Unit 5 - From Oncogenes and TSGs to Drugs Flashcards Preview

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Flashcards in Unit 5 - From Oncogenes and TSGs to Drugs Deck (93)
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1

genetic disease

irreversible

SNP

gross chr rearrangement

2

epigenetic

reversible - affects ways in which genes can be transcribed, how many copies of mRNA you can make

DNA methylation - affecting gene exp

histone modifications - methylation, acetylation - affecting gene exp

3

Point mutations

single nucleotide base changes

present in DNA, transcribed into RNA - can result in the encoded protein

4

nonsense mutation

altered codon encodes a termination codon

inappropriate termination of translation

shortened (truncated) protein

5

missense mutation

 

altered codon encodes a different AA

protein will contain an incorrect AA - missense mutation

could result in a non-functional (most) or hyperactive protein

6

silent mutation

altered codon encodes for the same AA

7

gross chr rearrangement

increased/decreased copy numbeer and gene expression

8

how is DNA organised

into chromatin by DNA binding proteins (histones)

9

Nucleosomes and histones

Protein in middle - DNA around

tails are piece of protein of histones - stick out - highly modified - charged

10

changes in chromatin conformation

11

what is RB

a transcriptional repressor

12

RB pathway

RB binds to the transcriptional activator E2F

E2F promote the expression of genes involved in cell proliferation

mutations in both alleles of RB1 lead to the retinal cancer -retinoblastoma

RB1 is a tumour suppressor

RB pathway is de-regulated in virtually every human cancer

13

role of INK4 family

14

2 types of genes altered in cancer cells

oncogenes e.g. myc, ras, abl

protein products act as ACCELERATORS of cell division or promote the cancer phenotype

tumour suppressor genes (TSG) e.g. RB, p53, BRCA1, BRCA2

protein products normally act as BRAKES on cell division or counteract the cancer phenotype

15

inheritance pattern - oncogenes vs TSGs

oncogenes = dominant

TSGs = recessive

16

what is RAS

a proto-oncogene and a central node of multiple pathways relevant to cancer

Mediates signalling through tyrosine kinase receptors

In order to activate another pathway

Survival - cell cycle progression - when active, promotes phenotypes related to cancer

17

normal vs mutant RAS gene

this mutant protein lacks GTPase activity, so it is active (on) all the time

18

mutations in RAS gene - what does the gene encode

what does mutation lead to

encodes RAS GTPase protein

leads to production of an altered RAS protein that binds GTP but cannot break it down to GDP

so RAS protein is active (on) all the time

RAS signalling pathway is continuously activated

cell proliferation is stimulated - promotes tumour formation

19

prevalence of mutations in RAS

20

c-MYC and Burkitt's lymphoma

cancer of what type of cell

type of mutation

results in

cancer of lymphocytes - common in parts of Africa

caused by translocation of gene for c-MYC transcription factor

c-MYC gene translocated from chr 8 → chr 14

enhanced production of c-myc protein

stimulates cell proliferation - tumour formation

21

how does Myc regulate proliferation

through CDKs

Myc is a TRANSCRIPTION FACTOR

Protein that binds to DNA in order to promote transcription

Works with MAX to activate transcription of genes

Transcribe - cyclin D and CDK4 (promote cell cycle progression)

Excess of kinase it binds and sequesters the KIP protein - causes its degradation - cyclin kinase inhibitor - inhibits cyclin E

MYC + MAX = transcriptional activator

However when myc binds MIZ1 it is a transcriptional repressor

22

MYC + MAX =

transcriptional activator

but when myc binds MIZ1 it is a transcriptional repressor

23

MYC promotes function of

CDK4

promotes inhibitor

24

Li-Fraumeni Syndrome

pattern of inheritance

rare cancer-prone syndrome

inherit 1 mutated copy (allele) of p53

somatic mutations in other copy (allele) of p53 gene

early onset of variety of cancers - blood, breast, bone, lung, skin

both copies (alleles) of a TSG must be inactivated for a phenotype to result

p53 gene codes for p53 protein - named bacuase protein is 53 kDa - transcription factor

25

how are cellular stress signals mediated

by the p53 transcription factor

Downstream of a lot of signalling - tells cells we're under stress - lack of O2, loss of signalling factors etc

26

how does a mutated p53 react in response to DNA damage

loss of ability to arrest cell cycle progression after DNA damage

cell continues to divide in the presence of DNA damage

increase in mutations in genome - genome instability

cells lacking p53 also fail to undergo apoptosis (cell death) after DNA damage

  • because transcription of certain gene products required for apoptosis does not occur
  • also become resistant to some chemotherapeutic agents

27

what is required to cause most cancers

multiple lesions

e.g. model of progression of colorectal carcinoma

sequence of genetic events in progression of normal epithelial cell to carcinoma

28

tumours are __________

heterogenous

can spread

cycling and resting cells

genetic info can vary in cells of the same tumour

29

therapeutic potential

30

MOA of nitrogen mustards

in use

DNA alkylation

cyclophosphamide