Oncogenes Flashcards
What is an oncogene?
A gene which has the potential to cause cancer when under specific conditions.
What is a tumour virus?
A DNA or RNA virus that is acutely or slowly transforming and can cause cancer within cells.
Why doesn’t the integration of a retrovirus into a host’s genome kill the cell?
The provirus needs to be transmitted onto daughter cells during mitosis to form viral particles.
What is a slowly transforming virus?
A virus which causes cancer after many months of viraemia through the insertional activation of an oncogene.
What is a acutely transforming virus?
A virus which causes a tumour rapidly due to a viral oncogene.
What is the genetic difference between slow and acutely transforming viruses?
Acutely have a viral oncogene.
What is a viral oncogene?
They are homologous to cellular DNA in hosts, with similar nucleotide sequences suggesting that one was derived from the other.
What did the discovery of viral oncogenes result in?
The discovery of human oncogenes, as the homologous sequences must also have the potential to cause cancer.
What is the link between the Simian Sarcoma Virus and oncogenes?
The V-sis oncogene that causes a sarcoma from the infection of SSV, is homologous to the beta chain of PDGF. PDGF normally functions via paracrine signalling but was found to also have autocrine signalling. Self stimulation increases the risk of cancer.
What evidence is there that PDGF is linked to sarcomas?
Osteosarcomas and gliomas where found to secrete PDGF and have PDGF recpetors for self stimulation.
What is a GF and which are at risk of causing cancer?
GF control cytoplasmic signalling to drive proliferation.
EGF, IGF, TGFalpha and beta, Haematopoietic GF
What is the belief now about the association of retroviruses and cancer?
Retroviruses are not involved in cancer, except HTLV1, but led to the discovery of similar oncogenes in humans.
How was the role of in c-Myc Bursal lymphomas found?
Avian leukosis virus causes lymphomas in chickens. It is a slowly transforming retrovirus that integrates close to c-myc gene. This shows that there is a homologous sequence to the virus near c-myc. Insertion at c-myc leads to deregulated gene expression.
What is the lag phase?
The time interval before a random provirus insertion occurs sufficiently close to c-myc by chance.
What happens when c-myc expression is deregulated?
The normally low level, regulated protein causes high levels of transcription of its protein, leading to constitutive activation of c-myc.
What causes Burkitt’s lymphoma?
A chromosomal translocation between the c-myc gene on chromosome 8 with an Ig gene on chromosome 2, 14 or 22. Causes constitutive synthesis of c-myc due to the Ig gene enhancer. = B cell tumour
What is the normal function of myc?
It is a TF, produced at a transient pulse for proliferation after GF stimulation. It heterodimerises with Max to activate transcription of growth genes.
What is the function of Max homodimerisation?
Predominates in non-stimulated cells to repress transcription.
What is the problem with gene amplification?
An increase in the number of copies of a gene leads to over expression and can be used as a prognostic indicator and can cause early relapse.
How are RTK and TK domains implicated in the development of cancer?
An AA change of partial deletion in its genes can cause constitutive TK activity, independently to GF = anti-apoptotic and proliferation signals
Gene amplification and overexpression can lead to homodimeristaion and constitutive activation
Give two examples of cancer caused by overexpression of genes.
HER2 in breast cancer
EGFR in lung cancer
What is pp60cSrc?
A non-receptor TK that does not require an extracellular signal. It has an intracellular SH2 domain that binds target proteins. Src induces intracellular signalling.
How Src associated with cancer?
Found to have increased activity in >50% of cancers due to overexpression e.g. colon, liver, lung, breast pancreatic.
A mutation can lead to the loss of tyrosine-527 which acts as a block for the signal transducing conformation. Loss of this locks TK in its signalling form.
What is a chimeric protein?
A protein with aberrant functions as a result of chromosome translocations within the coding region of a gene. This causes transcription to start as one protein but finish as another. It deregulates TK for uncontrolled proliferation.
What is the translocation involved in promyelocytic leukaemia?
PML-RARalpha
Which is the most frequently mutated oncogene in cancer?
Ras (H,K,N)
What does the ras oncogene code for?
p21ras - G protein regulated by GTP binding.
How does ras become constitutively active?
Mutations within 12, 13, 61. Can lead to loss of intrinsic GTPase activity e.g. in carcinogen induced cancers in smokers
How can mutations in oncogenes be tested?
Cell transfection assay identifies transformed loci.
Why is lag present in tumour development?
Multiple oncogenes and mutations are involved in the development. Lag occurs whilst the other genetic mutations arise, altering the genotype.
How might an oncogene be altered?
Altering the function through: -Point mutations at specific sites -Chimeric fusion through translocation Altering expression: -Chromosomal translocations that change the regulatory sequences influencing it
