on inhibitors of cyclins

38. Binds to RTK

39. Attacks

40. Secreted by activated immune cells

41. P53

42. Upregulates p21 function

43. Drives inhibits cyclin dependent kinases and cells stop dividing – senescence – G0

44. PUMA

45. Activated by p53 that leads to cells death

46. Inhibits Bcl2

47. Makes mitochondrial membrane more unstable

48. Cytocochrome c is released

49. Apotosome and caspase 9

50. Apoptosis

51. Checkpoints within mitosis

52. What is regulating G2 and metaphase checkpoints and drive to S phase and see what is required and see if they act as tumor suppressors or proto oncogenes

53. Examples of Oncogenes

54. GFs

55. Overexpression can cause cancers

56. PDGF – platelet derived growth factor

57. Sarcomas

58. Fibrosarcomas

59. There are two genes (oncogenes) that express amounts of PDGF

60. V-sis

61. TRK receptor

62. Binds to JrK – Nerve Growth factor, neurotrophins, brain derived nuerotrophic factor (BDNF)

63. Thyroid

64. Breast

65. Ras – inability to hydrolzyze GTP to GDp – making it on all the time

66. Single point mutations

67. Raf

68. Src kinase – v-src – sarcomas

69. Myc – regulated by ras – translocation, aplification, inserional mutagensis – 3 types of cancer

70. Cyclins – Bcl2 –

71. Types of Cancer

72. Carcinomas – Epithelium

73. Throat lining, skin, intestines

74. Sarcomas

75. Muscles or Connective Tissue

76. Leukias/Lymphomas

77. Hematopoietic System

78. Nervous System

79. Neuromas

80. Gliomas

81. Astrocytomas

82. What types of Mutations are taking place?

83. Gene amplification

84. Some muation has caused gene to be respresnted in multiple ways, causing an overexpression of that gene product

85. Chromsomes rearrangement

86. Overexpression of proteins that enhance production of that particular gene of interest

87. Fusio nevent – gene made is on all the time

88. Her2 receptor

89. Single mutation in transmembrane region

90. Thinks bound to GF

91. Deletion – receptor is always on signaling for cell to divide

92. TRK receptor

93. RTK, bound by GFs, autphosphorylation

94. Mutations: gene rearragnement replaces EXdomain of receptor ith a muscle tropomysoin protein involved in smooth muscle contraction, losing resulatory EXC domain and TRPM is sticking out.

95. Links with trasmembrane