Cancer 2:Oncogenes and tumour supressor genes

Question 1

What is the cancer cell phenotype (hallmarks of cancer)

Answer 1

1. Disregards signal to stop proliferating
2. Disregards signals to differntiate
3. Capacity for sustained proliferation
4. Evasion of apoptosis
5. Ability to invade
6. Ability to promote angiogenesis

Question 2

State the cell cycle and the amount of time in each

Answer 2

G1- 10hrs
S- 7.5hrs
G2- 3.5hrs
M=1hrs

Question 3

How long does the cell cycle occur for

Answer 3

22hrs

Question 4

What is the purpose of cycle checkpoints

Answer 4

growth arrest ensures genetic fidelity

Question 5

What are the cycel checkpoint

Answer 5

After G1:

check for cell size/favourable environmental factors

check for DNA damage

After S: none

After G2: check for damaged/unduplicated DNA, check for unduplicated centrosomes

After metaphase of M: check for chromosome attachment to the mitotic spindle

Question 6

Which proteins are accumulated and destroyed during the cell cycle

Answer 6

Cyclins, cycle dependent kinases, cycle dependent kinase inhibitors

Question 7

What drives a cell through a checkpoint

Answer 7

Permanent activation of a cyclin can drive a cell through a checkpoint.

Question 8

What are proto-oncogenes

Answer 8

code for essential proteins involved in maintenance of cell growth, division and differentiation.

Question 9

What is the difference between proto-oncogene and oncogene

Answer 9

following a mutation (1 can be enough!), the protein product no longer responds to control influences

Question 10

What can be abnormal about an oncogene

Answer 10

aberrantly expressed, over-expressed or aberrantly active.

Question 11

Outline the methods of oncogene actiation

Answer 11

1. Mutation in coding sequence (point mutation)
2. Gene amplificatin (multiple gene copies i.e. too much proto-oncogene)
3. Chromosomal translication (chimaeric genes)
4. Insertional mutagenesis (viral infection)

Question 12

By what mechanism does oncogene activation then cause abnormal protein activity

Answer 12

1. Mutation in coding sequence (point mutation) –> ABERRANTLY ACTIVE PROTEIN
2. Gene amplificatin (multiple gene copies) –> OVERPRODUCTION OF NORMAL PROTEIN
3. Chromosomal translication (chimaeric genes)
4. Insertional mutagenesis (viral infection)

3/4 CAN LEAD TO: 
STRONG ENHANCER (increases normal protein level e.g. burkitt's lymphoma) ... strong enhancer from another chromosome during fusion which increaes expression of the protein 

or

FUSION TO ACTIVELY TRNASCRIBED GENE OVERPRODUCES PROTEIN OR FUSION PROTEIN IS HYPERACTIVE (e.g Philadelphia chromosome)

Question 13

What is the philalphia chromsome

Answer 13

Chr 9 ABL switches with the short arm on 22

left behind: 9q+, Ph22q- (with BCR-ABL)

BCR-ABL is powerfullt expressed…. few situations where a SINGLE DNA CHANGING event can cause cancer

Question 14

How are signal transduction proteins relvant in cancer

Answer 14

Proteins involved in signal transduction are potential critical gene targets (proto-oncogenes)

Question 15

Give types of receptors which could be protooncogenes

Answer 15

Nuclear/cytosolic receptor

Tyrosin kinase receptor

G-protein coupled receptor

Question 16

How does each signal transduction protein affect proliferation

Answer 16

Nuclear/cytosolic receptor: (imapcts transcription/translation–> proliferation)

Tyrosine kinase (phosphorlation cascade–> proliferation)

GPCR: (activates kinase casade–> phosphoryation cascade–> proliferation)

Question 17

Give examples of proteins in each of the proto-oncogenes

Answer 17

Tyrosine: membrane: met (heptaocyte growth factor receptor), neu (HER2), inside membrane src, ret

GPCR: membrane: ras, gip-2, inside membrane: raf, pim 1 (confused as I thought ras and raf was tyrosine kinase)

Intraacellular: myc, fos, jun

Question 18

What does RAS do

Answer 18

Ras (on the membrane)

Binds GTP, activating it. This then activates RAF. (inside of membrane) to cause signalling cascade which increases proliferation

Dephosphorylation of the GTP to GDP switches RAS off.

RAF will stop

Question 19

How can RAS go wrong

Answer 19

Mutant RAS fails to dephosphorylate GTP and remains active.

This then keeps on stimulating RAF and thus proliferation

Question 20

How does RAS and RAF work

Answer 20

Ligand binds receptor (e.g. tyrosine kinase)

RAS is tethered to the membrane.

RAS binding GTP will then allow it to bind RAF, activating it.

Dephopsorylation will cause the RAF to dissocaite

Question 21

Why can damage to a single proto-oncogene, not both of the genes, cause cancer

Answer 21

Because it is now damaged.

Having a normal proto-oncogene will not then remove the activty of the oncogene

Question 22

Outlne the function of SRC proto-oncogene gene. How can it be activated .

Give examples of human cancers associated with this gene

Where the product of the gene located

Answer 22

Tyrosine kinase

Mechanism of activation: overexpression/C-terminal delection

Breast, colon, lung

Protein in the cytoplasm

Question 23

Outlne the function of Myc proto-oncogene gene. How can it be activated .

Give examples of human cancers associated with this gene

Answer 23

Transcription factor (for lots and lots of genes including c-Myc which does cyclin D1 and others)

Mechanism of activation: translocation

Location of protein (TF) is nuclear

Human cancers: Burkitt’s lymphoma

Question 24

Outlne the function of Jun proto-oncogene gene. How can it be activated .

Give examples of human cancers associated with this gene

Answer 24

Transcription factor

Mechani of activation:
Overexpression/ deletion

Location of protein is nuclear

Human cancers: Lung

Question 25

What are the two types of RAS and what are they associated with

Answer 25

Ha-RAS and Ki-RAS.... they are G proteins

Question 26

Outline the function of Ha-RAS and Ki-RAS, how are they activated, where are they present and the assoaited human cacners

Answer 26

BOTH: function is G protein, point mutation is mechanism of activation and location is cytoplasmic Ha-RAS: bladder Ki-RAS: colon/lung

Question 27

What is a tumour supressor gene

Answer 27

Typically proteins whose function is to regulate cellular proliferation, maintain cell integrity.

Question 28

Give an example of a tumour supressor gene

Answer 28

Retinoblastoma protein

Question 29

t/f each cell has the same number of copies of proto-oncogenes and tumour supressor genes

Answer 29

T... they both have 2 copies

Question 30

DIFFERENTIATE tumour supressor and oncogene in terms of mutation or deletion

Answer 30

Tumour supressor: Mutation or deletion of one gene copy is usually insufficient to promote cancer. Mutation or lost of both copies means loss of control. need to lose 2 to lose the positive function Oncogene, only one gene needs mutating to gain a negative acton

Question 31

Outline the features of inherited cancer susceptibility

Answer 31

Family history of related cancers. Unusually early age of onset. Bilateral tumours in paired organs. Synchronous or successive tumours. Tumours in different organ systems in same individual. Mutation inherited through the germline.

Question 32

How were tumour supressor genes

Answer 32

Due to inherited cancer susceptibility

Question 33

What is retinoblastoma

Answer 33

Malignant cancer of developing retinal cells.

Question 34

Outline the two types of retinoblastoma

Answer 34

SPORADIC... usually affects one eye, in older individuals. Due to mutations built up over the lifetime HEREDITARY.... Hereditary cases can be unilateral or bilateral and multifocal.

Question 35

Explain the cause of hereditary retinoblastoma protein

Answer 35

Due to mutation of the RB1 tumour suppressor gene on chromosome 13q14. RB1 encodes a nuclear protein that is involved in the regulation of the cell cycle.

Question 36

Outline the functional classes of tumour supressor genes

Answer 36

OVERALL: SUPPRESS THE NEOPLASTIC PHENOTYPE ``` Regulate cell proliferation Maintain cellular integrity Regulate cell growth Regulate the cell cycle Nuclear transcription factors DNA repair proteins Cell adhesion molecules Cell death regulators ```

Question 37

Outlne the function of p53 tumour suppressor gene. How can it be activated . Give examples of human cancers associated with this gene

Answer 37

Cell cycle regulator Nuclear Many (colon, breast, bladder, lung etc)

Question 38

Outlne the function of BRCA1 tumour suppressor gene. How can it be activated . Give examples of human cancers associated with this gene

Answer 38

Cell cycle regulator Nuclear Breast, ovarian, prostate

Question 39

Outlne the function of PTEN tumour suppressor gene. How can it be activated . Give examples of human cancers associated with this gene

Answer 39

Tyrosine and lipid phosphatase Cytoplasmic Prostate glioblastoma

Question 40

Outlne the function of APC tumour suppressor gene. How can it be activated . Give examples of human cancers associated with this gene

Answer 40

Cell signalling Cytoplasmic Colon

Question 41

Outlne the function of p16-INK4A tumour suppressor gene. How can it be activated . Give examples of human cancers associated with this gene

Answer 41

Cell cycle regulator Nuclear Colon and others

Question 42

Outlne the function of MLH1 tumour suppressor gene. How can it be activated . Give examples of human cancers associated with this gene

Answer 42

Mismatch repair Nuclear Colon /gastric

Question 43

What is p53 and why is it different to other tumour suppressor

Answer 43

Although p53 is a tumour supressor gene, mutants of p53 act in a dominant manner and mutation of a single copy is sufficient to get dysregulation of activity. (i.e. this is different.... as if it is an oncogene! Because oncogene usually only takes 1 mutation whereas TSG usually needs to damage 2 copies). Because the damage becomes DOMINANT

Question 44

What is p53 usually bound to and what is the effect

Answer 44

MDM2... usually bound to p53, and this makes p53 inactive When instruction to release p53 from MDM2, p53 becomes active

Question 45

What signals p53 to become released from MDM2

Answer 45

``` Oxidative stress NO Hypotxia Ribonucleotide depletion Mitotic apparatus dysfunction Oncogene activation DNA replication stress Double-strand breaks telomere erosion ```

Question 46

What happens when p53 is released

Answer 46

It works with other p53 proteins to activate either regulation of p53 target genes (in mild and physioligical stress) or of protein-protein interactions in sever stress

Question 47

What can activated p53 do

Answer 47

Mild stress: Metabolic homeostasis/antioxidant defence/DNA repari/growth arrest Sever stress: senescene apoptosis

Question 48

What is APC tumour supressor gene associated with

Answer 48

Familial adenomatous polyposis coli

Question 49

In FAP what is the genetic change

Answer 49

deletion in 5q21 resulting in loss of APC gene (tumour suppressor gene)

Question 50

What is APC involved in

Answer 50

Involved in cell adhesion and signaling in the WNT pathway apc control the activity of b-catenin and thereby preventing uncontrolled growth Mutation of APC is frequent event in colon cancer

Question 51

Outline the route to cancer in colon cancer

Answer 51

Damage to APC-->hyperproliferative state (not cancer yet)--> DNA metholation (K-RAS) --> adenoma --> p53 damage --> carcinoma -->metastasis to liver

Question 52

Compare oncogene and tumour supressor gene

Answer 52

.....

Question 53

What is meant by critical gene target

Answer 53

in 90% of the genome, mutations don't matter. In critical gene targets.... TSG/proto-oncogenes, can be problematic