Week 5- Genetics of cancer Flashcards
what is differentiation
during embryogenesis, tissues and organs are formed in a regulated process
what is terminal differentiation
when cells are not programmed to divide
what does it meant have undergone transformation
if a cell lose control of their own division giving rise to abnormal cell masses called tumours
what is a benign tumour
if the tumour is not invasive
what are malignant tumours
if the tumour is invasive
what is metastasis
when the tumour spreads to other organs by the blood or lymphatic vessels
what are the 4 phases f the cell cycle
- gap (G1)
- synthesis (S)- DNA replication occurs
- gap 2 (G2)
- mitosis (M)- dividing cells separate
what does the gap phases allow
cell time needed to replicate proteins and organelles
what happens at cell-cycle check points
internal and external environments are monitored to ensure conditions are favourable for divisions
what are cell-cycle check points regulated by
cyclins and cyclin-dependant kinases (CDK)
what is the role of CDKs
they are activated when they bind to cyclins and then phosphorylate proteins required for cell progression
what happens to cyclins to ensure the cell cycle goes in one direction
thet are rapidly degraded after they have completed their job
how is cell cycle entry regulated in complex organisms
via an intracellular signalling system that responds to extracellular signals
what do extracellular signals include
growth factors produced by other cells (paracrine) or by the cells itself (autocrine)
what do extracellular signals tigger
the activation of signal transduction pathways that ultimately switch on the genes required for cell cycle progression
what are cancer critical genes
defects in genes required to regulate cell division causing cancer
what are the 2 types of cancer critical genes
- proto-oncogenes
- tumor suppressor genes
what are proto-oncogenes
genes which cause cancer from gain of function mutations. when mutated to cause cancer they are called oncogenes
what are tumour suppressor genes
genes which cause cancer from loss of function mutations
what is sous tacoma virus (RSV)
a retrovirus- must convert its RNA genome into DNA to be integrated
what is c-src
a proton-oncogene which activates cellular pathways involved in cell growth and division
what happens if c-src is mutated to become oncogenic
signalling pathways become hyperactive, resulting in increased proliferation, survival, and invasion leading to transformation
what are the classes of oncogenes
- growth factors (EGF)
- growth factors receptors (EGF receptors)
- membrane associated G proteins (RAS)
- cytoplasmic signal transducers (MEK)
- nuclear transcription factors (MYC)
how can the gain of function in proto-oncogenes arise
- excessive amount of protein
- abnormal protein
- novel protein in excess
how were tumour suppressor genes understood
from the study of retinoblastoma
what is retinoblastoma
childhood cancer which occurs from transformation of immature neural cells in the retina
what happens in sporadic and familiar retinoblastoma
- sporadic: tumours form in only one eye
- familial: tumours form in both eyes and often earlier, suggesting an underlying predisposition
what is Rb
a tumour suppressor which regulates G1-S phase cell-cycle checkpoint
what is p53
a major tumour suppressor described as the ‘guardian of the genome’
what is the function of p53
arresting the cell cycle in response to DNA damage
what happen to p53 in normal cells
constantly degraded due to interaction with Mdm2 (an E3 ubiquitin ligase)
what happens to p53 and Mdm2 when DNA is damaged
response is activated where Mdm2 and p53 are phosphorylated
what happens to p53 after it has been phosphorylated
functions as a transcription factor where it transcribes p21
what does p21 protein do
prevents binding of cyclin D to CDK4, inactivating the complex.
This results in loss of Rb phosphorylation and arrest at G1.
This arrest allows the cell to repair the damaged DNA.
what happens if DNA damage is catastrophic and cannot be repaired
p53 will induce a type of programmed cell death called apoptosis
what is Bax
a pro-apoptotic factor induced expression by p53
what does the phosphorylation state of p53 depend on
whether p53 induces cell-cycle arrest or apoptosis
what would the loss of 53 allow
cell division to occur without repairing DNA, can lead to further genetic instability, allowing further mutations to accumulate and cancer to develop and increases survival of cancer cells
who is more predisposed to a range of cancers
people with gremlin mutations in DNA repair genes
what are telomeres
sequences at the end of DNA which get shorter with each round of cell division
what do critically short telomeres trigger
cell to stop dividing
how do cancers continue to divide
cancers reactivate telomerase, an enzyme which extends telomeres during division, making the cell immortal
what is telomerase reverse transcriptase (TERT)
catalytic component of the enzyme telomerase
what do the mutations in TERT promote found in cancers create
new binding sites for ETS and GABP transcription factors
how do people get TERT promoter mutations
genetically inherited
what are micro RNAs (miRNAs)
type of non-coding RNA that control gene expression by degrading target mRNAs
how is a RISC complex formed
when miRNAs associate with proteins
what happens to mRNAs bound to the RISC complex
either cleaved and degraded or transitionally repressed
how can miRNAs be tutor suppressors
if they trigger deflation if oncogene mRNAs
how can miRNAs be oncogenes
if they trigger degradation of tumour suppressor mRNAs
how do normal cells become metastatic
when multiple mutations are needed in a range of genes
