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SEM 4:Cellular Pathology > Oncogenes and Tumour Suppressor Genes > Flashcards

Oncogenes and Tumour Suppressor Genes Flashcards

1
Q

What are the major functional changes in cancer?

A
  • Increased growth: loss of growth regulation, stimulation of environment promoting growth e.g. angiogenesis
  • Failure to undergo programmed cell death (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

Summarise function of oncogenes and tumour suppressors

A

Oncogenes: Gain of function

Tumour Suppressor: Loss of function

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3
Q

Oncogene

A
  • An altered gene whose product can act in a dominant fashion to help make a cell cancerous. Oncogene is a mutant form of a normal gene involved in the control of cell growth or division.
  • Any cellular gene that upon activation can transform cells.
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4
Q

Tumour Suppressor Gene

A

A gene whose normal activity prevents formation of cancer. Both genes for the tumour suppressor must be mutated. Loss of this function by mutation enhances the likelihood that a cell can become cancerous.

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5
Q

Mutations in Oncogenes

A

Gain a mutation in one of the alleles will activate the gene.

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6
Q

Mutations in Tumour suppressors

A

Gain a mutation in one allele but not enough to have an effect. Need two mutations - one in each allele.

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7
Q

Examples of oncogenes

A

MyC

Ras - normal cell growth signaling pathways

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8
Q

Examples of tumor suppressors

A

Rb - retinoblastoma

p53 - the guardian of genome

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9
Q

How is an oncogene created?

A

During evolution, the virus can acquire fragments of genes from the host at integration sites and this process results in the creation of oncogenes.

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10
Q

Bishop and Varmus ‘The Oncogene Hypothesis’

A
  • Identified the v-src oncogene as responsible for causing cancer
  • Used hybridization experiments, and found c-src gene present in many species
  • C-src involved in the positive regulation of cell growth and cell division.
  • Following infection, the v-src oncogene was expressed at high levels in the host cell, leading to uncontrolled host cell growth, unrestricted host cell division, and cancer.
  • When proto-oncogenes are exposed to carcinogens (various agents) may transform cells by ‘switching on’ the endogenous oncogenic information.
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11
Q

Which virus are most of us infected with?

A

Epstein-Barr virus

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12
Q

What percentage of cancers are caused by oncoviruses?

A

15-20%

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13
Q

How are viral oncogenes transmitted?

A

By either RNA or DNA viruses

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14
Q

How do DNA viruses infect cells?

A

They cause lytic infection leading to the death of the cellular host or can replicate their DNA along with that of the host and promote neoplastic transformation.

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15
Q

How do DNA viruses initiate and maintain tumours?

A

Encode various proteins along with environmental factors

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16
Q

How do RNA viruses induce cancer?

A

Integrate DNA copies of their genomes into the genome of the host cell and as these contain transforming oncogenes they induce cancerous transformation of the host.

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17
Q

What is LMP-1?

A

An oncogene produced by the Epstein-Barr virus that is always switched on and feeds into pathways pushing survival the cell to tumourigenesis.

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18
Q

What type of activations can oncogenes undergo?

A

Mutations, Insertions, Amplifications, and Translocations which lead to the loss of response to growth regulatory factors. One allele needs to be altered.

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19
Q

What are the 4 types of proteins involved in the transduction of growth signals?

A
  1. Growth factors
  2. Growth factor receptors
  3. Intracellular signal transducers
  4. Nuclear transcription factors
    Proto-oncogenes encode components of the growth factor signal transduction pathway.
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20
Q

The function of oncogene proteins

A

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

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21
Q

What proteins can oncogenes be?

A

Can be growth factor receptors (e.g. ErbB) and intracellular signalling molecules (Ras and Raf).

22
Q

What is the function of Ras and Raf?

A

Ras and Rag activate the ERK MAP kinase pathway, leading to the induction of additional genes (e.g. fos) that encode potentially oncogenic transcriptional regulatory proteins.

23
Q

Naming of Ras

A

Ras genes were identified from two cancer-causing viruses. These viruses were discovered originally in rats hence the name Rat sarcoma

24
Q

What are RAS proteins?

A

Small GTPases that are normally bound to GDP in a neutral state.

25
Q

What percentage of cancers have oncogenic activation of ras?

A

about 30% of human cancer

26
Q

What is the most commonly mutated oncogene?

A

Ras - activated Ras occurs by point mutations

27
Q

Examples of point mutations in Ras

A

Glycine to valine - bladder carcinoma

Glycine to cysteine - lung cancer

28
Q

Which point mutations cause hyperactivate Ras?

A

In point mutations, in codons 12, 13 and 61.

29
Q

Describe the activation of Ras

A
  1. An extracellular growth factor binds to the receptor
  2. This promotes the recruitment of RAS proteins to the receptor complex.
  3. Recruitment promotes Ras to exchange GDP (inactive Ras) with GTP (active Ras).
  4. Activated Ras then initiates the remainder of the signaling cascade (mitogen-activated protein kinases).
  5. These kinases ultimately phosphorylate targets, such as transcription factors to promote the expression of genes important for growth and survival.
30
Q

How does Ras become inactivated?

A

Ras hydrolyzes GTP to GDP fairly quickly, turning itself “off”.

31
Q

What happens when point mutations occur in the Ras proteins?

A

There is a loss of GTPase activity of the RAS protein normally required to convert active Ras back to inactive Ras.

32
Q

What happens when Ras is hyperactivated and passes checkpoints?

A

When it passes, the DNA damage repair are not checked and bypasses the checkpoints.

33
Q

What are genes in the MYC oncogene family?

A

Consists of 3 members:

  • C-MYC encodes c-Myc
  • MYCN encodes N-Myc
  • MYCL encodes L-Myc
34
Q

Where was the MYC oncogene originally identified?

A

Identified in avian myelocytomatosis virus (AMV)

35
Q

What is the MYC oncogene family?

A

Belong to a family of transcription factors that regulate the transcription of at least 15% of the entire genome

36
Q

What are the downstream effects of the MYC family?

A
  • Involved in ribosome biogenesis
  • Protein translation
  • Cell-cycle progression and metabolism
  • Biological functions such as cell proliferation, differentiation, survival, and immune surveillance
37
Q

What percentage of cancers is MYC oncogene overexpressed in?

A

at least 40% of tumors

38
Q

What does the MYC encode?

A

It encodes a helix-loop-helix leucine zipper transcription factor that dimerizes with its partner protein, Max, to transactivate gene expression.

39
Q

When is the MYC oncogene deregulated?

A

It is deregulated when MYC is activated when it comes under the control of foreign transcriptional promoters. Such activation is a result of chromosomal translocation

40
Q

Burkitt’s Lymphoma

A
  • Epstein Barr virus is associated
  • A high-grade lymphoma can affect children from the age of 2 to 16 years.
  • In central Africa, children with chronic malaria have reduced resistance to the virus. This is known as classical African or endemic BL.
41
Q

What are the three characteristic chromosomal translocations in BL?

A

Chromosome 2
Chromosome 14
Chromosome 22

42
Q

What happens when there is chromosomal translocation in MYC?

A

The MYC gene goes under the regulation of the Ig heavy chain. Therefore, c-myc expression is deregulated.

43
Q

What is common in all three translocations?

A

A region form one of three chromosomes with a section of chromosome 8.

44
Q

What percentage of leukaemias are CMLs?

A

15-20%

45
Q

What is the translocation that most patients with CML have?

A

The Philadelphia chromosome is the product of the chromosomal translocation t(9,22)(q34;q11) generating the BCR-ABL fusion protein - tyrosine kinase.

46
Q

What is the result of the Philadelphia translocation?

A

The tyrosine kinase activity of the oncogene ABL is constitutive leading to abnormal proliferation.

47
Q

What are the therapeutic strategies for CML?

A

Imatinib (Gleevac) - a tyrosine kinase inhibitor - 96% remission in early-stage patients

48
Q

What is another name for tumour suppressor genes and why?

A

Sometimes referred to as anti-oncogenes. They are called this as they counteract the effects of oncogenes.

49
Q

The action of tumour suppressors

A
  • The products act as stop signs to uncontrolled growth, promote differentiation or trigger apoptosis.
  • Therefore, they are usually regulators of cell cycle checkpoints (e.g. RB1), differentiation (e.g. APC) or DNA repair (e.g. BRCA1).
50
Q

How is the loss of tumour suppressor gene function done?

A
  • Requires inactivation of both alleles of the gene
  • Inactivation can be a result of mutation or deletion
  • Tumour suppressor genes are defined a recessive genes
51
Q

What are some of the different functions of TS?

A
  • Regulators of cell cycle checkpoints (e.g. RB1)
  • Differentiation (e.g. APC)
  • DNA repair (e.g. BRCA1)
    TS isn’t specific to one cancer
52
Q

What is retinoblastoma?

A

It is a rare childhood cancer (1 in 20,000) that develops when immature retinoblasts continue to grow very fast and do not turn into mature retinal cells.

SEM 4:Cellular Pathology (13 decks)

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