Weeks 13-14
Major concept goals
-All cancer cells have alterations in the cell signaling pathways that promote cell proliferation
-Cancer is caused by multiple (3-10) genetic mutations that create the hallmarks of cancer cells
-While some of the mutations are inherited or caused by environmental factors like UV light, most are generated by DNA replication errors during S-phase of the nuclear cycle
-There are two types of cancer causing mutations, activating mutations in a single allele of a gene called oncogenes (which are dominant and therefore sufficient for promoting cancer) and inactivating mutations in both alleles of tumor suppressor genes (which are recessive and therefore necessary to prevent cancer)
-Cell proliferation pathways function by inhibiting the function of Rb to inhibit S-phase entry, so that activating mutations anywhere upstream of this pathway can promote Rb inhibition.
-Cell proliferation preventing pathways function by sensing excess myc activity and activating p53 to inhibit CDK activation, so that mutations in p53 will enable to cells to proliferate when they would normally stop dividing.
-Loss of p53 and the ability to pause the nuclear cycle and repair DNA damage is the main way that radiation and chemotherapy target and kill cancer cells
Overview of content
I. Processes altered in cancer
A. Which cell behaviors we have talked about might be altered in cancer? (All but organelle formation)
B. The hallmarks of cancer cells
C. Why should we talk about cancer?
II. What is cancer?
A. An overgrowth of cells that disrupt organism function
B. Mutations cause cancer
1. Where do the mutations come from? Familial, environmental, DNA replication errors
C. Given the high number of mutations, why is cancer so rare?
D. Evolution of cancer at the cellular level
E. Oncogenes and tumor suppressors
III. Mutations promoting cell proliferation in cancer
A. The growth factor pathway promotes the expression of myc, which is commonly over active in cancer
B. Myc leads to the expression of cyclin D, the activator of CDK4 in G1
C. Cyclin D/CDK4 inactivates Rb, Rb inhibits E2F, a transcription factor that promotes S-phase
IV. Mutations disrupting inhibition of proliferation in cancer
A. p53 is the most common tumor suppressor mutation in cancer
B. p53 is a transcription factor that when active can promote the expression of p21 a G1/S CDK inhibitor
C. p53 becomes activated by excessive proliferation promoting signals (like lots of active myc)
D. The link between p53(-) and chemotherapy