23 - RTKs in Cancer Flashcards
(36 cards)
What can multiple RTK inputs cause?
Multiple RTK inputs can cause cells to divide, replicate DNA, and undergo cytokinesis to create two new cells
What do RTK inputs stimulate?
- They stimulate survival pathways through the activation on PI3K and PKB
- Stimulate cell differentiation which is important in specialisation of cells for example differentiation of blood cells into red and white
What happens if you remove growth factor stimulation?
When you remove growth factor stimulation this causes cells to die which is also a regulated response, there are two types: apoptosis and necrosis
What happens to RTKs during cancer?
What happens during cancer is there is hyperactivation of stimulation of RTKs, often in the absence of ligand
o So, in this case what happens is the cells lose their ability to die, we get uncontrolled promotion of cell survival, cells undifferentiate so they return to a simpler state and divide uncontrollably
What research has been done in oncogenes and cell growth?
Considerable effort has been made to characterise the signal transduction pathways involved in the control of cell growth and proliferation by growth actor and oncogenes
What has the study of cell transformation lead to?
The study of cell transformation by oncogenes has led to many advances in the elucidation of normal cell proliferation control pathways
What work first suggested a link between growth factors and growth of cancer cells?
The first suggestion of a link between growth factors and growth of cancer cells came from work suggesting that transformed cells might synthesise and secrete growth factors which would act in an AUTOCRINE or PARACRINE fashion to stimulate growth
What can mutations result in (relating to oncogenesis)?
There are normally growing cells but sometimes mutations occur that lead to aberrant cell proliferation
* So uncontrolled cell proliferation we get expansion of the population and they start to swamp the normally growing cells so they become the minor growing population
What can be amongst the senescent cells?
Amongst the senescent cells we begin to generate cancer cells and they can proliferate
o At this point we have loss of tumour suppressors which normally control proliferation
o There is also expansion of malignant cells
Timeline of the discovery of oncogenes
1916- Francis Peyton Rous
- Rous sarcoma virus
- Ground up cancerous tumour from a chicken and filtered out everything larger than a virus
- The resulting liquid produced cancer when injected into other chicken
1966- Rous shared the Nobel Prize for Physiology or Medicine for his work
1976- J. Michael “Moke” Bishop and Harold Varmus discover oncogenes
-Identified the src gene as a cancer-causing gene is Rous sarcoma virus
- Whose normal functions have gone awry
1989 - Bishop and Various win the Nobel Prize in Physiology or Medicine
What was most important about the discovery of oncogenes?
More important than the technical details was the revolution this caused in thinking about cancers
How many known oncogenes are there?
There are now over 80 known oncogenes that have been identified
Quote by J.M. Bishop?
“If a cellular gene can cause cancer, then aberrations of normal cellular metabolism can cause cancer” -J.M. Bishop
What are oncogenes?
Mutated versions of normal regulatory genes (proto-oncogenes)
Where are oncogenes from?
From host genome (c-onc) or viruses (v-onc)
Proto-oncogene activation to an oncogene can occur by:
o Point mutation
o Overexpression/ amplification
o Deletion of regulatory domains
o Gene fusion (chromosomal translocation)
What is more dominant: an oncogene or porto-oncogene?
An oncogene is dominant over a proto-oncogene
What are oncogenic targets?
Oncogenic targets are genes that regulate cell growth and proliferation (including apoptosis and cellular senescence)
List the protein products of oncogenes (what can be mutated?)
- Growth factors (e.g., PDGF and EGF)
- Protein-tyrosine kinases (e.g., Src)
- Growth factor receptors (e.g., PDGF and EGF receptors)
- G proteins (e.g., Ras and Gs mutations)
- Cytoplasmic kinases (e.g., RAF)
- Survival proteins (e.g., PI3-kinase)
- Nuclear proteins (e.g., androgen receptor)
What is the history of RTKs as oncogenes?
- RTKs have a long history of involvement in human cancer
- It was originally found that the protein sequence of the EGF receptor was closely related to the protein encoded by the transforming oncogene v-ERB-B of the avian erythroblastosis virus
- This suggests that the erythroblastosis virus has hijacked part of the EGF receptor involved in signal transduction after growth factor binding
Structure of the EGF receptor and the v-Erb-B protein
- The EGF receptor contains two cysteine rich extracellular domains and a cytoplasmic tyrosine kinase domain
- The vErbB protein lacks most of the extracellular portion of the EGF receptor required for EGF- binding but possess all but the final 32 C-terminal cytoplasmic amino acids
How many times has cancer been observed in RTKs?
Increased receptor signalling (cancer) has been observed in at least 10 (of 20) RTK familiar
Why has cancer been observed in RTKs?
This is a result of CONSTITUTIVE ACTIVATION by:
o Receptor over-expression
o Somatic mutation (genetic alterations)
o Receptor amplification (autocrine/paracrine loops)
Explain the different methods of constitutive activation
- MUTATION of the receptor to truncate it (point mutations) which lead to its activation
- OVER EXPRESSION of the receptor itself leading to receptor clustering and activation in the absence of ligand
- Autocrine growth factor loops, overproduction of ligand and they act on neighbouring cells to overstimulate transcription (RECEPTOR AMPLIFICATION)
