Biology 3 - Cancers are Genetic Diseases (Keith Spriggs)

Question 1

How are growth signals transduced?

Answer 1

By signalling pathways; involving the products of oncogenes and tumour suppressor genes

Question 2

How are the effects of tumour suppressor genes and oncogenes ultimately observed?

Answer 2

In gene expression changes

Question 3

What is a gene?

Answer 3

It is not universally agreed; for the purposes of this module it is a functional unit of inherited DNA. In mammals, one gene encodes for one protein. 
We have two copies of every gene, one maternal and one paternal.

Question 4

What are oncogenes?

Answer 4

Aberrant (mutated) versions of proto-oncogenes.
Proto-oncogenes act in healthy cells to promote proliferation and survival. If proto-oncogenes are inappropriately activated or over-expressed (e.g. by mutation) then they become oncogenes.

Question 5

What are tumour suppressor genes?

Answer 5

The products of tumour suppressor genes protect against cancer initiation and progression.
Pro-apoptotic
If tumour suppressor cells are inactivated or repressed (e.g. by mutation), cancer is more likely.

Question 6

How is DNA translated into protein?

Answer 6

Gene encoding for one protein (a.k.a a sequence of nucleotides)
RNA polymerase transcribes to pre-mRNA; this has to undergo splicing to remove introns. Exons are ligased and then translated to protein.

Question 7

How are genes regulated?

Answer 7

– Chromatin remodeling
– Transcription
– mRNA processing (splicing, stability)
– microRNAs
– Translation (protein synthesis)
– Post translational modifications

Question 8

What is ‘Epigenetics’? Give some examples.

Answer 8

Changes that affect gene expression without changing DNA base sequence. 
Histone modifications (acetylation or methylation)
DNA modifications (cytosine methylation --> promotor repression)

Can be inherited by daughter cells
Alter the accessibility of DNA for transcription

Question 9

What is chromatic?

Answer 9

DNA packaged and wrapped around histones

Question 10

What determines how tightly packed chromatic are?

Answer 10

Modification of histone tails e.g. by acetylation and methylation determines how tightly packaged the DNA is

Question 11

What is associated with ‘open’ chromatin domains?

Answer 11

Acetylation

Question 12

What is associated with ‘closed’ chromatic domains?

Answer 12

Methylation

Question 13

What need to remain free of histone in the chromatic complex?

Answer 13

Transcribed DNA that is upstream to allow RNA polymerase II complex to assemble.

Question 14

What are HDAC inhibitors?

Answer 14

Histone Deacetylases (HDACs) remove acetyl groups from histones and induce p21.
HDACs are therefore important, attractive drug targets (Vorinostat, Romidepsin, Panobinostat).

Question 15

What are the effects of HDAC inhibitors in cancer?

Answer 15

HDAC inhibitors are anti-angiogenesis and promote apoptosis. they also induce p21 that leads to cell-cylce arrest/differentiation.

Question 16

How is transcription controlled?

Answer 16

Transcription factors positively and negatively regulate how much mRNA is made for each gene.
Transcription factors and mediators cooperate to direct RNA pol II to start transcribing the gene.

Question 17

What factors can transcription be affected by?

Answer 17

The amount of transcription of a gene often determines the amount of protein expressed.
Transcription can be affected by changes in protein levels (e.g. transcription factors)
Changes in DNA structure (e.g. histones, DNA methylation)
Changes in DNA sequence (e.g. mutation of transcription factor binding sites).

Question 18

What is the role of p53?

Answer 18

It is a tetramer, transcription factor that binds to target promoters to regulate transcription
Detects when things are wrong and prevents proliferation (so this role gives it tumour suppressor properties).

Question 19

How does p53 perform it’s regulatory role?

Answer 19

p53 tetramers bind (along with other transcription factors i.e. p21, BAX and p53R2
Down regulates proto-oncogenes such as VEGF and MYC

Question 20

What happens if p53 is mutated?

Answer 20

Can be oncogenic

Question 21

How is RNA processing control maintained?

Answer 21

Splicing

Question 22

How can the splicing of Rb happen?

Answer 22

Retinoblastoma is a tumour supressor that inhibits transcription factors necessary for cell cycle progression.
If a single base mutation happens, the reading frame of RNA shifts and exon 22 can be spliced meaning that Rb is removed.
Exon 22 is missed giving rise to non-functional protein

Question 23

What is UTR?

Answer 23

Untranslated region

Question 24

What are microRNAs?

Answer 24

Short RNA molecules that don’t code for anything but that can bing to complementary 3’ UTRs of target mRNAs.
They can inhibit translation (protein synthesis)
They can cause mRNA degradation.

Question 25

What are microRNAs that inhibit tumour suppressors?

Answer 25

Oncomirs

Question 26

What are microRNAs that inhibit oncogenes?

Answer 26

Tumour suppressor miRs

Question 27

What happens in mutations occur in mIRs or the binding sites?

Answer 27

Regulation cannot be maintained by the mIRs

Question 28

What kind of mutation gives rise to Breast Cancer caused by BRCA1?

Answer 28

Mutation in BRCA1 3’ UTR changes the binding site for mIR-320 and so the microRNA can no longer maintain regulation.

Question 29

How is translation regulated?

Answer 29

Complex control of gene expression

Question 30

How do oncogenic mutations affect translation?

Answer 30

Increase the activity and abundance of ribosomes and translation factors
Via the MTORC pathway downstream of EGFR

Question 31

What does a C –> T mutation in the 5’ UTR of MYC gene cause?

Answer 31

Increased ribosomal recruitment and leads to the increased synthesis of the oncoprotein MYC

Question 32

What changes to post-translation modifications can cause cancer?

Answer 32

p53 function will be affected by PTMs

Ubiquitination (addition of ubiquitin by MDM2) targets p53 for degredation