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Clinical pathology specialities: Cellular Pathology > Cellular pathology: Oncogenes and tumour suppressors > Flashcards

Cellular pathology: Oncogenes and tumour suppressors Flashcards

1
Q

What are some of the major functional chnages that occur to cells during cancer?

A
  • Increased growth (loss of growth regulation, stimulation of environment promoting growth e.g. angiogenesis)
  • Failure to undergo apoptosis or senescence
  • Loss of differentiation (including alterations in cell migration and adhesion)
  • Failure to repair DNA damage (including chromosomal instability)
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2
Q

What are the 2 major types of mutated gene that contribute to carcinogenesis?

A
  • Oncogenes
  • Tumour suppressor genes
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3
Q

What is an oncogene?

A
  • A mutated form of a proto-oncogene whose protein product is produced in higher quantities or has increased activity and therefore acts in a dominant manner
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4
Q

Does a proto-oncogene need a mutation in only one or in both alleles to become an oncogene?

A
  • A proto-oncogene only needs a mutation in one allele to become an oncogene
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5
Q

What is a tumour suppressor gene?

A
  • A gene whose normal activity prevents formation of a cancer.
  • However a loss of this function by mutation enhances the likelihood that a cell can become cancerous
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6
Q

Does a tumour suppressor gene need only one or both alleles to be mutated to lose its function?

A
  • A Mutation needs to occur in both alleles of tumour suppressor gene for it to become inactive
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7
Q

Explain the experiment that allowed Peyton rous to induce sarcoma in healthy chickens?

A
  • He removed the sarcoma from the breast of a chicken and broke it up into small pieces
  • He ground those small pieces with sand and put them through a fine pore filter
  • Fine pore filter produced a cell free filtrate which was collected and injected into a young healthy chicken
  • Young healthy chicken then developed sarcoma
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8
Q

What did the fact that peyton rous was able to induce sarcoma in helathy chicken mean for the understanding of sarcoma?

A
  • During experiment the carcinogenic agent was small enough to pass through a filter
  • Because filter was able to exclude bacteria but not viruses it meant that a virus must be responsible for the induction of tumour formation
    *
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9
Q

What is the name of the virus that is able to induce sarcoma in chickens?

A
  • Rous Sarcoma Virus
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10
Q

Why did retroviruses become an important experimentally for our understanding of oncogenes?

A
  • Technological advances
  • Increased funding
  • Improved tissue culture techniques
  • Discovery that RNA genome could be reverse transcribed back into DNA by reverse transcriptase
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11
Q

What about the Rous Sarcoma virus meant that it’s able to induce sarcoma?

A
  • The rous sarcoma virus was found to contain an extra gene in its genome compared to a typical retrovirus
  • This gene is called v-src and was identified as the first oncogene
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12
Q

What did Michael bishop and Harold Varmus discover about the v-src gene in rous sarcoma virus?

A
  • They discovered a gene with a homologous sequence to the v-src gene in uninfected chickens and other organisms - e.g. fruit flies to humans
  • This gene was called c-src and was identified as the first proto-oncogene
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13
Q

Upon further examination what did Harold Varmus and Michael bishop discover about the realtionship between c-src and v-src genes?

A
  • They found out that the Rous sarcoma virus had ‘kidnapped’ the c-src gene (a proto-oncongene) from a host cell and had then transformed that gene into v-src (an oncogene)
  • This discovery formed the basis of the idea that oncogenes are altered forms of proto-oncogenes
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14
Q

Explain how the Rous sarcoma virus was able to acquire the c-src gene during its evolution

A
  • Rous sarcoma virus infected host cell with s-src gene present
  • Virus then reverse-transcribed its viral RNA into DNA (provirus)
  • The provirsus was then integrated next to the c-src gene in the host cell chromosomal DNA
  • Eventually provirus is translated and transcribed along with the c-src sequence which results in the production of viral proteins needed for production of new viral particles
  • Due to co-translation of c-src with provirus the new viral particles of rous sarcoma acquired altered from of c-src gene called v-src within their genome.
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15
Q

What protein product is produced via the expression of the v-src oncogene?

A
  • 60kDa intracellular tyrosine kinase
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16
Q

What are the two types of oncovirus, virus that cause cancer?

A
  • DNA oncovirus
  • RNA oncovirus
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17
Q

How can an oncogene become activated?

A
  • An allele of proto-oncogene can go through:
    • Mutation
    • Amplification/duplication
    • Translocation
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18
Q

How does a point mutation in an proto-oncogene lead to activation of an oncogene?

A
  • Point mutation in coding sequence of proto-oncogene leads to encoded protein having altered structure/function to normal protein
  • Point mutation in regulatory sequences of proto-oncogene lead to overpression of that proto-oncogene
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19
Q

How does amplification/gene duplication in an proto-oncogene lead to activation of an oncogene?

A
  • Amplification/gene duplication leads to multiple copies of the same proto-oncogene present within the genome
  • All these copies are then transcribed and translated leading to increased production of the encoded protein
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20
Q

How does translocation in an proto-oncogene lead to activation of an oncogene?

A
  • A DNA regulatory sequence can translocate from a distant site next to proto-oncogene and alter the expression of that proto-oncogene
  • This leads to increased production of the protein encoded by the proto-oncogene
  • A protein-coding gene can translocate from a distant site next to to the proto-oncogene and fuses with the proto-oncogene to form a fusion gene
  • This fusion gene is then transcribed and translated to form a fusion protein
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21
Q

Proto-oncogenes encode the proteins of the growth factor signal transduction pathway. What are the 4 types of protein that make up this pathway?

A
  • Growth factors e.g. EGF
  • Growth factor receptors e.g. ErbB
  • Intracellular signal transducers e.g. Ras and Raf
  • Nuclear transcription factors
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22
Q

What genes are the most commonly mutated proto-oncogene in human cancers?

A
  • ras genes
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23
Q

Ras genes encode for ras protein. What type of protein is the ras protein?

A
  • Ras proteins are small GTPases that are normally bound to GDP in a neutral state and are bound to GTP when active
24
Q

Where within the ras gene do the point mutations that cause it to become an oncogene usually occur?

A
  • Codons 12, 13 and 61
25
Q

Name some specific mutations of the ras gene and the cancer this mutation is associtated with

A
  • Glycine to valine at position 12 - bladder carcinoma
  • Glycine to cysteine - lung cancer
26
Q

Describe the normal activity of Ras protein

A
  1. Growth factor will bind to receptor on extracellular domain binding site
  2. This results in the recruitment of Ras protein to the receptor via phosphorylation of the receptor
  3. Once recruited RAS will unbind GDP and bind to GTP to become active Ras
  4. Activated Ras then initiates the remainder of the signalling cascade which results in the activation of a number of protein kinases
  5. These kinases ultimately phosphorylate targets, such as transcription factors that promote expression of genes important for the cell cycle
27
Q

Explain how the activity ras protein changes as a result of it having a point mutation

A
  • Point mutation within ras gene results in loss of GTPase activity of ras protein so ras protein is unable to hydrolyse GTP back to GDP
  • This results in constituitive activation of ras protein
28
Q

What does the constant activation of ras protein as a result of a point mutation in the ras oncogene mean for a cell?

A
  • It means that cells will constantly produce proteins needed to stimulate cell cycle and so will constantly go through the stages of the cell cycle and grow
29
Q

What genes make up the MYC oncogene family and what proteins do these genes encode for?

A
  • C-MYC - encodes for c-Myc protein
  • MYCN - encodes for N-Myc protein
  • MYCL - encodes for L-Myc protein
30
Q

Describe the normal activity of the Myc family of proteins

A
  • Myc proteins are helix-loop-helix leucine zipper transcription factors that dimerizes with its partner protein, Max, to cause expression of particular genes
31
Q

Explain how the myc genes becomes oncogenes

A
  • myc gene on chromosome 8 translocates to either chromosome 2, 14 and 22
  • When myc gene translocates to chromosome 14 it becomes regulated by a strong promoter of the immunoglobulin heavy chain (IgH)
  • This results in the constituitive expression of the myc gene resulting in constant production of Myc protein
32
Q

What specific chromosomal transloaction of a myc gene results in Burkitt’s lymphoma?

A
  • Chromosomal translocation of c-myc gene from chromosome 8 to chromosome 14
33
Q

What oncovirus is able to cause Burkitt’s lymphoma?

A
  • Epstein Barr virus
34
Q

95% of Chronic myelogenous leukaemia patients carry the Philadelphia chromosome. What is the philadelphia chromosome and how is it produced?

A
  • Philadelphia chromosme is the defective and short chromosome formed as a result of the chromosomal translocation between the ABL gene on chromosome 9 and the BCR gene on chromosome 22
  • This chromosomal translocation results in production of BCR-ABL 1 fusion gene which when expressed produces the BCR-ABL fusion protein
35
Q

What effect does the chromosomal translocation that results in the production of the BCR-ABL1 fusion gene have on fusion protein that it produces?

A
  • Tyrosine kinase activity of the oncogene ABL becomes constitutive leading to abnormal proliferation
36
Q

Explain how tumour suppressor genes were discovered

A
  • Henry Harris and his colleagues fused normal cells with tumour cells which yielded hybrid cells containing chromosomes form both parents.
  • These cells were not capable of forming tumours
  • This meant that genes derived from the normal parent cell acted to inhibit or suppress tumour development
  • These genes came to be known as tumour suppressor genes
37
Q

What are some of the functions of tumour suppressor genes? For each function give an example of a tumour suppressor gene with that function

A
  • Regulators of cell cycle checkpoints (e.g. RB1),
  • Differentiation (e.g. APC)
  • DNA repair (e.g. BRCA1)
38
Q

What is retinoblastoma?

A
  • A rare childhood cancer that develops when immature retinoblasts continue to grow very fast and do not turn into mature retinal cells.
39
Q

What is leukocoria?

A
  • Occurs when the retina reflects light back in a white colour and can occur as a result of the development of a tumour due to retinoblastoma
40
Q

What are the two forms of retinoblastoma and what is the difference between the 2 forms?

A
  • Familial (inherited) form
  • Sporadic form
  • In the familial form a germline mutation in the RB gene is passed on to all cells of the child. A second mutation is then acquired in a particular retinoblast leading to a tumour
  • In the sporadic form both mutations occur in a particular retinoblast leading to a tumour.
41
Q

What chromosome is the retinoblastoma gene (RB1) present on?

A
  • Chromosome 13
42
Q

What are the 3 members of the retinoblastoma gene family?

A
  • Rb/(p105/110)
  • p107
  • Rb2/p130
43
Q

What are some features of the retinoblastoma protein (pRb)?

A
  • pRb is a multi functional protein (110kDa) with over 100 binding partners
  • It’s a transcriptional co-factor that can bind to transcription factors and either inhibit or induce transcription factor activity
44
Q

Describe the structure of the retinoblastoma protein

A
  • Contains a carboxy terminus (C-terminus) and a amino terminus (N-terminus)
  • Contains a small pocket subunit between the two terminuses
  • Contains a large pocket subunit which is just the small pocket subunit and the C-terminus
45
Q

What is the main binding partner of pRb and which part of the protein does it interact with?

A
  • E2F transcription factor
  • Interacts with the large pocket
46
Q

What is the normal function of the retinoblastoma protein in the cell cycle?

A
  • When active it regulates the cell cycle by inhibiting the G1 to S phase transition
  • It does this by binding to E2F and preventing it from inducing the expression of genes required for the S phase
47
Q

What are the different ways in which the retinoblastoma can be inactivated?

A
  • Phosphorylation by Cyclin D – Cdk 4 complex
  • Genetic mutation
  • Viral oncoprotein binding
48
Q

What occurs a a result of the inactivation of retinoblastoma protein?

A
  • Cells move through G1 into S phase unchecked which can lead to cells going through rapid cell proliferation and eventually becoming tumourogenic
49
Q

In most tumour cells the p53 gene is often mutated. What does this suggest?

A
  • This suggests that in order for a tumour cell to survive the p53 tumour suppresor protein must not be active
50
Q

Describe the structure of the p53 protein

A
  • Contains an amino transactivation domain
  • Contains a central DNA binding domain
  • Contains a tetramerization domain
  • Also contains a carboxyl regulatory domain
51
Q

Why are levels of p53 normally low in cells?

A
  • p53 levels kept low by MDM2 protein
52
Q

How does MDM2 regulate the level of p53 in cells?

A
  • MDM2 binds p535 to form a complex in the nucleus where MDM modifies the carboxyl terminus of p53 and targets it for degradation by the proteasome
53
Q

How long is the half life of wild type (non-mutated) p53?

A
  • 20 minutes
54
Q

How can p53 become activated?

A
  • Stress signals are able to activate p53
  • Signals are sensed by mainly kinases that then phosphorylate p53 e.g. ATM/ATR
  • Phosphorylation of p53 disrupts the interaction between it and MDM2 which prevents it from being targeted for degradation via the proteosome
55
Q

Where do most of the mutations in the p53 gene in tumourigenic cells occur?

A
  • Mainly occur in part of gene that codes for DNA binding domain of p53 protein
56
Q

What are some of the therapeutic stratgeies aimed at restoring normal p53 function?

A
  • PRIMA-1, Restores mutant p53 by modifying the thiol groups in the core domain of the protein
  • Nutlin- is a potent MDM2 antagonist and so prevents p53 from being targeted by proteosomal degradation
  • RITA binds to p53 and can restore mutp53 activity
  • Inhibitors of CRM1 result in nuclear accumulation of p53

Clinical pathology specialities: Cellular Pathology (13 decks)

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