Unit 1 Flashcards
Does one mutation always cause cancer?
no, could casue cancer or could just kill cell
What must cancer have?
- a mutation
- sustain proliferative signaling/ sustained angiogenesis
- tissue invasion and metastisis
- evasion of apoptosis
- promoting gene instability leading to mutation
- limitless replicative potential throuhg increased telomerase activity
- self-sufficiency of growth signals
- insensitivity to anti-growth signals
- avoidance of immune system to evade apoptosis
- tumor promoting inflamation
What is angiogenesis?
- production of new blood vessels into tumor for a nutrients
How do cells sustain proliferative signaling?
- cancer cells activate TF to produce angiogenesis
- stimulators such as VEGF or decrease production of growth inhibitors like throbospondin
How does tissue invasion and metastasis happen?
- decrease of cell to cell adhesion through mutant cadherins
- increased cell motility
- ## increase of protease production degrading ECM
What are cadherins?
- protein binding in ECM
What is the seed soil hupothesis?
- metastisis is product of favorable interactions between tumor cells (seed) and organ microenvironment (soil)
What is metastasis?
- colonization of secondary organs
What is a pro of metastasis?
- new resources, more space, possibility for evolution and new mutation
What is a metastasis cons?
- new environment (unknown) more chance of detection, could lose all exploring cells
What is the ras-mapk pathway?
- growth factor bound to receptor
- clustering and autophosphorylation of receptor
- activation of ras
- activation of protein kinases (RAS, MEK, MAPK)
- synthesis of cyclin and CDK activating cell cycle
- then is potentially oncogenic
What is the Jak-Stat pathway?
- binding of ligand to receptor causes receptors to cluster together and phosphorylation Jak molecules
- jack p phosphorylates receptor
- stat molecules interact with R-P and become phosphorylated
- stat-p joins to form dimers
- stat-dimers enter nucleus and bind to DNA of specific genes
- transcription of genes activated
- protein production to stimulate cell proliferation
How do cells avoid apoptosis?
- typically due to p53 mutation
- p53 is typically in every cell but both p53 copies must be mutated
- could be rare or you could inherit mutated p53
- dna is made unstable by dna polymerase mutations, environmental toxins
What is p53?
- genome gaurdian, protein/ tumor supressor gene that is alerted to potential mutations and then tells DNA polymerase to fix or tells cell to kill itself
In a healthy cell what does p53 do?
- p53 binding always stop cells when properly phosphorylated
How do cells obtain limitless replicative potential through increased telomerase activity?
- telomere length is maintained
- 90% of cancer cells have increased telomerase activity
What do telomeres do?
- encode for specific proteins but do protect the genes tahat do
What happens to telomeres as we age?
- decrease telomerase activity
What is the relationship between replicative abilty and telomerase activity?
directly proportional
How do cell have self-sufficiency of growth signals?
- doesn’t rewuire growth signals to continue cell division, makes their own growth signals
- they don’t need something else to tell them when to grow, they just do
- ex. mutant ras protein leading to uncontrolled ras=map K pathway
How do cells maintain insensitivity to anti-growth signals?
- typically during g1 and related to cyclins
- helps evade cell checkpoints
- most true antigrowth signals are g1
How to cells avoid immune system detection and evade apoptosis?
- can camouflage with host cells proteins and receptors to look normal
- could spread to bone marrow to prevent production to finding agents
What does tumor promoting inflammation do?
- cancer cells take over normal inflammatory response of immune cells are subverted to tumor-promoting cells
- now immune system is helping tumor
- cells now secrete pro-survival, pro-migration, and anti-detection factors
- decrease cancer adherance to host cells so they can migrate and colonize.
What does cancer cells de-regulating cellular genetics do?
- often affects metabolism
- increased metabolic rate could be good and bad because available resources will be used faster
What is the difference between carcinagens and mutagens?
carcinagons are known to cause cancer and mutagens are thought to potentially cause cancer
How are carcinogens dealt with?
- removal, education, prevention
WHat is the aimes test?
- if it mutates when blue is added it is a mutagen, the more it grows the more dangerous/ toxic it is
If something is amutagen will it become a carcinogen?
- no
What is an oncogene?
- gene which in certain circumstances can transform a cell into a tumor cell
What is a proto-oncogene?
- normal gene that can become an oncogene due to mutation or increased expression
How does a proto-oncogene transform until a oncogene?
through a mutation
- proto-oncogene is still a normal gene until it mutates
Who named the oncogene?
- Todaro and Robert in 1969
Who confirmed the oncogene and SRC?
- first confirmed oncogene in 1970
- peyton rous discovered SRC in 1911
Who discovered proto-oncogenes?
- Stehlin, Bishop, Varnus
What do proto-oncogenes?
- help regualte cell growth and cell differentiation thorugh secreted growth factors
- cell surface receptors
- signal transduction
- DNA binding nuclear proteins (also TF)
- involved in mitogenic signalsregulating cell cycle
How do proto-oncongenes become oncogenes?
- viral integration in DNA
- mutation within proto-oncogene or in regulatory region like promoter causing change in protein structure
- increse in amount of protein/ gene amplification
- chromosomal translocation or chromosomal abnormality
- point mutation
What does viral integration in DNA work?
- increases protein activity in levels
What does increase in amount of protein and gene amplification do?
- increases prtein levels nad activity
- gene amplification
What is gene amplification?
- normal growth stimulating excess copies of RAS (a TF)
What does chromosomal translocation or abnormality do?
- increases protein levels and activity
- burkits lymphoma bc of increased myc (tf) produciton
What does a point mutation do?
- increases protein activity but protein levels stay the same
- ras to oncogene because of point mutation in GTP activation site
What are BCL2?
- a family of apoptotic genes (form cancer if messed with) involved with lymphoma and leukemai
What is the difference between hodgekins and non-hodgekins lymphoma?
- hodgekins is typically more treatable
- hodgekins ktypically affects younger people
- both types refer to b cells
What is the result of oncogene activation?
- flooding of cells with replicaiton signals leading to uncontrolled stimulation of intermediary growht pathways which leads to cell growth because of increase of TF leading to cancer
What are the cell signal transduction mechanisms?
- 2ndary messengers
- receptor types
- gf
- hormones
What is the general flow of cell signaling?
- receptor ligand binding
- signal transduction from secondary messengers
- cell response
- changes in gene expression
What is the signal amplification pathway?
- reception to transduction to response
- each next step = more molecules activated
What are the advantages to a signal amplification pathway?
- only need a little bit to get a lot (efficient)
- fast
- energy conserving
- multiple regulatory checkpoints
What is a g-protein coupled receptor?
- transmembrane
- membrane bound
- had ligand and binding site
- triggers events when bound
- kinases phosphorylate
What is the g-protein coupled receptor pathway?
- ligand to receptor to uncoupling g protien to enzyme to second messenger to responses
Why do we care about calcium concentrations?
- membrane potential and ion gradients
- NT release
- muscle contraction
DO cancer cells have mutated TKR ?
could
- this would increase ras-map-k increasing cell growth and mitosis and decreasing apoptosis
How does steroid signaling work?
- steroids go through plasma membrane and sneak through cytoplasm to bind
- still binds to ligand in cytoplasm
- sneaks through pores and binds directly to dna to cause translation
What do hormones trigger?
- trigger cell growth and division
What does estrogen + cause ?
breast cancer
What is her2+?
- breast cancer discovered in 1982
- human epithelial growth factor receptor
- easy converts to oncogenes
What are tumor suppressor genes?
- repression of gens that are essential for continuing cell cycle
- coupling the cell cycle to DNA damage (if DNA is damaged, cell cycle halts
- if damage can’t be repaired cell should initiate apoptosis
What are the types of tumor suppressor genes?
- gatekeeper genes
- caretaker genes
- landscaper genes
What are gatekeeper genes?
- decrease cell proliferation
What are caretaker genes?
- genes involved in DNA repair and chromosome maintenance
What are landscaper genes?
genes endcode gene products that control the micro-environment in which cells grow
- think about pH, tmep, ion conc., nutrients
What are examples of gatekeeper genes?
- RB, p10
What are examples of caretaker genes?
p53
What are examples of landscaper genes?
- cadherin protein coding
- ecm protein genes
What do BRCA and 1+2 do?
- blocks entry of cell into S phase by inducing CDK inhibitor p21
What is NF1?
- inhibits RAS by absence of growth factor
- inactivation of NF1 allows RAS to be constitutively active which promotes unregulated cell growth
What is VH1?
- normal VH1 inhibits elongin which helps transcription
What causes Li fraumeni syndrome?
- p53 mutation in germline
What is li fraumeni syndrome?
- cancer runs in my family
- inherited predisposition to develop cancers in many organs due to germ line mutations of p53
- affected individuals can carry germline mutation
- if mutation occurs in 2nd allele of a cell can lead to cancer of that issue
What is RB gene?
- typically a childhood gene
- in the back of the eye
- fertilized egg has 50% chance of inheriting of RB gene (then it only takes 1 hit)
- fertilized egg has no mutation, one copy gets mutated early on (that one copy then increases number of mutated ones so more mutated in time
- as tumor increases in size it puts pressure on optic nerve and can lead to blindness
- not metastatic
What is the APC gene?
- responsible for hereditary colerectal cells
- functions simmilar to RB gene
- B-catenin activates certian TF that activate several genes included in myc
- mutant APC can’t bind B-cat to down regulate its activity
What is AKT?
- oncogene regulated by p10 tumor suppressor gene
What is p10?
- phosphatase that suppresses cell growth in absence of growth factor
- p10 inhibits kinase
What happens to mutated p10?
- mutated p10 goes to pip3 increase in activity and AKT activity increases
- p10 then removes phsophate from pip3-pip2- no akt
hormone and growth factors bind to phosphorylate to cell growth - akt is typically what’s mutated
mutated p10= no off switch and p53 can’t work
What is p53?
- guardian of the genome
- activates DNA repair enzymes
- arrests growth by keeping cell cycle in g1/2 point while dna damage is repaired
- initiates apoptosis if DNA damage can’t be repaired
- eventually mutated in most cancers
