4.26.2010 Cancer Continued 1. Neoplastic Change (after film/film) a. Mutations i. Primarily occur after birth ii.

. Some are inherited, much rarer though iii. Environmental changes/chemical cues and metabolic events 1. P53 has been associated with more than 50% of known cancers 2. P53 can regulates apoptosis and cell senescence 3. P53 is the guardian of the genome a. Senses DNA damage and will send to senescence to be repaired or if it cant be repaired, will undergo senescence and enter G0 b. Types of Cancers i. Carcinomas 1. epithelial cells = lining of intestines mucosa and skin 2. melanoma = very invasive ii. Sarcomas iii. Leukamias and Lymphomas iv. Nervous System 1. Neuromas 2. Gleiomas 3. Astrocytomas c. Some cells tend to form secondary tumors in only certain tissues i. Seed and soil hypothesis 1. Certain cancer cells will embed and metastesize in certain tissues only 2. Unknown why 2. Mechanisms that lead to activation of protooncogene and inactivation of tumor suppressor genes a. Tumor suppressor genes i. Normal function is to regulate cell proliferation or shut down if there is DNA damage ii. Inhibits cell mitosis iii. P53 iv. Retinoblastoma (Rb) gene and protein 1. In unpied state, binds E2F, a transcription factor a. When Rb Pi by Ras pathway releases E2f i. E2F drives gene transcription to make cells for movement into S phase b. Protooncogenes i. Proteins that are active that drive cell mitosis ii. Ras, especially in mutated, always on form 1. Binds GTP to be active a. Functions as a serine/threonine kinase i. Pi targets like G1-Cdk cyclins

1. Drives entrance into S phase iii. [V] Src has SH2 domain (V means after viral infection) 1. Binds RTK a. Activated i. Drives cell mitosis iv. Receptor Tyrosine Kinases 1. In mutated forms, can act as oncogenic proteins a. Upregulate cell mitosis when on 3. Mutational Events that can lead to cancerous cells/oncogenic transformations a. TSG i. One allele is mutated doesnt matter 1. P53 is able to be made by one functional allele ii. Both alleles 1. KOs function of TSG 2. Cell can divide in unregulated way 3. Doesnt respond to DNA damage 4. Will divide in culture unregulated b. Protooncogenes i. Gain of functions lead to oncogenic function ii. Only a single mutation is necessary on a single allele 1. Leads to oncogenic transformation a. Leads to overproduction of a protein that is always on i. Over production of Ras or RTKs 1. Divides in unregulated way 4. Pathways a. Growth factors i. Bind RTKs 1. Activate signaling pathways by autophosphorylation, such as Ras a. Can lead to gene expression and cell proliferation i. Pi of cyclins at G1 to move cell to S phase ii. Rb can be Pied > E2F released > drives gene production and cell proliferation b. Raf> Map Kinase > Erk > gene transcription factor c. Myc i. Overexpression ii. Protooncogene iii. Gain of function of myc leads to an increase in cell proliferation d. Rb i. Acts as TSG when unPied with E2F ii. If Rb is a TSG, cyclin/CDK Pi Rb > releases E2F > gene transcription > Mitosis 1. Cyclin/Cdk enhances and is a protooncogene b. Anti Growth Factors i. Signals from outside of cell that inhibit cell growth 1. Smads

ii. Tumor necrosis factor 1. A GF that is secreted by immune cells when they recognize viral or cancerous types of cells 2. Binds to receptor a. Activates receptor i. Turns on signaling pathway 1. Can directly inhibit cyclins, shutting down Pi of Rb 2. Upregulate p21 synthesis regulation/activation a. P21, a CKI, used in mitosis and checkpoint phases to bind to ATP binding site of CDKs and inhibit ability to phosphorylate targets iii. Can upregulate activity of p21 1. P21 I a tumor suppressor iv. Can directly inhibit roles of cyclins v. Shut down mitosis, so tumor suppressor vi. P53 1. Activates p21 2. Moves cell to senescence for repair 3. Primary tumor suppressor 4. Can cause cell to apoptose a. Activates PUMA i. Inactivates Bcl-2 (which normally keeps mitochondrial membrane stable) 1. Cytochrome c is now released a. Helps for apotosome i. Activates caspase 9 ii. Activates caspase 3 iii. Apoptosis c. Look at checkpoints for mitosis and understand whats happening at G2/metaphase-anaphase/G1 checkpoints 5. Oncogenes (Table) a. PDGF platelet derived growth factor i. Mitogen (a very powerful one) 1. Drives mitosis ii. Overexpression leads to rapid proliferation iii. Mutations that encode PDGF and drive unrestricted proliferation 1. V-sis a. Overproduction of PDGF and binding to receptors of cells that have it b. Sarcomas (muscle cells) c. Occurs after viral infection b. TRK receptor i. Binds many GFs/family of receptors

1. Nerve GFs 2. Neurotrophins 3. Brain derived neurotrophic factor ii. Mutation leads to activation of TRK receptor 1. RTK 2. Tropomyosin is expressed as part of the TRK receptor, leading to dimerization at all times 3. Leads to, primarily, thyroid cancers c. ERB2 Receptor i. Amplification of receptor function b/c EXC domain is deleted d. Ras i. Proto-oncogene ii. Can generate lots of types of cancers iii. Ras is always bound to GTP and always active, always Pi Map Kinases e. Raf i. Melanomas f. Src i. SH2 domain ii. V-src 1. Leads to src kinase activation a. Responsible for overactive kinase after viral infection iii. Sarcomas iv. DNA rearrangements g. Myc i. Upregulates gene transcription h. Cell Cycle i. CDK cyclins ii. Bcl2 iii. Regulate mitosis and apoptosis iv. Mutation slcan act as oncogenes as well 6. Proto-oncogene a. Mutations i. Mutation in a coding sequence ii. point mutation mutaiton of single nucelotide iii. Deletion iv. Gene amplification 1. Multiple areas that cause a protein to be over expressed 2. Causes an ENHANCED but not ABNORMAL level of protein v. Chromosomes rearrangement 1. Nearby sequence is put in the promoter sequence of nearby gene a. Leads to increased amount of protein 2. Fused event a. Piece of one protein is put near coding region of protein of interest so on at all times and cant be regulated b. Her2 mutaitons i. Point mutation

ii. Dimerization of receptor iii. Breast cancer c. ERB2 i. Mutaiton takes away EXC binding domain so cant respond to GFs at all and are active, leading to cell proliferation d. TRK receptor i. Normally, a single transmembrane protein with EXC domain, binds to GF, dimerizes, leads to autophosphorylation and activation ii. 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. iii. Linked as if dimerized by receptor and then autophosphorylated and activated all the time iv. 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