Week 7 Flashcards
What are the two types of epithelial cancers and what kind of cells do they arise from?
- Adenocarcinoma – arise from specialized cells in epithelial tissue that secrete substances into ducts or cavities
- Squamous cell carcinomas – arise from epithelial cells in epithelial tissue forming protective cell layers
What is the difference between normal cells and cancer cells in how they exhibit contact inhibition?
- Normal cells exhibit contact inhibition of division and movement at confluence compared to cancer cells
What are the Six Essential alterations that can lead to cancer?
- Self-sufficiency in growth signals
- Insensitivity to anti-growth signals
- Evasion of apoptosis
- Limitless replicative potential
- Tissue invasion and metastasis
- Sustained angiogenesis
What are the 5 proteins involved with proto-oncogenes and controlling cell growth?
- Growth factors
- Growth factor receptors
- Intracellular transducers
- Nuclear transcription factors
- Pro- or anti-apoptosis proteins
What are the 3 proteins involved with tumor-suppresors?
- Cell cycle control proteins
- DNA repair proteins
- Pro- or anti-apoptosis proteins
In proto-oncogenes, what occurs to the function and what is the inheritance pattern usually?
- Two main characteristics of proto-oncogenes
- Gain of function
- Dominant (need one mutated allele)
In tumor-suppressor, what occurs to the function and what is the inheritance pattern usually?
- Two main characteristics of tumor-suppressor
- Recessive (need two mutated alleles)
- Loss of function
What experiment laid the importance of oncogenic viruses as a genetic paradigm for cancer?
- Experiment by Payton Rous with Rous Sarcoma Virus (RSV)
How was the experiment by Payton Rous with Rous Sarcoma Virus (RSV) conducted?
- What was the impact and the conclusion?
- Extracted sarcoma from chicken 1 → injected into chicken 2 → chicken 2 develops sarcoma
- Impact: defines system for cancer research
- Later found that cancer is derived from our own genome
Compare and contrast a typical RNA virus with a Rous Sarcoma Virus.
- RNA Viruses
- Typical RNA Virus: includes genes for core proteins, reverse transcriptase, and envelope proteins → no cancer
- Rous Sarcoma Virus: includes typical RNA virus genes + src gene which causes cell transformation → cancer
What are the three differences between proto-oncogenes and oncogenes?
- Critical difference between proto-oncogenes and oncogenes
- Expression at inappropriate time in cell cycle (fos)
- Constitutive activity (abl)
- Failure to productively interact with negative regulator (ras)
What are the three mutational routes to the genesis of an oncogene?
- Deletion or point mutation: hyperactive protein made in normal amounts
- Gene amplification: protein overproduced
- Chromosome rearrangement: regulatory sequences rearrangned by fusion
What is an example of the deletion or point mutational route to the genesis of an oncogene?
Excessive Ras Activation (important in cell proliferation)
What is the normal pathway of Ras Activation?
- Normal: growth exchange factor (GEF) binds Ras-GDP → exchange of GDP for GTP → Ras-GTP is active → GAP binds Ras-GTP → GAP hydrolyzes Ras-GTP → Ras-GDP is inactive
What is the pathway that Ras takes leading to cancer (compared to the normal)?
- Cancer: Ras is unresponsive to GAP and cannot hydrolyze GTP, leaving Ras in active form
- Normal: growth exchange factor (GEF) binds Ras-GDP → exchange of GDP for GTP → Ras-GTP is active → GAP binds Ras-GTP → GAP hydrolyzes Ras-GTP → Ras-GDP is inactive
What is an example of the gene amplification to the genesis of an oncogene?
- Her2/neu overexpression leads to breast cancer
What are two examples of chromosomal rearrangement to the genesis of an oncogene and how do they occur?
- Burkitt’s Lymphoma – t(8,14)
- Results in fusion of c-myc (transcription factor) to immunoglobin gene → overexpression
- Chronic myelogenous leukemia – t(9,22)
- Results in fusion of abl (tyrosine kinase gene) and bcr genes → constitutively active tyrosine kinase
How does oncogene collaboration occur?
- Protein components of cytoplasmic mitogen signaling pathways combine with cell cycle control proteins in the nucleus
What is the classical and non-classical presentation of the recessive inheritance of tumor supressor genes in familial cancer syndrome?
- Recessive
- Classic: presence of one WT allele prevents tumor
- Non-classic: haploinsufficiency – only one allele needs mutation for tumor development
What effect does germ line inheritance have on tumor supressor mutations?
- Germ-line inheritance (familial) increases susceptibility to somatic loss of second allele
Compare and contrast familial vs sporadic mutations.
- Familial: inherited germline mutation + somatic mutation
- Sporadic: two somatic mutations (two-hit hypothesis)
What are the six mechanisms that may lead to loss of hetrozygosity?
- Six ways of eliminating one allele
- Nondisjunction (chromosome loss)
- Nondisjunction and duplication
- Mitotic recombination
- Gene conversion
- Deletion
- Point mutation
How can the disruption of apoptosis regulators lead to cancer?
- Discuss this in terms of anti-apoptosis and prop-apoptosis.
- Give examples of families of proteins related to each.
- Disruption of apoptosis regulators in cancer
- Anti-apoptosis: upregulation of these proteins leads to cancer
- Bcl2 family of proteins
- Pro-apoptosis: down regulation of these proteins leads to cancer
- Bax family of proteins
- Anti-apoptosis: upregulation of these proteins leads to cancer
Compare and contrast extrinisic vs intrinsic apoptotic pathways.
- Where do they both converge?
- Extrinsic: activation of death receptors → caspases pathway
- Intrinsic: directly activates caspases
- Both converge at mitochondria on caspase3 and release of cytochrome C from mitochondria → death
Explain the checkpoints in the cell cycle and the importance of having these checkpoints.
- Importance: keeps the cell from moving too quickly through growth and division
-
G1 checkpoint: environment favorable for S phase
- Restriction point – point at which cell commits to cell cycle
- G2 checkpoint: all the DNA properly replicated to enter mitosis
- Metaphase checkpoint: all chromosomes attached to spindle
What are two main regulators of the cell cycle and what are their pathways?
- RTK activates Ras-GTP → → activates cyclin dependent kinases → phosphorylate Rb → allows for cell proliferation
- P53 activates p21 → p21 deactivates cyclin
What is the physiology of a normal RTK (receptor tyrosine kinase) and a mutated RTK (two examples)?
- Normal RTK: ligand-dependent firing/dimerization
- Deactivation of RTK occurs through endocytosis
- Mutated RTK
- Signal point mutations or deletions in the tyrosine kinase receptor can cause ligand-independent firing/dimerization
- Autocrine Signaling: through activation of GF gene, cells can self-produce ligand for RTK
Why is Ras important and what are its main three functions?
- Ras proteins lies at the center of a network of interacting pathways and has influence in a large number of downstream processes
- Promotes cell proliferation
- Promotes cell differentiation
- Contributes to differentiated cell functions
What is the role of GEF and GAP in Ras pathways?
- GEF or GAP can be affected by multiple distinct upstream signals that allow them to act on Ras through multiple pathways
- Different cell types use different combinations of pathways to regulate Ras
What is the Ras activation pathway? (Its huge and detailed)
- Ligand binds to one subunit of Receptor Tyrosine Kinase (RTK) → cross-phosphorylation of RTK dimer at cytoplasmic tyrosines → SH2 domains on proteins bind to phosphotyrosine depending on the 3 AA residues after Y → recruits SOS → SOS complex acts on Ras-GDP to replace with Ras-GTP → Ras-GTP binds signaling partners → activates kinases → activate TFs → transcription
How does the loss of RB1 or the intervention of CKIs cause cells to proliferate?
- RB1 controls the cell cycle at various checkpoints
- Cyclin-dependent kinase inhibitors (CKIs such as p21) inhibit cyclin-dependent kinases (CDKs) → if CKIs have mutations, the RB pathway is disrupted → cancer
How does RB function in relation to E2F, p21, p53, and Cyc/CDK4?
What are the two main functions of p53?
- Two functions of p53
- Activates transcription of p21: stops cell cycle and allows for DNA repair
- Activates expression of pro-apoptotic proteins (Bax)
What is an inhibitor of p53 and what does it result in?
- Inhibitors of p53
- MDM2 – binding to p53 leads to degradation and downregulation of transcription
What are the three consequneces of p53 mutation or loss?
- Cell loses ability to produce CKIs that inhibit CDKs and block the cell cycle to allow for DNA repair
- Cell loses ability to undergo apoptosis and die
- Loss of p53 increases genomic instability – increase in accumulation of additional mutations due to lack of repair mechanisms
Does tumorigenesis require one route or multiple routes?
- Multiple routes of acquire hallmark capabilities to the same endpoint: cancer
- Does not occur in specific order
- Mutations increase in age
Describe the fundamental pathway of colon cancer as an example of a cancer that takes multiple pathways to produce tumors.
- Colon cancer: Beta-catenin (APC) → Ras Pathway → TGF-beta → p53
- Each step has different genetic paths that end in colon cancer
What does the rate of tumor progression depend on (4 things)?
- Cell number
- Rate of cell division
- Mutation rate (genomic instability)
- Selective advantage of a particular mutation