4 classes of genes that are the principal targets of cancer causing mutations
- Proto-oncogenes (growth promoting)
- Tumour suppressor genes
- DNA repair genes
- Apoptosis-regulating genes
What are the 8 hallmarks of cancer?
8 fundamental changes in cell physiology
- Self-sufficiency in growth signals
- Insensitivity to growth -inhibitory signals
- Altered cellular metabolism
- Evasion of apoptosis
- Limitless replicative potential (immortality)
- Sustained angiogenesis
- Ability to invade and metastasize
- Ability to evade the host immune response
- Growth factors
- Growth factor receptors
- Signal transducers
- Transcription factors
- Cell cycle proteins
Most important kind of growth factor receptor?
Tyrosine kinase receptor
Give examples of the 3 kinds of oncogenic mutation in growth factor receptors
- Point mutation in ERBB1 results in constitutively activated EGFR in lung cancer
- Amplification of ERBB2 results in constitutively activated HER2 receptor in breast cancer
- Gene rearrangement resulting in EML4-ALK fusion receptor causes constitutive activation of the ALK tyrosine kinase receptor in lung adenocarcinoma
Tyrosine kinase receptor activation activates what signal transducer?
What are the two different arms activated by RAS?
- RAS-RAF-MAPK-MYC-D cyclins
T or F: activated RAS can completely substitute for receptor tyrosine kinase activity
What is the most common type of RAS mutation?
What family of proteins does RAS belong to?
Membrane associated G proteins
What do GAPs do?
GAPs are GTPase activating proteins. Once activated, RAS has intrinsic GTPase activity that dephosphorylates GTP (causing RAS activation) to GDP (causing RAS inactivation). GAPs amplify this intrinsic GTPase activity by more than 1000-fold, terminating signal transduction by RAS and preventing uncontrolled RAS activity.
Give an example of a GAP that is mutated in a familial tumour syndrome
NF1 - Neurofibromin 1 - is a GAP that is mutated in neurofibromatosis type 1.
What are the functions of AKT?
- Activate mTOR - a sensor of cellular nutrient state, which when activated stimulates protein and lipid synthesis
- Inactivate pro-apoptotic molecules BAD and FOXO
What is the function of PTEN?
Inhibit actions of PI3K
T or F: nonreceptor tyrosine kinases activate different pathways to receptor tyrosine kinases
Give an example of a nonreceptor tyrosine kinase proto-oncogene
ABL on chromosome 9. A BCR-ABL translocation results in consititutively activated ABL and chronic myeloid leukaemia.
Give an example of a nonreceptor tyrosine kinase proto-oncogene point mutation.
JAK2 - relieves the normal dependence of haemopoietic progenitors on signalling by growth factors such as erythropoietin.
The transcription factor most commonly involved in human tumours is?
Mechanisms by which MYC promotes neoplastic cell growth?
- Activate D cyclins which cause progression through cell cycle past the G1/S restriction point
- Enhance ribosome assembly
- Induce metabolic reprogramming and the Warburg effect
- Upregulate expression of telomerase
- Reprogram somatic cells into pluripotent stem cells
Why are defects in the G1/S checkpoint more important in tumorigenesis than defects in the G2/M checkpoint?
Defects in the G1/S checkpoint lead not only to growth dysregulation but predispose to the mutator phenotype.