WEEK 13 (Cancer) Flashcards
What is Epigenetics?
The study of chromosome-associated changes that affect gene expression but do not alter the nucleotide sequence of DNA
What are the properties of Epigenetic effects?
- Can be inherited from one cell to its progeny cells
- May be present in either somatic or germ-line cells
What are examples of Epigenetic modifications?
- DNA Methylation
- Histone modifications (acetylation & phosphorylation)
What is DNA Methylation responsible for?
- Gene silencing associated with parental imprinting
- Heterochromatin gene expression
- X chromosome inactivation
What are Proto-oncogenes?
Encode transcription factors that stimulate expression of other genes, signal transduction molecules that stimulate cell division, and cell-cycle regulators that move the cell through the cell cycle
How do Proto-oncogenes function?
- Normal cells become quiescent and cease division -> REPRESS the expression of most proto-oncogenes or modify the activities of their products
- In cancer cells -> One or more proto-oncogenes are altered in such a way that the activities of their products cannot be regulated in a normal fashion
What are Tumor-suppressor genes?
Genes whose products normally regulate cell-cycle checkpoints or initiate the process of apoptosis
What happens when Tumour-suppressor genes function normally and when they are mutated?
FUNCTION NORMALLY = Halt progress through the cell cycle in response to DNA damage or growth-suppression signals from the extracellular environment
MUTATED/INACTIVATED = unable to respond normally to cell-cycle checkpoints or are unable to undergo programmed cell death if DNA damage is extensive
What are Ras gene family proteins?
- Encodes signal transduction molecules associated with the cell membrane and regulate CELL GROWTH and DIVISION
- Stimulate the cell to divide in response to external growth factors
How do Ras proteins function?
1) Ras proteins alternate between an inactive and active state by binding either GUANOSINE DIPHOSPHATE (GDP) or GUANOSINE TRIPHOSPHATE (GTP)
2) Growth factor receptors on the cell membrane bind to the growth factor -> Results in AUTOPHOSPHORYLATION of the cytoplasmic portion of the growth factor receptor
3) NUCLEOTIDE EXCHANGE FACTORS migrate to the plasma membrane and cause RAS to release GDPP and bind GTP, activating it -> Ras sends signals through CASCADES of protein phosphorylations in the cytoplasm
4) Activation of NUCLEAR TRANSCRIPTION FACTORS stimulate expression of genes whose products drive the cell from QUIESCENCE into the CELL CYCLE
5) Once signals sent to nucleus, Ras hydrolyses GTP to GDP and becomes inactive
What do mutations that convert Ras protooncogene to an oncogene result in?
Prevent the Ras protein from hydrolysis GTP to GDP and freeze the Ras protein into its “on” conformation -> Constant stimulation of the cell to divide
What is the most frequently mutated gene in human cancers and what does it code for?
TP53 gene
TP53 gene encodes a transcription factor that REPRESSES or STIMULATES transcription of more than 50 different genes
What are the properties of the P53 protein?
- Continuously synthesised but rapidly degraded -> low levels in cells
- Normally bound to MDM2 -> MDM2 tags P53 for degradation and sequesters the transcriptional activation domain of P53 -> Prevents phosphorylations and acetylations that convert the P53 protein from an inactive to an active form
How can heterozygosity occur?
Chromosome deletions/rearrangements
How does Familial Adenomatous Polyposis result in cancer?
Individuals inherit one mutant copy of the APC gene located on the long arm of chromosome 5 (mutations include DELETIONS, FRAMESHIFT and POINT MUTATIONS) -> Normal APC gene product acts as a TUMOUR SUPPRESSOR controlling growth and differentiation -> Presence of heterozygous APC mutation causes EPITHELIAL CELLS of the colon to partially escape cell-cycle control -> Cells divide to form small clusters of cells called POLYPS or ADENOMAS
