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Year 2 - Cancer > Oncogenes and tumour suppressor genes > Flashcards

Oncogenes and tumour suppressor genes Flashcards

1
Q

What are the hallmarks of cancer?

A
  • Ignore signals to stop proliferating
  • Ignore signals to differentiate
  • Capacity for sustained proliferation
  • Evasion of apoptosis
  • Ability to invade
  • Ability to promote angiogenesis
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2
Q

How long is each phase in the cell cycle?

A

G1 - 10 hours
S - 7.5 hours
G2 - 3.5 hours
M - 1 hour

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3
Q

Where are the checkpoints in the cell cycle and why are they there?

A

After G1 - checks for cell size, ensure genetics are normal
After G2 - checks DNA that replicated is not damaged
After M - Checks chromosome is attached to mitotic spindle, then cytokenisis occurs

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4
Q

What are cyclins?

What normally happens in the cell cycle to cyclins and how can permanent activation of cyclins be dangerous?

A
  • Specific proteins accumulate/ are destroyed during the cycle (cyclins, CDKs, CDK inhibitors)
  • Permanent activation of a cyclin can drive a cell through a checkpoint
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5
Q

What are proto-oncogenes?

A

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

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6
Q

What is bad about oncoegenes?

A

The oncogenes can be over expressed, abherrently active or abherrently expressed

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7
Q

What are the different ways in which oncogenes are formed?

A
  • A mutuation. This may produce a gene that codes for an aberrantly active protein
  • Gene amplification (multiple gene copies) so there is a lot more of the protein produced due to amplification, and this is a problem for the cell.
  • Chromosomal translocation (chimeric genes)
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8
Q

Why may gene amplification occur?

A
  • It can occur due to problems with a polymerase protein

- Having multiple copies of a gene will lead to overproduction of the gene product

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9
Q

What are chimeric genes?

A

Genes that are formed by combinations of portions of one or more coding sequences to produce new genes (e.g. the swapping of tips of chromosomes).

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10
Q

When are chimeric genes dangerous?

A
  • This can be a problem if one of the pieces of translocated DNA is a promoter, leading to upregulation of the other gene portion (this occurs in Burkitt’s Lymphoma)
  • Insertional mutagenesis: This can also be a problem if the fusion gene formed produces an abnormal protein (e.g. Philadelphia chromosomes in CML)
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11
Q

What is the Philadelphia chromosome?

A

It is formed by the translocation of chromosome segments from chromosomes 9 + 22.

ABL - chromosome 9
BCR - chromosome 22

Resulting BCR-ABL fusion gene -> development of cancer

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12
Q

What do proto-oncogenes code for?

A
  • Growth factors
  • Growth factor receptors
  • Intracellular transducers (signalling proteins)
  • Intracellular receptors
  • Transcription factors
  • Cell cycle regulatory proteins
  • Cell death regulators
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13
Q

What happens if a GF is abherrent?

A

When it binds it may cause an abherrent response

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14
Q

Give examples of proto-oncogenes, how they are formed, what they do and the cancers they are associated with

A

SRC -> overexpression/deletion, tyrosine kinase, breast/colon/lung

MYC -> translocation, TF, Burkitt’s

JUN -> overexpression/deletion, TF, lung

Ha-RAS -> point mutation, G protein, bladder

Ki- RAS -> point mutation, G protein, colon/lung

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15
Q

What does RAS code for?

A

For a family of proteins such as Ki-Ras and Ha-Ras, which are membrane-bound GTPases that are important in the stimulation of cell proliferation.

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16
Q

How does RAS normally work?

A
  • Normally, upon binding GTP, RAS becomes active
  • When bound to GTP, it is active so it interacts with a protein called RAF and signals via phosphorylation
  • It activates the kinase cascade leading to the production of gene regulatory proteins
  • Ras passes the signal on to other proteins within a signal transduction cascade
  • The cell goes into a proliferative phase
  • Dephoshorylation of the GTP to GDP to switch Ras off
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17
Q

How does mutant RAS lead to cell proliferation?

A
  • Mutant RAS will fail to dephosphorylate GTP, meaning that the GTP persists so RAS remains active
  • Consequence: increased signalling with the RAF protein -> continuous proliferative stimulation
18
Q

What is the RAS pathway part of?

A

A much more complex signalling cascade called the mitogen-activated protein kinase cascade (MAPK)

19
Q

What is RAS important in?

A

The signal transduction pathway - RAS recieves GF signals, and passes them through the signal transduction cascade. The ultimate response is proliferation by the cell.

20
Q

NOTE

A

A single protein being changed in quite a complex series of protein activities is sufficient to keep the cell in a proliferative state.

21
Q

Where are mutations in RAS found?

Do all tumours/cancers have mutations in the same RAS?

A
  • RAS oncogenes detected in many human tumours
  • It is rare in some tumours (breast cancer), but very common in other tumours (pancreatic cancer – 95%)
  • So there is tissue specificity, and tumours are commonly form-specific
  • Different isoforms of the enzymes are problematic in different tumours
22
Q

Give examples of mutations and which codons are affected in order for GTP hydrolysis to be inhibited

A

The mutation at codons 12 (Gly), 59 (Ala) and 61 (Gln) inhibit GTP hydrolysis

23
Q

What are tumour suppressor genes?

A

Regulate cell proliferation and maintain cell integrity (essential activities in the cell)

24
Q

How many copies of a TSG are in a cell and what must happen in order for cancer to be promoted?

A

2, the two hit hypothesis so deletion/mutation of one isn’t enough to promote cancer, both must be affected, unless it is dominant (e.g. p53)

25
Q

Does the two hit hypothesis apply to oncogenes?

A

No, mutation/deletion of one copy is usually sufficient to produce an oncogene.

26
Q

What are the different classes of TSGs?

A
  • Regulate cell proliferation
  • Maintain cellular integrity
  • Regulate cell growth
  • Regulate the cell cycle
  • Nuclear transcription factors
  • DNA repair proteins
  • Cell adhesion molecules
  • Cell death regulator

ALL THESE SUPPRESS NEOPLASTIC PHENOTYPE

27
Q

What does ‘inheriting’ cancer mean?

A

Inheriting a pre-disposition to cancer (germline mutation)

28
Q

Retinoblastoma - inherited cancer
How does hereditary differ from sporadic onset?
What is it and what is the mutation causing it? What does it normally encode?

A
  • It is a malignant cancer of developing retinal cells
  • Sporadic disease usually involves one eye
  • Hereditary causes can be unilateral or bilateral and multifocal
  • It is caused by mutation of the RB1 tumour suppressor gene on the chromosome 13q14
  • RB1 encodes a nuclear protein that is involved in regulation of the cell cycle
29
Q

What is Knudson’s two hit hypothesis?

A
  • If you get loss of heterozygosity to the second copy of the TSG, you have two damaged copies. This promotes cancer
  • If you have ‘sporadic cancer’ (somatic mutation), these are mutations you acquire by the process of living (ageing, lifestyle etc.), you acquire two over your life
  • Or you could inherit one mutation and acquire the second
30
Q

Give examples of TSGs in humans, what they do and what cancers they are involved in

A

p53 is a cell cycle regulator with a nuclear location, it is expressed in its mutated form in 50% of all human tumours (colon, breast, lung etc)

APC is a gene involved in cell signalling. It is cytoplasmic and very commonly associated with colon cancer

BRCA1 is a cell cycle regulator, nuclear and is associated with breast/ovarian and prostate cancer

31
Q

What stops p53 activity?

When is p53 activated?

A
  • p53 is held in check by a protein called Mdm2
  • This STOPS p53 from being active
  • If there is some kind of cellular stress/DNA damage, p53 is activated
32
Q

What proteins does p53 transcribe when there is cellular stress/DNA damage?

A

p21 (Waf1) – binds and inhibits cyclin dependent kinases and cyclins to arrest cell cycle

MDM2 (hDM2)– binds to and inactivates p53 (autoregulatory loop)

BAX – member of BCl-2 family (promotes apoptosis)

33
Q

What happens when a cell has damaged DNA?

A

p53 increases to induce G1 arrest, in attempt to resolve the problem. It orchestrates a whole series of transcriptional events, to produce proteins that try to resolve the damage. If it repairs the cell, life continues as normal. If the damage is too bad, p53 will commit the cell to apoptosis

34
Q

How many copies of the APC gene must be damaged to promote cancer?

A

The APC tumour suppressor gene is a more typical TSG. You have to damage both copies of it to get an effect.

35
Q

What pathway is APC involved in?

What does APC normally do?

A
  • WNT pathway
  • This is a signal transduction pathway that leads to transcriptional upregulation in the nucleus
  • A major factor of this pathway is beta-catenin (driver of the proliferative process)
  • APC controls the activity of beta-catenin by inhibiting it
  • Anything that damages APC is likely to leave beta-catenin to work in an unregulated manner
  • Therefore uncontrolled growth
36
Q

Which cancer is APC mutation involved in?

A

colon, FAP

37
Q

What is FAP (familial adenomatous polyposis)?

A
  • Sufferers develop hundreds and thousands of colon polyps
  • These individuals become highly susceptible to colon cancer later in life
  • Loss of APC appears to predispose colonic epithelial cells to a hyperproliferative state
  • The treatment for these individuals is the removal of the colon in their 20s
  • 90% of these people are susceptible to colon cancer otherwise
38
Q

How common is colorectal cancer?
Where is it very prevalent?
What does this suggest?

A
  • One of the major forms of cancer worldwide
  • Colorectal cancer is highly prevalent in the western world
  • It appears to have an environmental aetiology (cause)
39
Q

How does colorectal cancer develop?

A
  • If epithelium experiences damage to its DNA (e.g. APC is damaged), we begin to see hyperproliferative polyps developing on the colon
  • Further damage to DNA (e.g. mutation of a proto-oncogene), the tumour starts to develop (adenoma)
  • If we then see changes in p53, a rather nasty disease begins to progress (development of carcinoma, metastatic potential)
40
Q

Compare oncogenes and TSGs

A

oncogene:
active in tumour, specific translocations/mutations, rarely hereditary, dominant at cell level, broad tissue specificity, leukaemias and lymphomas

TSGs:
inactive in tumour, deletion/mutation, mutation can be inherited, recessive at cell level, considerable tumour specificity, solid tumours

Year 2 - Cancer (9 decks)

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