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molecular basis of disease > oncogenes and tumour suppressor > Flashcards

oncogenes and tumour suppressor Flashcards

1
Q

What are some major functional changes happening in cancer?

A
  1. increased growth (loss of growth regulation, stimulation of environment promoting growth, eg: angiogenesis)
  2. failure to undergo programmed cell death (apoptosis) or senescence
  3. loss of differentiation (including alterations in cell migration and adhesion)
  4. failure to repair DNA damage (including chromosomal instability)
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2
Q

What are oncogenes?

A
  • their normal function is to make cells divide
  • in cancer they pick up mutations that make oncogenes permanently active, uncontrolled division.
  • oncogene: ‘gain of function’
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3
Q

What are tumour supressor genes?

A

-tumour suppressor genes are like the car’s brakes, their function to stop division.
- in cancer, pick up mutations that swtich gene off.
tumour gene : “loss of function”, so can’t stop division = uncontrolled division.

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4
Q

What is needed for ‘loss of function’ in tumour supressor genes?

A

both genes for tumour supressor must be mutated if only one is mutated there is no loss of function.

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5
Q

What was Rous’s protocol for inducing sacroma in chickens- discovery of oncogenes?

A
  • Frances Peyton Rous began work in 1910 and discovered Rous sarcoma in chickens
    1. chicken with sarcoma in breast muscle
    2. remove sarcoma and break up into small chunks of tissue
    3. grind up sarcoma with sand
    4. Collect filterate that has passed through fine-pore filter
    5. inject filterate into young chicken
    6. observe sarcoma in injected chicken
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6
Q

What are principles of Rous’s experiment which enabled discovery of Rous virus?

A
  1. carcinogenic agent was small enough to pass through a filter
  2. The filter used excluded bacteria, it was not small enough to exclude viruses
  3. This resulted in Rous concluding that a virus must be responsible for the induction of tumour formation.

=> Discovered that sarrcoma was transmissible through viruses - Rous Sarcoma virus

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7
Q

Why was Rous virus so important?

A
  • because it was a retrovirus
  • Retroviruses are important experimentally :
    => technological advances
    => improved tissue culture techniques
    => the discovery of reverse transcriptase, RNA genome, replicates via DNA intermediate and that they are enveloped.
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8
Q

What is the SRC genes?

A

-decades later oncogenic transformation by this virus was found to be caused by an extra gene contained in its genome an ‘oncogene’ called v-src.

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9
Q

What is the oncogene hypothesis?

A
  • Harold and Micheal

=> discovered that viral SRC is a mutated gene kidnapped from host cell.

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10
Q

What is a kidnap gene?

A
  • accidental integration of dsDNA provirus into host cell chromosomal DNA because they are in close proximity.
  • co- transcription of viral and c-src sequence
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11
Q

What is the oncogene hypothesis?

A

Bishop and Varmus used different strains of Rous sarcoma virus in their research they

  1. identified the v-src oncogene as a responsible for causing cancer
  2. used hybridisation experiments, and they found that the c-src gene was present in the genome of many species.
  3. they then showed that the host cell c-src gene was normally involved in the positive regulation of cell division
  4. following infection, however, the v-src oncogene was expressed at high levels in the host cell, leading to uncontrolled host cell growth, and cancer.
  5. proto oncogenes are normal genes that can control growth.
  6. various agents, including radiation, chemical carcinogens and exogenous viruses may transform cells by “switching on” the endogenous oncogenic information, turning proto-oncogenes to oncogenes .
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12
Q

How are oncogenes activated?

A
  • mutations, insertions, amplifications and translocation, changes sequence of DNA to makes altered gene so altered protein, it loses ability to respond to loss of growth regulatory factors.
  • one mutation in one allele is enough to activate oncogenes
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13
Q

What is the function of proto oncogenes in a cell?

A

=> majority on oncogene proteins function as elements of the signalling pathways that regulate cell proliferation and survival in response to growth factor stimulation.

  • oncogenes act as growth factors (EGF),
  • growth factor receptors (ErbB)
  • intracellular signalling molecules (Ras and Raf)
  • RAS and Raf activate the ERK MAP kinase pathway, leading to the induction of additional genes that encode potentially oncogenic transcriptional regulatory proteins.

if mutation occurs in any of these pathways oncogenes can be activated.

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14
Q

What are characteristics of RAS oncogene family?

A

RAS oncogene family that helps growth and survival.

  • ras genes were identified from studies of two cancer - causing viruses : Harvey sarcoma virus and Kristen sarcoma virus, these viruses were discovered originally in rats hence the name RAt Sarcoma.
  • RAS proteins are small GTPase that are normally bound to GDP in a neutral state
  • oncogenic activation of ras seen in about 30% of human cancer
  • most commonly mutated oncogene
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15
Q

What mutations in codons occur in RAS oncogene?

A
  • point mutation in codons 12, 13, and 61
  • Glycine to valine= bladder carcinoma
  • Glycine to cysteine = lung cancer
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16
Q

outline the intracellular signal cascade of RAS oncogene family(normal function of RAS).

A
  1. binding of extracellular growth factor signal
  2. promotes recruitment of RAS proteins to receptor complex
  3. recruitment of RAS exchange GDP (inactive Ras) with GTP (active Ras)
  4. Activated Ras then initiates the remainder of the signalling cascade (mitogen activated protein kinases)
  5. These kinases ultimately phosphorylate targets, such as transcription factor to promote expression of genes important for growth and survival.

=> Ras hydrolyses GTP to GDP fairly quickly, turning itself “off”

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17
Q

What happens in the intracellular transduction cascade when there is a mutation?

A
  • mutation causes hyperactivity of Ras protein (product of oncogene) issues signals on its own.
  • loss of GTPase activity of RAS protein required to return active RAS to inactive RAS GDP.
  • targets are phosphorylated causing transcription factors to be free promote DNA replication = uncontrolled growth .
18
Q

What is MYC and how is it activated?

A

MYC is a oncoprotein that belongs to a family of transcription factors that regulate 15% of entire genome transcription.
MYC is overexpressed in the majority of human cancers.

MYC is activated when it comes under the control of foreign transcriptional promoters, this leads to deregulation of oncogenes that derives relentless proliferation.
-such activation is result of chromosomal translocation.

19
Q

What is the structure of MYC?

A
  • it encodes a helix-loop-helix leucine zipper transcription factor that dimerizes with partner protein, Max, to transactive gene expression.
  • consists 3 members C-MYC, MYCN, and MYCL, which encodes c Myc, N-Myc and L-Myc respectively
  • originally identified in avian myelocytomatosis virus (AMV)
20
Q

How does activation of MYC lead to Burkitt’s lymphoma?

A
  • Epstein Barr virus is associated with Burkitt’s lymphoma (BL)
  • in Africa, children with chronic malaria infections have a reduced resistance to the virus (African or endemic BL)
  • BL cases carry one of three characteristic chromosomal translocations that place the MYC gene under the regulation of the Ig heavy chain. Therefore c-myc expression is deregulated which derives relentless proliferation.
21
Q

What are the 3 chromosomal translocations in BL?

A

-chromosome 2
-chromosome 14
-chromosome 22
=> in all 3 translocations a region form one of these 3 chromosomes fused to a section of chromosome 8.

22
Q

Outline Chronic Myelogenous Leukaemia (CML) as another example of chromosomal translocation responsible for activation of oncogenes?

A
  • 95% of CML patients carry the philadelphia chromosome, that is the product of the chromosomal translocation of chr9 (ABL) and Chr22 (BCR) generating the BCR-ABL fusion protein(Philadelphia chromosome).
  • As a result of this translocation the tyrosine kinase activity of the oncogene ABL, leading to abnormal proliferation.
  • fusion protein between ABL (9) and BCR (22) has enhanced tyrosine kinase activity.
  • therapeutic strategies for CML include imatinib a tyrosine kinase inhibitor
  • 96% remission in early- stage patients.
23
Q

How were tumour suppressor discovered?

A
  • 1996 Henry Harris performed somatic cell hybridisation experiments.
  • fusion of normal cells with tumour cells resulted in hybrid cells containing chromosomes from both parents.
  • genes derived from normal parent acted to inhibit or suppress tumour development so the normal cell must produce something that prevents tumour growth (tumour suppressor)
  • The first tumour suppressor gene was identified by studies of retinoblastoma, a rare childhood eye tumour.
24
Q

What is Retinoblastoma?

A
  • rare childhood eye cancer
  • develops when immature retinoblasts continue to grow fast.
  • eye containing tumour will reflect light back in a white colour “cat’s eye appearence” = leukocoria
25
Q

Where is the hereditary mutation in the retinoblastoma 1 (Rb1) gene?

A

on chromosome 13 (13q14)

26
Q

What are 2 forms of retinoblastoma?

A

-two forms of the disease, familial (40%) and sporadic (60%)

27
Q

what is the two hit hypothesis?

A
  • existence of RB1 gene was predicted in 1971
  • development of retinoblastoma requires 2 mutations, known to correspond to the loss of both functional copies of the Rb gene- “two hit” hypothesis.
  • “loss of heterozygosity” often used to describe the process that leads to inactivation of the second hit in its remaining functional copy of a tumour suppressor gene a heterozygous cell receives a second hit thereby becoming homozygous for mutated gene.
    1st hit is hereditary and second is sporadic or both first and second hits are sporadic.
28
Q

What is the role of tumour suppressor genes?

A
  • AKA anti-oncogenes, body has mechanisms to police processes that regulate cell numbers
  • tumour suppressor gene product act to stop signs to uncontrolled growth, promote differentiation or trigger apoptosis.
  • therefore they are usually regulators and regulate cell cycle checkpoints(egRB1), regulate differentiation (eg. APC) or regulate DNA repair (eg. BRCA1)
  • Loss of tumour suppressor gene function requires INACTIVATION OF BOTH ALLELES OF GENE
  • recessive genes
29
Q

What is the protein structure of retinoblastoma protein?

A
  • RB gene family includes 3 members which are collectively known as pockets (large pockets, small pockets)
  • pRb is a multi functional protein and can bind to many partners
  • the RB structure acts as a scaffold for these multiple protein interaction.
  • Rb functions in diverse cellular pathways such as apoptosis and cell cycle by stimulating or inactivating activity of interacting proteins
30
Q

What is the main binding partner of RB?

A

E2F transcription factor, interacting with large pocket.

31
Q

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

A
  • main function of RB is to regulate the cell cycle by inhibiting G1 to S phase transition.
  • 2 important proteins involved in all cell cycle are : cylins and their associated dependent kinases (CDK)
  • passage of a cell through the cell cycle is regulated cylins and CDKs
32
Q

How does retinoblastoma function via phosphorylation/dephosphoralation activity to reduce proliferation and suppress tumours in the cell cycle?

A
  • Rb protein is a tumour suppressor that regulates the activity of E2F transcription factor for the expression of genes required for S phase
  • Rb activity is regulated by phosphorylation.
  • when Rb tumour suppressor is active it can inhibit cell proliferation.
  • When Rb is dephosphorylated it is active and remains bound to E2F, blocking the progression of to S phase giving cellular mechanisms time to repair damage or apoptosis of damaged cell to prevent them moving into the next phase of the cell cycle.
  • When there is external physiological signals RB, Cylin D and E families and their CDK phosphorylates RB. Hyperphosphorylation causing it to be inactive.
  • Inactive Rb is no longer bound to E2F and E2F is released and migrates to the nucleus to induce transcription.
  • when RB is inactive cell cycle progression from G1 to S occurs quickly giving no time for checkpoints to identify any damage or to arrest any cells.
33
Q

What are ways other than phosphorylation to inactivate function of RB?

A
  • mutation, viral oncoproteins
  • viral inactivations disrupt E2F binding or destabilise Rb, eg: Adenovirus (E1A) , papilloma (E7) and polyoma (large T antigen) these products of virus destabilise the RB and E2F structure.
  • without RB/ or inactivated RB allows cells to move from G1 to S without usual checks and regulation.
34
Q

What is the structure of tP53?

A

structure:
- amino transactivation domain, a central DNA binding domain, a tetramerization domain and a carboxyl regulatory domain
- can bind to 300 different gene promoter regions (main role as transcription factor)

35
Q

How is tp53 degraded in normal/ healthy cells?

A
  • normally levels of p53 are low in cells
  • low levels are maintained by MDM2 protein , uniquitin ligase (also an oncogene).
  • In unstressed cells (normal healthy cells) MDM2 binds to p53 flagging it to proteasomes to degrade it , bc p53 is not needed, only needed when there is stress (mutation).
36
Q

How is tP53 levels maintained to regulate genes involved in DNA damage?

A
  • Damage in cells cause stress signals that are able to activate p53
  • signals are sensed by mainly kinases that then phosphorylate p53
  • phosphorylation of p53 disrupts the interaction it and MDM2 thus prevents the proteosomes from degrading it.
  • So tP53 can survive.
  • thus P53 can regulate genes involved in DNA damage repair, apoptosis, and cell cycle arrest to prevent damaged cells from progressing in the cell cycle.
37
Q

P53 mutations

A
  • mutational inactivation is considered to be one of the most common molecular mechanism behind the dysfunction of P53
    -extensive mutation search revealed that more than half of human cancers carry loss of function mutation of p53
    as the role of p53 is to suppress tumourgenesis, tumour cells try mutate tp53 first.
38
Q

What do therapeutic strategies aim to do?

A

As p53 supresses tumourgenisis it is a target for therapeutics
-retro-virus mediated gene transfer of wild-type(non-mutated) TP53 gene into both human lung tumour cell lines and xenograft models could lead to inhibition of tumour cell growth.
=> PRIMA-1 restores mutant p53 by modifying the thiol groups in the core domain of the protein (back to unmutated form)
=> Nutlin - is a potent MDM2 antagonist so prevents MDM2 binding and tagging it for proteosome degradation so it can stay in the nucleus longer.
=> RITA binds to P53 and can restore mutp53 activity
=> inhibitors of CRM1 result in nuclear accumulation of p53

39
Q

What is the function of tP53?

A
  • transcription factor
  • first suppressor gene to be identified
  • involved in sensing DNA damage and regulating cell death/ apoptosis - inhibits tumourgenesis
  • mutated in 30-50% of humans
  • high mutation frequency suggests that tumour cells try to eliminate tp53 hence why it must have a suppressing function.
  • tumour p53 specialises in preventing the appearance of abnormal cell.
40
Q

Why is genetic analysis and personalised medicine so important?

A
  • not two tumours are the same so personalised medicine is important to generate drugs that precisely target tumours.
  • people with the same cancer can have different forms of disease so responses to treatment vary.

molecular basis of disease (29 decks)

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