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Cancer > 2. Oncogenes and tumour suppressors > Flashcards

2. Oncogenes and tumour suppressors Flashcards

1
Q

What are the hallmarks of the cancer cell phenotype?

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

Outline the cell cycle

A
  • G0 - quiescent phase (not replicating)
  • G1 - cell makes sure it has enough nutrients, nucleotides etc. to replicate
  • G1 checkpoint - growth arrest to ensure the genetic fidelity of the cell
  • S - chromosome duplication
  • G2 - check for damaged or unduplicated DNA
  • M - mitosis (check for chromosome attachment to mitotic spindle)

Specific proteins accumulate/are destroyed during the cycle e.g. cyclins, CDKs, CDK inhibitors

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3
Q

What does the permanent activation of cyclin do?

A

Can drive a cell through a checkpoint

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4
Q

What are proto-oncogenes and how can a mutation effect it?

A
  • Code for essential proteins involved in maintenance of cell growth, division and differentiation
  • Mutation converts a proto-oncogene to an oncogene
  • Protein products of oncogenes no longer respond to control influences
  • Oncogenes can be aberrantly expressed, over-expressed or aberrantly active
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5
Q

What are the different ways a proto-oncogene may undergo a mutation and how does it affect protein production?

A
  • Mutation in coding sequence (can be single base) - aberrantly active protein
  • Gene amplification - lot more protein produced
  • Chromosomal translocation (chimeric)/viral mutagenesis: viruses can insert their own DNA into ours - normal DNA transcribed at a higher rate (strong enhancer or fusion of genes - overproduction of gene)
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6
Q

What are chimeric genes?

A

Genes that are formed by combinations of portions of one or more coding sequences to produce new genes

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7
Q

What is translocated in Burkitt’s lymphoma?

A

Chimeric genes
• Swap over of genetic material can go wrong
• Promoter is translocated
• Leads to up-regulation of the other gene portion

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8
Q

Describe the Philadelphia Chromosome as an example of chromosomal translocation in cancer

A
  • Translocation of ABL from chromosome 9
  • Translocation of BCR from chromosome 22
  • BCR-ABL fusion gene => over-expression => development of cancer
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9
Q

List the essential activities that proto-oncogenes code for (functional classes)

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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10
Q

What is Ras?

A
  • Family of GTPases

* Includes Ki-Ras and Ha-Ras - membrane-bound GTPases important in the stimulation of cell proliferation

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11
Q

How does Ras normally work?

A
  • GTP binds with Ras, activating it
  • Active Ras can interact with RAF and signal via phosphorylation
  • It activates the kinase cascade
  • This leads to the production of gene regulatory proteins
  • Ras passes the signal on to other proteins within a signal transduction cascade
  • Cell goes into a proliferative phase
  • Dephosphorylation of GTP => GDP switches Ras off
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12
Q

How does a mutation affect Ras?

A
  • Ras fails to dephosphorylate GTP
  • GTP persists so Ras remains active
  • Increased signalling with RAF protein
  • Continuous proliferative stimulation
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13
Q

Which complex signalling cascade is the Ras pathway part of?

A

Mitogen-activated protein kinase cascade (MAPK)

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14
Q

How specific are Ras oncogenes?

A

• Detected in many human tumours, but there is still tissue specificity:
e.g. rare in breast cancer, very common in pancreatic cancer
• Tumours are commonly form specific e.g. K-RAS in lung, colon, pancreas and N-RAS in AML
• Different isoforms of the enzyme can be problematic in different tumours
• Mutation at codons 12 (Gly) 59 (Ala) and 61 (Gln) inhibit GTP hydrolysis

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15
Q

What do tumour suppressor genes (TSGs) do?

A

Regulate cell proliferation and maintain cell integrity

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16
Q

How many copies of TSGs in each cell and how many must be damaged to promote cancer?

A

• Each cell has two copies of each TSG
• Both TSGs must be damaged to promote cancer
• Mutation/deletion of one gene copy is usually insufficient to promote cancer (2-hit hypothesis)
- unless the mutant gene acts dominant e.g. p53

17
Q

List the functional classes of TSGs

A
  • Regulate cell proliferation/cycle
  • Maintain cellular integrity
  • Nuclear transcription factors
  • DNA repair proteins
  • Cell adhesion molecules
  • Cell death regulators
18
Q

Describe the effects, treatment and cause of retinoblastoma

A
  • Malignant cancer of developing retinal cells
  • Found in children
  • Sporadic disease, usually involves one eye - usually from damage sustained through life
  • Can be hereditary - unilateral or bilateral and multifocal
  • Results in chalky looking eye
  • Treatment is removal of affected eye
  • Caused by mutation of the RB1 TSG on chromosome 13q14
  • RB1 encodes a nuclear protein involved in the regulation of the cell cycle
19
Q

What is Knudson’s two-hit hypothesis?

A
  • If you get loss of heterozygosity to the second copy of the gene - you have 2 damaged copies of the TSG
  • This promotes cancer
  • Sporadic cancer (somatic mutation) - mutation you acquire by the process of living
20
Q

What is p53?

A
  • Cell cycle regulator (transcription factor)
  • Nuclear location
  • Expressed in its mutated form in >50% of all human tumours
21
Q

What is APC?

A
  • Gene involved in cell signalling

* Cytoplasmic and commonly associated with colon cancer

22
Q

Which cancers do mutations in BRCA1 increase the risk of?

A
  • Breast
  • Ovarian
  • Prostate
23
Q

Summarise how p53 works

A

• p53 is activated in response to DNA damaging agents
• It increases to induce G1 arrest to resolve the problem
• Apoptosis if damage is too bad
• Then transcriptionally activates a series of proteins:
- p21 (Waf1) - binds and inhibits cyclin dependent kinases and cyclins to arrest cell cycle
- MDM2 (hDM2) - binds to and inactivates p53 (autoregulatory)
- BAX - member of the BCl-2 family, promotes apoptosis
• Mutation of p53 affects these activities - damaged cell won’t be repaired and divide with damage or may go into mitotic failure and die

24
Q

How many copies of a gene do ‘inherited cancers’ usually affect?

A

One

25
Q

How many mutated copies does it take for p53 to become dysregulated?

A
  • One, even though it is a TSG

* Acts in a dominant manner

26
Q

What proportion of p53 transforming mutations occur in DNA binding domains?

A

98% (40% of which are at 6 ‘hot-spots’ near the DNA-binding surface)

27
Q

How do the 6 hot-spot sites involved in p53 mutations interact with DNA?

A
  • Arg 248 and 273 directly contact DNA

* The other 4 residues stabilise the DNA binding structure of p53

28
Q

How many copies of APC need to be damaged for an effect?

A

2 - more typical TSG

29
Q

Describe the pathway that APC is involved in?

A
  • WNT pathway
  • Signal transduction pathway that leads to transcriptional upregulation in the nucleus
  • APC inhibits beta-catenin - a driver of the proliferative process
  • Therefore APC prevents uncontrolled growth
30
Q

What does the loss of the APC gene result in?

A

• Familial adenomatous polyposis
• Predisposes colonic epithelial cells to a hyperproliferative state
• Causes development of hundreds of thousands of benign adenomatous polyps of the colon
- not cancer but a highly proliferative state
• Highly susceptible to colon cancer later in life (90%)

31
Q

How can the effect of APC loss be treated?

A
  • Effect: predisposition to hyperproliferative state of colonic epithelial cells
  • Treatment: removal of colon in their 20s to prevent chances of getting cancer in the polyps
32
Q

How does colorectal cancer develop?

A
  • Damage to DNA of epithelium e.g. APC damaged
  • Hyperproliferative polyps
  • Further damage e.g. mutation of proto-oncogene
  • Tumour starts to develop (adenoma)
  • Damage to p53 => development of carcinoma, metastatic potential
33
Q

Compare oncogenes to TSGs (respectively)

A

Oncogenes/TSGs
• Gene active in tumour / inactive in tumour
• Specific translocations, point mutations / deletions or mutations
• Rarely hereditary / can be inherited
• Dominant / recessive at cell level
• Broad tissue specificity / considerable specificity
• Leukaemia and lymphoma / solid tumours

Cancer (15 decks)

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