KINESIOL 1Y03 Lecture Notes - Lecture 14: Apaf1, Retina, Microtubule
23 Jun 2018
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Tumour suppressor genes and oncogenes
Tumour suppressor genes: genes which protect cells from uncontrolled growth hence
inhibit tumourogenesis; both alleles must undergo mutation for malignant change, unless a
germline mutation is present in one allele
Oncogenes: genes that promote oncogenesis; only one allele must be mutated for the gene
to have a role in cancer development
Proto-oncogene: normal gene coding for a protein which regulates cell growth or
differentation often by affecting signal transduction or execution of mitogenic signals, which
can become an oncogene following mutation or amplification
Mutation: change in the normal base sequence of DNA
-can involve a single base (“point mutation”) or involve larger sections of DNA
through deletions, insertions or translocations
-may be silent, even in the coding region, due to the redundancy of the code, though
are more commonly silent if they affect the non-coding region of DNA
-somatic mutations occur in somatic tissue so are nonheritable; they are common
(one per cell division) and are only harmful if they affect certain genes
-germline mutations occur egg/sperm cells and affect all somatic cells of the
offspring; they occur rarely and will cause cancer development only in a specific
tissue or organ
Cancer development is a multistage process involving both germline and somatic
mutations of genes
many mutations in several distinct genes are required for normal cells to become
cancerous; this progressive accumulation explains the age incidence of cancer
all cells in a tumour originate from a single clonal cell but not all have the same genotype
as they are genetically unstable
this genetic instability hence variancy gives rise to selection; cells with the strongest
growth properties are selected
Regulatory mutations
Some of the most important regulatory regions are in the 5’ non-coding flanking
regions
Mutations in promoter sequences (regulate gene) or enhancer sequences (regulate
gene activity) or repressor regions (suppress gene expression) can affect growth in
cancer
e.g. HER2 (growth signaling molecules) over-expression due to gene amplification in
non-coding region of chromosome 17 in breast cancer
Cancer-associated mutations affect:
1) cytokines / growth factors
2) receptor genes
3) cell signaling genes
4) TF genes
5) Cell cycle control genes
6) Cell death/survival genes
7) DNA repiair genes
8) Cellular differentiation genes
Cancer-associated epigenetic factors include:
1) Phosophorylation
2) Dephosphorylation
find more resources at oneclass.com
find more resources at oneclass.com
3) Methylation
4) Demethylation of DNA
5) Cellular exposure to hormones
6) Cellular exposure to carcinogens
Cell cycle disruption in cancer
Tumour suppressor genes act as braking signals during G1 to stop or slow the cell
cycle before S phase
DNA repair genes active throughout the cycle, especially during G2 after DNa
replication, before the chromosome prepares for division
Oncogenes
RAS
Activated in many cancer e.g. CRC
Protein subfamily of small GTPases involved in cellular signal transduction
Enhances cell growth, differentiation and survival
c-myc
over-expressed in CRC, amplified in lung ca and re-arranged in lymphoma
TF which regulates expression of 15% of genes through binding Enhancer box sequences (‘E-
boxes’) thus acting as a classical transcription factor, and through recruiting Histone
AcetlyTransferases (HATs) thus regulating global chromatin structure
CDK4 = familial melanoma
MET = hereditary papillary renal cancer
BCL2 = follicular melanoma
Tumour suppressor genes
Maintain normal cellular processes by:
-Control of cell division (Rb, p53)
-Responses to stress (p53)
-control of signaling pathways (APC)
find more resources at oneclass.com
find more resources at oneclass.com
Document Summary
Tumour suppressor genes: genes which protect cells from uncontrolled growth hence inhibit tumourogenesis; both alleles must undergo mutation for malignant change, unless a germline mutation is present in one allele. Oncogenes: genes that promote oncogenesis; only one allele must be mutated for the gene to have a role in cancer development. Proto-oncogene: normal gene coding for a protein which regulates cell growth or differentation often by affecting signal transduction or execution of mitogenic signals, which can become an oncogene following mutation or amplification. Mutation: change in the normal base sequence of dna can involve a single base ( point mutation ) or involve larger sections of dna through deletions, insertions or translocations. Cancer development is a multistage process involving both germline and somatic mutations of genes. Many mutations in several distinct genes are required for normal cells to become cancerous; this progressive accumulation explains the age incidence of cancer.
