4.26.2010 – Cancer Continued

1. Neoplastic Change (after film/film)a. Mutations

i. Primarily occur after birthii. 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 cancers2. P53 can regulates apoptosis and cell senescence3. P53 is the ‘guardian of the genome’

a. Senses DNA damage and will send to senescence to be repaired or if it can’t be repaired, will undergo senescence and enter G0

b. Types of Cancersi. Carcinomas –

1. epithelial cells = lining of intestines mucosa and skin2. melanoma = very invasive

ii. Sarcomasiii. Leukamias and Lymphomasiv. Nervous System

1. Neuromas2. Gleiomas3. Astrocytomas

c. Some cells tend to form secondary tumors in only certain tissuesi. Seed and soil hypothesis

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

2. Unknown why2. Mechanisms that lead to activation of protooncogene and inactivation of tumor

suppressor genesa. Tumor suppressor genes

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

ii. Inhibits cell mitosisiii. P53iv. Retinoblastoma (Rb) gene and protein

1. In unpi’ed state, binds E2F, a transcription factora. When Rb Pi by Ras pathway releases E2f

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

b. Protooncogenesi. Proteins that are active that drive cell mitosis

ii. Ras, especially in mutated, always on form1. Binds GTP to be active

a. Functions as a serine/threonine kinase i. Pi targets like G1-Cdk cyclins

1. Drives entrance into S phaseiii. [V] Src – has SH2 domain (V means ‘after viral infection’)

1. Binds RTKa. Activated

i. Drives cell mitosisiv. Receptor Tyrosine Kinases

1. In mutated forms, can act as oncogenic proteinsa. Upregulate cell mitosis when on

3. Mutational Events that can lead to cancerous cells/oncogenic transformationsa. TSG

i. One allele is mutated – doesn’t matter1. P53 is able to be made by one functional allele

ii. Both alleles1. KO’s function of TSG2. Cell can divide in unregulated way3. Doesn’t respond to DNA damage4. Will divide in culture unregulated

b. Protooncogenesi. Gain of functions lead to oncogenic function

ii. Only a single mutation is necessary on a single allele1. Leads to oncogenic transformation

a. Leads to overproduction of a protein that is always oni. Over production of Ras or RTKs

1. Divides in unregulated way4. Pathways

a. Growth factorsi. Bind RTKs

1. Activate signaling pathways by autophosphorylation, such as Rasa. Can lead to gene expression and cell proliferation

i. Pi of cyclins at G1 to move cell to S phaseii. Rb can be Pi’ed > E2F released > drives gene

production and cell proliferationb. Raf> Map Kinase > Erk > gene transcription factorc. Myc

i. Overexpressionii. Protooncogene

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

d. Rbi. Acts as TSG when unPi’ed with E2F

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

1. Cyclin/Cdk enhances and is a protooncogeneb. Anti Growth Factors

i. Signals from outside of cell that inhibit cell growth1. Smads

ii. Tumor necrosis factor1. A GF that is secreted by immune cells when they recognize viral or

cancerous types of cells2. Binds to receptor

a. Activates receptori. 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 p211. P21 I a tumor suppressor

iv. Can directly inhibit roles of cyclinsv. Shut down mitosis, so tumor suppressor

vi. P531. Activates p212. Moves cell to senescence for repair3. Primary tumor suppressor4. Can cause cell to apoptose

a. Activates PUMAi. Inactivates Bcl-2 (which normally keeps

mitochondrial membrane stable)1. Cytochrome c is now released

a. Helps for apotosomei. Activates caspase 9

ii. Activates caspase 3iii. Apoptosis

c. Look at checkpoints for mitosis and understand what’s 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 proliferationiii. Mutations that encode PDGF and drive unrestricted proliferation

1. V-sis a. Overproduction of PDGF and binding to receptors of cells

that have itb. Sarcomas (muscle cells)c. Occurs after viral infection

b. TRK receptori. Binds many GFs/family of receptors

1. Nerve GFs2. Neurotrophins3. Brain derived neurotrophic factor

ii. Mutation leads to activation of TRK receptor1. RTK 2. Tropomyosin is expressed as part of the TRK receptor, leading to

dimerization at all times3. Leads to, primarily, thyroid cancers

c. ERB2 Receptori. Amplification of receptor function b/c EXC domain is deleted

d. Rasi. Proto-oncogene

ii. Can generate lots of types of cancersiii. Ras is always bound to GTP and always active, always Pi Map Kinases

e. Rafi. Melanomas

f. Srci. SH2 domain

ii. V-src 1. Leads to src kinase activation

a. Responsible for overactive kinase after viral infectioniii. Sarcomasiv. DNA rearrangements

g. Myci. Upregulates gene transcription

h. Cell Cyclei. CDK cyclins

ii. Bcl2iii. Regulate mitosis and apoptosisiv. Mutation slcan act as oncogenes as well

6. Proto-oncogenea. Mutations

i. Mutation in a coding sequence ii. point mutation – mutaiton of single nucelotide

iii. Deletioniv. Gene amplification

1. Multiple areas that cause a protein to be over expressed2. Causes an ENHANCED but not ABNORMAL level of protein

v. Chromosomes rearrangement1. Nearby sequence is put in the promoter sequence of nearby gene

a. Leads to increased amount of protein2. Fused event

a. Piece of one protein is put near coding region of protein of interest so on at all times and can’t be regulated

b. Her2 mutaitonsi. Point mutation

ii. Dimerization of receptoriii. Breast cancer

c. ERB2i. Mutaiton takes away EXC binding domain so can’t respond to GFs at all

and are active, leading to cell proliferationd. 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