Cycle 9 - Development and Cancer Flashcards
What are silent mutations?
Mutations where the codon changes but the amino acid produced is the same (redundancy), so there is no obvious effect
What are missense mutations?
Missense mutation occur when a codon changes into another codon that makes another amino acid
- Difficult to predict consequences
What are nonsense mutations?
Nonsense mutations occur when a codon changes into a stop condon, ending translation early
- If it is early in the sequence, it likely will destroy the protein
- If it is at the end, maybe it will have no effect, just some end piece is lost
What are frameshift mutations?
Frameshift mutations are insertion/deletions of a base paur, which changes all the amino acids after it
- Likely to be the most severe
- The protein could be too short; a stop codon could be created due to shifting
- THe protein could be too long; the original stop codon could be lost due to shifting
- However, the splicing of introns/exons would not be affected unless the mutation is inserted directly into the splce signal
State the characteristics that make Drosophila an attractive model system
- Genetic control of pattern formation is well documented in Drosophila and apply to many other species as well as humans
- Development is quick
- A complex multicellular organism
- Cheap to raise
- Similar genome as humans
Describe the main stages of Drosophila embryonic development
- Begins at fertilized egg
- Cell doesn’t divide, the nucleus does (unusual)
- Cellularization (movement to the sides, formation of separate pole cells)
- Gastrulation: segmentation
- Hatches into larvae, then eventually it forms a pupae, and the becomes a fly
Describe the role of maternal effect genes in Drosophila development
Explain Bicoid and Gurken
-
Maternal effect gene: is transcribed in mother but translated in offspring (pack eggs with mRNA and proteins)
- mRNA is stopped from translating via masking proteins which come off when the offspring is ready
- Bicoid (anterior posterior) is an important gene
- Mothers pack one end with bicoid mRNA: lots of bicoid = head region
- Gurken (dorsal ventral) is an important gene
- These genes help orient the nuclei to tell them what genes to express
What are segmentation genes?
Segmentation genes are turned on by bicoid, and divide the embryo into segmeents/stripes
What are homeotic genes?
Homeotic genes are turned on by segmentation genes, and create the proper structure in a sigen segment (ex., legs, wings)
Describe the structure/function of the “homeobox” in homeotic genes
- A homeobox is a 180 bp sequence within the homeotic genes coding for a DNA-binding domain (i.e., it is a transcription factor)
- Transcription factors are proteins that help turn specific genes “on” or “off” by binding to nearby DNA.
- Ex., a homeotic gene in the leg segment is a transcription factor that stimulates expression for leg-specific genes
Describe the significance of evolutionary conservation of Hox genes
- Hox genes are a subset of homeobox genes
- Many organisms have all of their hox genes together in the genome in the same order of which they are expressed
- This shows that it is a very ancient genetic system
Describe the function of caspases
Caspases are proteases; they chop up essential proteins and assist in program cell death
- Describe the path of programmed cell death cascade (C. elegans)
- C. elegans cells are transparent so it is useful to study
- As it develops, 1 cell becomes 959 cells, but 131 cells die as part of normal development using CED genes
- CED genes (cell death genes) are found in every cell and are part of a protein cascade
- The death signal is received by the death signal receptor
- CED-9 is inhibited from blocking CED-4
- CED-4 can activate CED-3
- CED-3 kills the cell by activating proteases and nucleases
- Note that these signals can also be internal (ex., DNA damage of infection can trigger apoptosis)
Describe the role of programmed cell death in Drosophila development
- In drosophila, one genome code for a larva first, and then a fly
- It does this through imaginal discs that sit in the larvae, which expand to create legs and wings when it receives a blast of hormone
- All the unneeded larvae tissue gets destroyed through apoptosis
- Unique Drosophila gene called the reaper, works with the grim protein to trigger cell death
- In the promoter of reaper, there are multiply types of control (pictured)
- p53: when DNA repair is suppresed, the reaper is gene expressed
State the most common cancers in Canada
Why might cancer mortality rates vary across geographical areas in Canada?
- Breast cancer, prostate cancer, colon cancer, lung cancer are most common
- Variation of geographcial mortality due to
- Access to healthcare
- Different genetic populations, age difference, lifestyle difference
- Different environment
Describe why identical twins may have different cancer indicidence
- Environmental factors (carcinogens)
- Lifestyle choices
- Epigenetic effects: twins have very similar DNA methylation patters (epigenetic) at 3 yrs, but at 26 yrs they have a large difference
Describe how DNA methylation can regulate gene expression
- DNA methylation is epigenetic (changes over time due to environmental factors)
- DNA methylation adds a methy group to a gene segment, repressing it by calling the HDAC (histone deacytelase complex) that increases the tightness of histones
State some hallmarks/characteristics of cancer cells
- Sustaining proliferative signalling
- Don’t die when they are supposed to
- Evading growth suppressors
- Activating invasion and metastasis
- Enabling replicative immortality
- Inducing angiogenesis (make new blood vessels)
- Resisting cell death
- Tumours are constantly evolving and changing under selection pressure
What is heritability?
Describe the heritability of cancer in humans
Heritability: the proportion of phenotypic variability we can attribute to genotypic variability
Heritability for cancer is 0.27-0.42
Describe mechanisms by which a virus could cause cancer without causing mutation
- The virus could introduce genes that disrupt cell cycle control or turns regulatory genes off in the host
- Stop cyclin from being degraded, stimulate EGF (growth factor) receptors, stimulate EGF activity, etc.
What are cyclin/CDK complexes?
- CDK are cyclin dependent kinases
- A kinase is a constitutive (constant) protein that phosphorylates other proteins to activate or inactivate
- CDK are only functional if they are bound to cyclins, which are produced cyclically
- This is post-translational modification
- They enable the cell to progress through the cell checkpoints
What are driver mutations?
- Driver mutations are mutations that confer a growth advantage on cells
- These include
- Mutations that stimulate growth and survival
- Mutations that reduce genome maintenance
- Mutations that affect cell fate
Describe cell fate and how a driver mutation can occur
- Firstly, cancer cells are de-differentiated (resemble undifferentiated embryonic cells)
- Cell fate is represented by a landscape
- High topography = instability = cell type will easily change into something different
- Normally development follows the blue line which is barred from changing state by the purple hills (genes that regulate growth)
- The red line is an abnormal trajectory caused by getting over the barrier; “cancer is just another cell fate”
Describe proto-oncogenes, tumor suppressor genes, and oncomirs in normal development
- Proto-oncogenes are genes in normal cells that encode various kinds of proteins that stimulate cell division
- Examples are growth factors and transcription factors that regulate the expression of the structural genes for progression through the cell cycle
- Tumour suppressor genes are genes in normal cells encoding proteins that inhibit cell division, ex., TP53
- These genes slow down cell division at the end of embryogenesis and regulate cell cycle
- Oncomirs are miRNA that regulates cell cycling
Describe proto-oncogenes, tumor suppressor genes and oncomirs in cancer
Proto-oncogenes can become deregulated and become oncogenes; genes that stimulate the cell to progress to the cancerous state of the unregulated cell cycle
- Ex., EGFR (growth factor)
- EGF is received by the EGFR (extensive pathway)
- If upregulated, it will stimulate extreme cell growth which can lead to cancer
Tumor suppressor gene mutations result in a decrease in the inhibitory action of the cell cycle controlling proteins they encode
Oncomirs
- Inappropriate expression of miRNA can promote cycling
- Different microRNAs are at play in different tumor types, use this to diagnose cancer type
- Overexpressed miRNA genes → can block target mRNAs important in inhibiting cell proliferation
- Inactivated miRNA genes → overexpression of proto-oncogenes
State the role of the TP53 gene
- A tumour suppressor
- It is a transcription factor that
- Increases DNA repair
- Interacts with cyclin/CDK (arrests cell by blocking it)
- Causes apoptosis
- Mutated TP53 → inactive p53 protein, results in Cdks that are continually active in triggering cell division regardless of conditions
Explain why cancer incidence tends to increase with old age
- More chances for mutations as we age
- You need 2 mutated alleles, so the longer you live the higher the probability that both alleles will be mutated
- Exposed to more carcinogens
- Telomeres are shorter
Describe embryogenesis
- Embryogenesis requires rapidly dividing cells that then need to stop once a certain point is reached
- Genes are required to stimulate cells that divide rapidly and others that cause cells to stop dividing rapidly
- This is controlled at the cell cycle checkpoints
Consider Drosophila parents that are both heterozygous for a loss of the bicoid allele. What proportion of their children will have no heads?
All of them will have heads: the child’s genes do not determine whether they will have a head or not, this is dependent on only the mother since the maternal effect genes are transcribed in the mother
- Thus, 1 working bicoid allele in the mum = all babies have heads
- If the mother has no working bicoid allele, no babies have heads
