Cancer Flashcards
What are the six mechanisms by which mutations in DNA can lead to cancer?
Copying errors during replication
Spontaneous cleavage of DNA molecules
Reaction with chemical by-products (free radicals)
Viruses through introduction of viral DNA
Reaction with genotoxic chemicals
Radiation
What is an oncogene?
A gene which has a gain of function when mutated that causes cancer.
Mutation in one gene is sufficient to cause uncontrolled proliferation
What is a tumour supressor gene?
Genes which regulate cell division and promote DNA repair. When mutated causes a loss of function which results in unregulated cell division, failure of DNA repair and failute of apoptosis.
Mutation in both genes required to have a damaging effect
Describe the role of HPV in cervical cancer
HPV is the major risk factor in cervical cancer and infection is associated with cervical neoplasia.
In long-term persistent infection, a part of the viral genome becomes integrated into the host DNA. HPV viral oncogenes E6 and E7 have been shown to be the main contributors to cancer development.
E6 promotes degradation of p53 and interacts with other pro-apoptotic proteins which prevents cell cycle arrest, DNA repair and apoptosis.
E7 binds to pRB in its unphosphorylated state which disrupts pRb-e2F complexes and prematurely induces the cell to enter S phase. E7 also interacts with cyclins and CDKs which promotes progression through the cell cycle.
What errors in growth factor signalling can result in cancer?
Over production of growth hormones
Over production of receptors
Receptors that are constitutively active
Constitutively active ras
Constitutively active kinases
Over production of transcription factors
Over production of cyclins
Name four features that contribute to the increased mutation rate in cancer cells
Failure of apoptosis
Defective DNA repair
Deregulation of the cell cycle
Disruption of mitotic control (genetic instability)
What is the function of pRb?
Acts as a transcriptional repressor at the G1 checkpoint (restriction point) by binding to E2F which prevents activation of transcription
As a cell enters G1 pRb becomes phosphorylated by cyclin D dependent kinases. pRb dissociates from E2F which then is able to activate transcription of DNA pol and other genes critical for G1.
pRb remains phosphorylated for the rest of the cell cycle and is dephosphorylated after mitosis.
What is the function of p53?
p53 is a key regulator in response to DNA damage. It co-ordinates DNA repair, proliferation and apoptosis.
The turnover of p53 is normally rapid, and is blocked by signals that indicate physiologic stress or DNA damage and the protein accumulates in the cell. This stops the cell cycling at G1 so that DNA damage can be repaired and prevents double-stranded breaks arising in DNA. p53 also activates apoptosis by inducing the expression of pro-apoptotic proteins.
Loss or mutation of p53 allows genetically damaged cells to proliferate, decreased repair of DNA damage and results in failure to activate apoptosis.
What are the four mechanisms that regulate CDKs?
- Association with cyclins
- Inhibitory phosphorylation
- Activating phosphorylation
- association with CDK inhibitors
How is DNA synthesis triggered in S phase?
S-phase CDKs are inhibited by CKIs.
G1 cyclin complexes phosphorylate CKI which triggers its degradation
Release of CKI activates S-phase cyclins which phosphorylate the replication complex.
This triggers DNA synthesis
How is progression through the cell cycle regulated?
Progression through the cell cycle is regulated by specific cell cycle checkpoints
Checkpoints are controlled by cyclin-dependent kinases which operate at different points in the cell cycle.
CDKs are controlled by the binding of specific cyclins which are synthesised and degradaded at specific points in each cell cycle. CDKs are inactive when cyclins are not bound.
Active CDKs phosphorylate intracellular proteins which moves the cell through the cycle.
Describe the role of the anaphase promting complex
Anaphase promoting complex controls the levels of the M-phase cyclins as well as other regulators of mitosis by targetting them for degradation.
It also controls the initiation of sister chromatid separation. In metaphase chromosomes align along the equator of the cell and are held together by a protein complex which prevents separation by the mitotic spindles.
APC targets securin which helps inhibit separation and therefore chromatids are able to migrate to opposite poles of the cell.
Mad2 is an inhibitor released when chromosomes are not attached to the spindle which blocks APC
Describe the signalling cascade for mitogenic growth factors
Growth factors bind to RTKs and induce recptor dimerisation. This triggers phosphorylation of receptors.
Adaptor proteins activate ras which activates the MAPK cascade. This results in the phosphorylation of transcription factors and leads to the transcription of G1 cyclins and other target genes.
Promotes cell division
Describe the signalling cascade for inhibitory growth factors
Inhibitory growth factors bind to Ser/Thr kinases and induces receptor dimerisation.
This causes phosphorylation of SMADs which forms a complex with co-SMAD.
The SMAD-co-SMAD complex migrates to thenucleus and activates transcription factors for inhibitory proteins e.g. CKIs
Results in anti-proliferative effects
