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Canc > Cancer 2:Oncogenes and tumour supressor genes > Flashcards

Cancer 2:Oncogenes and tumour supressor genes Flashcards

1
Q

What is the cancer cell phenotype (hallmarks of cancer)

A
  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
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2
Q

State the cell cycle and the amount of time in each

A

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

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3
Q

How long does the cell cycle occur for

A

22hrs

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4
Q

What is the purpose of cycle checkpoints

A

growth arrest ensures genetic fidelity

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5
Q

What are the cycel checkpoint

A

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

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6
Q

Which proteins are accumulated and destroyed during the cell cycle

A

Cyclins, cycle dependent kinases, cycle dependent kinase inhibitors

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7
Q

What drives a cell through a checkpoint

A

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

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8
Q

What are proto-oncogenes

A

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

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9
Q

What is the difference between proto-oncogene and oncogene

A

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

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10
Q

What can be abnormal about an oncogene

A

aberrantly expressed, over-expressed or aberrantly active.

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11
Q

Outline the methods of oncogene actiation

A
  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)
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12
Q

By what mechanism does oncogene activation then cause abnormal protein activity

A
  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)

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13
Q

What is the philalphia chromsome

A

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

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14
Q

How are signal transduction proteins relvant in cancer

A

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

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15
Q

Give types of receptors which could be protooncogenes

A

Nuclear/cytosolic receptor

Tyrosin kinase receptor

G-protein coupled receptor

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16
Q

How does each signal transduction protein affect proliferation

A

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

Tyrosine kinase (phosphorlation cascade–> proliferation)

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

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17
Q

Give examples of proteins in each of the proto-oncogenes

A

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

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18
Q

What does RAS do

A

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

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19
Q

How can RAS go wrong

A

Mutant RAS fails to dephosphorylate GTP and remains active.

This then keeps on stimulating RAF and thus proliferation

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20
Q

How does RAS and RAF work

A

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

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21
Q

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

A

Because it is now damaged.

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

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22
Q

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

A

Tyrosine kinase

Mechanism of activation: overexpression/C-terminal delection

Breast, colon, lung

Protein in the cytoplasm

23
Q

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

Give examples of human cancers associated with this gene

A

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

24
Q

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

Give examples of human cancers associated with this gene

A

Transcription factor

Mechani of activation:
Overexpression/ deletion

Location of protein is nuclear

Human cancers: Lung

25
Q

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

A

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

26
Q

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

A

BOTH: function is G protein, point mutation is mechanism of activation and location is cytoplasmic

Ha-RAS: bladder
Ki-RAS: colon/lung

27
Q

What is a tumour supressor gene

A

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

28
Q

Give an example of a tumour supressor gene

A

Retinoblastoma protein

29
Q

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

A

T… they both have 2 copies

30
Q

DIFFERENTIATE tumour supressor and oncogene in terms of mutation or deletion

A

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

31
Q

Outline the features of inherited cancer susceptibility

A

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.

32
Q

How were tumour supressor genes

A

Due to inherited cancer susceptibility

33
Q

What is retinoblastoma

A

Malignant cancer of developing retinal cells.

34
Q

Outline the two types of retinoblastoma

A

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.

35
Q

Explain the cause of hereditary retinoblastoma protein

A

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.

36
Q

Outline the functional classes of tumour supressor genes

A

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
37
Q

Outlne the function of p53 tumour suppressor gene. How can it be activated .

Give examples of human cancers associated with this gene

A

Cell cycle regulator

Nuclear

Many (colon, breast, bladder, lung etc)

38
Q

Outlne the function of BRCA1 tumour suppressor gene. How can it be activated .

Give examples of human cancers associated with this gene

A

Cell cycle regulator

Nuclear

Breast, ovarian, prostate

39
Q

Outlne the function of PTEN tumour suppressor gene. How can it be activated .

Give examples of human cancers associated with this gene

A

Tyrosine and lipid phosphatase

Cytoplasmic

Prostate glioblastoma

40
Q

Outlne the function of APC tumour suppressor gene. How can it be activated .

Give examples of human cancers associated with this gene

A

Cell signalling
Cytoplasmic
Colon

41
Q

Outlne the function of p16-INK4A tumour suppressor gene. How can it be activated .

Give examples of human cancers associated with this gene

A

Cell cycle regulator

Nuclear

Colon and others

42
Q

Outlne the function of MLH1 tumour suppressor gene. How can it be activated .

Give examples of human cancers associated with this gene

A

Mismatch repair

Nuclear

Colon /gastric

43
Q

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

A

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

44
Q

What is p53 usually bound to and what is the effect

A

MDM2… usually bound to p53, and this makes p53 inactive

When instruction to release p53 from MDM2, p53 becomes active

45
Q

What signals p53 to become released from MDM2

A 
Oxidative stress
NO 
Hypotxia 
Ribonucleotide depletion 
Mitotic apparatus dysfunction 
Oncogene activation 
DNA replication stress 
Double-strand breaks telomere erosion
46
Q

What happens when p53 is released

A

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

47
Q

What can activated p53 do

A

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

Sever stress:
senescene
apoptosis

48
Q

What is APC tumour supressor gene associated with

A

Familial adenomatous polyposis coli

49
Q

In FAP what is the genetic change

A

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

50
Q

What is APC involved in

A

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

51
Q

Outline the route to cancer in colon cancer

A

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

52
Q

Compare oncogene and tumour supressor gene

A

…..

53
Q

What is meant by critical gene target

A

in 90% of the genome, mutations don’t matter.

In critical gene targets…. TSG/proto-oncogenes, can be problematic

Canc (16 decks)

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