final - molecular biology of neoplasia 1 and 2 Flashcards
name three types of genes involved in cancer
- oncogene
- tumor suppressor gene
- caretaker gene
what is a protooncogene?
Gene that encodes a protein that stimulates or mediates cell proliferation; normal counterpart to an “oncogene;” typically activated by gain of function mutations
what is an oncogene?
Activated proto-oncogene, via either mutation or aberrant expression (over-expression or ectopic expression via chromosome rearrangement) that can promote cell growth in absence of normal mitogenic signals (autonomous proliferation); roughly 100 identified
example of a growth factor protooncogene
v-sis (these are rare)
what is an autocrine stimulation loop?
when a cell is stimulated to produce both a GF and its receptor simultaneously (PDGF/PDGF receptor)
what types of proteins can be encoded by oncogenes? (6)
- growth factors
- growth factor receptors
- signal transduction proteins
- nuclear regulation factors
- cell cycle proteins (cyclins)
- steroid type growth factor receptors
most common way for oncogene to affect growth receptors
- over expression of normal receptor
- ex. EGF-R family over expressed in 80% of squamous cell carcinomas
why are tumor suppressor genes (TSG) referred to as recessive oncogenes?
both alleles must be knocked out, which differentiates them from oncogenes
name some types of tumor suppressor genes
- transcription factors
- cell cycle inhibitors
- signal transduction molecules
- cell surface receptors
explain loss of heterozygosity (LOH) in TSGs
- almost all familial cancer involves one TSG mutation. When the complement allele is mutated there is loss of heterozygosity
- usually recombination or nondisjunction
- point mutation rare because usually repaired
what proteins regulate Rb?
cyclin D/CDK
what does Rb do?
- regulates G1/S phase transition
- key negative regulator of cell cycle
- shuts down E2F which is a TF for genes that promote cell cycle progression
what effect does a mutation in Rb have?
- removes key negative regulator of cell cycle
- LOH in Rb seen in many types of cancers
what does p53 do?
- induces apoptosis upon DNA damage
- guardian of the genome
- induces CD inhibitor p21 which shuts everything down at G1 and G2 and allows time for repair
- apoptosis through BAX if repair fails
result of p53 mutation
- in 50% of cancers
- increased mutation rate
unique quality of p53 mutations
can be a dominant negative allele, knocking out the other allele
why do some cancers over express p53?
a common mutation is MDM2 oncogene which increases the half life of p53
two mechanisms for evading apoptosis
- dysregulation of anti-apoptotic signals
- loss of pro-apoptotic signals
what is senescence and how can it be avoided?
- normal process by which cells enter G0 and stop dividing
- loss of Rb or p53 can circumvent this and multiply until crisis
what is immortalization
a cell finds a way to avoid senescence, for example by reactivation telomerase
what is required for angiogenesis?
- increased ratio of angiogenic inducers to anti-angiogenic regulators, knowns as “angiogenic switch”
- can happen during wound healing
- induced by cancer cells
name some common angiogenic inducers
- VEGF
- bFGF
define the steps that lead to tumor metastasis and the proteins involved (8 steps)
1) detachment and decreased cellular adherence: loss of cadherins
2) matrix degradation: increase of metalloproteinases and decrease in TIMPs
3) cell matrix attachments: integrins
4) angiogenesis: VEGF/VEGF receptors
5) motility and migration: GFs, cytokines, matrix molecules
6) vascular extravasion: integrins, host platelets, fibrin, and clotting factors
7) avoiding immune surveillance: cloaking of tumor antigens, inactivating leukocytes
8) survive and proliferate: first capillary bed? homing mechanism?
briefly explain monoclonality and clonal evolution
- mutations get passed on and subsequent divisions have additional mutations. can look at early lesion and find origin of mutations.
