Basic Science Flashcards
Differences between oncogenes and tsgs
Oncogene mutations at specific hot spots- TSG mutations throughout gene
Oncogene almost always missense and only one allele affected
TSG both alleles affected so get loss of heterozygosity
Which mutations are mutually exclusive with BRAF mutations?
KRAS
The two most commonest mutated oncogenes in human cancer?
PI3KCA
KRAS
What happens when CDK4 phosphorylates Rb protein?
Lowering of transcription factors essential for progression of cell cycle
What is senescence?
Permanent arrest of cell division
What is microRNA?
RNA 19-24 nucleotides long
Affect gene expression and protein translation
What does the INK4 family do in relation to the cell cycle?
Inhibits it!
What is a proto-oncogene?
A normal genetic element in a human which is normal and is found replicated in a virus which can cause malignant transformation
It seems likely that the oncogene went from the eukaryote to the virus
What are the three major DNA checkpoints?
G1/S
G2/M
S-phase
What is microRNA?
RNA 19-24 nucleotides in length
Affects gene expression and protein translation
Participates in processes like apoptosis
Can look at miRNA arrays and correlate with clinical things like survival!
What is the peptidome?
The low molecular weight part of the proteome
Peptides or protein fragments less than 50,000 daltons
Secreted from tumours
Float around circulation bound to carrier proteins
Looking into whether the patterns of the peptides can correlate with clinical things
Which genetic familial cause of CRC is associated with resistance to 5FU?
HNPCC
Lifetime risk of CRC with HNPCC?
60-80%
What is the prognosis like for CRC with MSI?
Favourable
But potentially associated with resistance to 5FU
What kind of drug is azacitidine?
DNA hypomethylating agent
Which cell type does neuroblastoma arise from?
Primitive sympathetic nervous system cells
Malignancy of Schwann cells?
Oligodendroma
What is Z line in oesophagus?
Border between squamous and glandular epithelium - looks like bright red dots on endoscopy
What is Philadelphia chromosome?
T(9;22) BCR-ABL fusion protein
If present in ALL it is a poor prognostic factor
Ames test
Tell how mutagenic something is
Use salmonella
See how quickly salmonella mutates in presence of mutagen
The hallmarks of cancer (six) plus two enabling and two emerging
Independence from growth signals Inhibition growth inhibitory signals Unlimited replicatory potential Evasion of apoptosis Angiogenesis Invasion and metastasis enabling : genome instability and mutation and tumour promoting inflammation Emerging:- evading immune destruction and disregarding cellular energetics
What are the stages of the cell cycle?
G0 G1 S G2 M
What are CDKs?
Cycline dependent kinases have to bind cyclin to be activated
When in the cell cycle are the major DNA damage checkpoints?
G1 to S (before make DNA)
During S
G2 to M (before start mitosis)
What is the R point in the cell cycle?
The restriction point (R) is a point in G1 of the animal cell cycle at which the cell becomes “committed” to the cell cycle and after which extracellular proliferation stimulants are no longer required.
Does TGF beta promote cell cycling or cause cell cycle arrest?
Cell cycle arrest. Cell is reponsive to TGF beta signalling before the R point is reached in G1- after that the cell is committed to completing the cell cycle
What is the effect of having mutated and non functioning Rb?
Mutated dysfunctional Rb can’t bind to E2F. The E2F is free to activate transcription of genes that are needed to enter S phase IE unprogrammed cell division
What are telomeres made from?
Repetitive DNA sequences and associated proteins called the SHELTERIN complex
What is telomerase?
Makes your telomeres longer by adding nucleotides
What is a reverse transcriptase?
An enzyme that makes DNA from RNA
What are the two pathways of apoptosis called?
Intrinsic - internal chemical/physical damage eg DNA damage or oxidative stress. Mediated by the mitochondria
Extrinsic -extra cellular signals called death factors
What are caspases?
Cysteine rich aspartase proteases
They are important in both the intrinsic and extrinsic apoptosis pathways
Which of the apoptosis pathways is mediated by the mitochondria
Intrinsic
Describe the extrinsic pathway of apoptosis?
Death factors bind to death receptors inducing conformational change of Intracellular domain and oligodimerisation. Conformational change exposes DEATH domains on their tails
Intracellular proteins FADD and TRADD bind to them
These proteins attract pro-caspase 8 start the caspase cascade
Name two main activators of angiogenesis
and four inhibitors
2 Activators VEGF and FGF (il 6 and 8)
4 Inhibitors Thrombospondin, interferon, angiostatin, endostatin
Which VEGF is bound by bevacizumab?
VEGF a
What do angiopoeitins bind to and what is their job?
Angiopoeitins bind to TIE receptors
Stabilise developing blood cells
What is the role of Flip in the apoptosis pathway?
It stops apoptosis by binding to the Intracellular protein FADD (which in turn is the one that normally binds to death receptors)
What is apoptosis?
Efficient programmed cell death where the cell swiftly shrinks, blebbing of the plasma membrane, chromatin condensation, intranucleosomal dna fragmentation. The cell corpse is then engulfed by other cells.
Name two gene mutations that help evade apoptosis?
P53
BCL-2
What is the function of bcl2
In mitochondria it suppresses apoptosis by inhibiting BAC And BAX
BAC and BAX are involved in apoptosis by when they are activated by DNA damage (via p53) they recruit SMAC and cytochrome c activating the caspase pathway
What is the Warburg effect?
Cancer cells seem to prefer aerobic glycosis to aerobic respiration even though aerobic respiration actually generates more ATP per molecule of glucose
This is despite the fact that cancer cells have normally functioning mitochondria
Which malignancy has c-myc amplification?
Small cell lung cancer, 10% of cases
translocation involving myc found in the majority of Burkitts lymphoma
What is c-myc?
A gene that codes for a transcription factor
How do the names of antibodies tell you their origin?
O= murine Xi= chimeric eg cetuximab, rituximab Zu= humanised eg trastuzumab, bevacizumab, Alemtuzumab, pertuzumab Mu= fully human eg panitumumab
What is NF kappa B?
A transcription factor
Name the two major mismatch repair mechanisms of the cell
Nucleotide excision repair
Base excision repair (PARP involved in this)
How are double stranded DNA breaks repaired?
Homologous recombination
What is the DNA repair problem in Xeroderma pigmentosum?
NER nucleotide excision repair
What is the DNA repair problem in Lynch syndrome?
Mismatch repair
What is the DNA repair problem in Bloom syndrome?
Helicase deficiency
What does aurora B kinase do?
Helps sister chromatids to separate
What is the difference between cell quiescence and senescence?
In cultured cells
Senescence is permanent - caused by serious stuff like prolonged DNA damage, telomere shortening or oncogene activation
Quiescence is temporary- can re enter the cell cycle. Usually if cell is starved, high density growth etc it goes into quiescence
What are cyclins?
The positive regulatory subunits of cyclin dependent kinases
Which cyclin and CDK are responsible for getting cells into and out of mitosis?
CDK1 and cyclin B
What happens to levels of cyclins during the cell cycle?
Fluctuate. Hence why called cyclins
Level of CDKs does not fluctuate during the cell cycle
Which cyclin is the first one to rise in the cell cycle during G1?
Cyclin D (dares to go first!) Associates with CDK4/6 to drive cell through G1
What is the purpose of the G1 checkpoint?
Cell cycle arrest if there is DNA damage- don’t want it to be replicated if going into S phase
What are the 4 mechanisms of CDK regulation?
Association with cyclins
Association with CDK inhibitors
Phosphorylation : can be both positive and negative
How are levels of cyclins regulated?
Cyclin gene transcription Protein degradation (by the proteasome)
Name the two main families of CDK inhibitors?
P16 INK family
P21 (Cip/Kip) family
What is the role of Rb in cell cycle progression?
RB regulates the transition from G1 to S phase
Normally RB binds E2F sequestering it and stopping it interacting with transcription factors
Mutations in the NBS1 gene result in which syndrome? What malignancy is more common?
Nijmegen breakage syndrome 1
Increased risk of NHL
Microcephaly
What is type 1 cell death?
Apoptosis
What are the three ligands of the death receptor pathway
TNF alpha
Fas
TRAIL
What percentage of tumour cells can give rise of metastasis?
Less than 0.01%
Where is CXCR4 seen and what does it do?
Expressed on the surface of circulating tumour cells
Interacts with CXCL12 expressed on certain organs eg LN, liver, lung bone
Involved in metastasis
