Oncogenes Flashcards
Name 4 types of mutation that can produce oncogenes from proto-oncogenes.
1) Point mutation
2) Chromosomal translocation
3) Gene amplification
4) Insertional mutagenesis
What is a point mutation?
A point mutation is a change in a single nucleotide that leads to a change in the amino acid sequence of a protein product, resulting in activation of the protein or inability to be regulated.
Example: RAS
What is a missense mutation?
A missense mutation is a change of a single base that results in a change of a single amino acid.
What is a nonsense mutation?
A nonsense mutation introduces a stop codon, leading to premature termination of protein synthesis.
What happens with a mutation in a splice junction?
A mutation in a splice junction may prevent correct splicing events, potentially missing out whole exons from mRNA.
What is the effect of mutations in regulatory elements?
Mutations in regulatory elements, such as promoters and enhancers, can lead to overexpression of mRNA and protein products.
What is a frameshift mutation?
A frameshift mutation occurs when a point mutation leads to a shift in the reading frame, altering all downstream amino acids.
What is chromosomal translocation?
Chromosomal translocation is the rearrangement of genetic material between different chromosomes, which may place a proto-oncogene under a more active promoter or fuse it with another gene.
Example: BCR-ABL
What is the Philadelphia BCR-ABL translocation?
The Philadelphia BCR-ABL translocation involves a translocation between chromosomes 9 and 22, fusing the ABL proto-oncogene with the BCR gene, leading to upregulated tyrosine kinase activity and driving the development of chronic myeloid leukaemia (CML).
What is gene fusion?
Gene fusion occurs when two genes combine to form a hybrid gene that produces a chimeric protein with oncogenic properties.
Example: PML-RARA
What is the PML-RARA fusion?
The PML-RARA fusion results from a translocation between chromosomes 15 and 17, fusing the ML gene with the RARA gene, disrupting normal retinoic acid signaling and blocking cell differentiation, leading to leukaemia.
What is gene amplification?
Gene amplification involves the production of multiple copies of a proto-oncogene, leading to overexpression of the gene and excessive amounts of normal protein, driving uncontrolled proliferation.
Example: HER2
What is the role of HER2?
HER2 is a receptor tyrosine kinase involved in cell growth signaling; its amplification leads to excessive cell signaling and breast cancer development.
What is insertional mutagenesis?
Insertional mutagenesis occurs when viral DNA is inserted near a proto-oncogene, leading to its overexpression or activation.
Example: Insertion of viral DNA near MYC
What is the effect of deletion mutations?
Deletion mutations are frequently associated with tumour suppressor genes and do not cause a gain of function.
What is the difference between oncogenes and proto-oncogenes?
Proto-oncogenes produce proteins that require growth factors for normal growth, while oncogenes are independent of growth factors, leading to malignant growth.
What are some oncogenic families?
Oncogenic families include growth factors, growth factor receptors, receptor tyrosine kinases, signal transduction proteins, and transcription factors.
What are Ras genes?
Ras genes include three versions: H-ras, K-ras, and N-ras, which encode for guanine nucleotide binding proteins (p21ras) and are involved in cell signaling.
What is the role of p21ras?
p21ras is a GTPase switch protein that regulates the duration of signals transduced from upstream receptor tyrosine kinases.
What happens when Ras genes are mutated?
Mutations in Ras genes can lead to a conformational change that reduces interaction with GTPase activating proteins, resulting in prolonged active GTP-bound states and increased activation of Ras pathways.
What are RHO and RAC?
RHO and RAC are small GTPases involved in maintaining normal epithelial polarity and cell junctions; their overexpression can lead to tumorigenesis and metastasis.
What are some Ras-directed therapies?
Ras-directed therapies target multiple pathways, including PI3K, AKT, RAF/MEK inhibitors, and EGFR inhibitors.
What is the significance of KRAS or NRAS mutations?
If KRAS or NRAS genes are mutated, cancers will not respond to Ras-targeted therapy.
What are receptor tyrosine kinases?
Receptor tyrosine kinases can bind to growth factors, cytokines, and hormones, with over 60 different classes including EGF and VEGF.
What are the structural features of receptor tyrosine kinases?
Receptor tyrosine kinases have extracellular ligand binding domains, a short hydrophobic transmembrane region, and an intracellular tyrosine kinase domain.
What mutations can affect receptor tyrosine kinases?
Mutations in the active site of receptor tyrosine kinases can block transforming activity, leading to constitutive activation.
What is Myc?
Myc is a nuclear oncogene and transcription factor that regulates the expression of many genes and is involved in various cellular processes.
What are the regulators of MYC?
MYC transcription regulators include Hedgehog, WNT, Notch, and JAK-STAT, while TGFB decreases MYC expression.
What are some therapeutic strategies targeting MYC?
Current strategies include small molecule inhibitors targeting MYC or MYC/Max, though they have low specificity and metabolic stability.
What is C-FOS?
C-FOS expression is rapidly enhanced by proliferative stimuli and produces a protein that forms a complex with c-jun, known as the transcription factor AP-1.
What happens when C-FOS is overexpressed?
Overexpression of C-FOS can induce osteosarcoma in mice.
