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Cellular Pathology > Oncogenesis and Tumour Suppressor Genes > Flashcards

Oncogenesis and Tumour Suppressor Genes Flashcards

1
Q

What are the 6 hallmarks of cancer defined by Hanahan and Weinberg?

A
  • enabling replicative immortality
  • activating invasion and metastasis
  • inducing angiogenesis
  • resisting cell death
  • sustaining proliferative signalling
  • deregulating cellular enegretics
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2
Q

Outline the cancer hallmark caused by mutated oncogenes

A

sustaining proliferative signalling

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3
Q

Outline the cancer hallmark regulated via faulty tumour suppressor genes

A

evading growth suppressors

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4
Q

Name 2 enabling characteristics of cancer

A

genome instability and tumour inflammation

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5
Q

Name 2 emerging hallmarks of cancer

A

avoiding immune destruction and reprogramming energy metabolism

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6
Q

What are the major functional changes that occur in cancer

A
  1. Increased growth (loss of growth regulation, stimulation
    of environment promoting growth e.g. 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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7
Q

What cell quality is lost allowing metastasis to occur?

A

Tumors also lose cell-cell adhesion which forms part of metastases

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8
Q

What cell mechanism regulates cell numbers?

A

growth, apoptosis and differentiation

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9
Q

What causes an increase in cell number?

A

Mutations in proliferation or apoptosis regulating genes causes an increase in cell no. leading to a clinically detectable cell tumour

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10
Q

What genes are involved in growth factor signalling?

A

Tumour suppressor genes

Oncogenes

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11
Q

What growth factor signals stimulate proliferation?

A

signals / messages from:
Growth factors; EGF, PDGF
Cytokines; growth hormone, interleukins
Hormones; oestrogen

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12
Q

Describe the growth factor signalling causing cell loss

A

Apoptosis - programmed cell death as a result of irrepairable damage

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13
Q

Describe the effect of mutated oncogenes

A

Many (proto)oncogenes are normally components of growth factor signalling pathways

When mutated produce products in higher quantities or whose altered products have increased activity
Therefore act in a dominant manner

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14
Q

Describe the effects of Tumour Suppressor genes

A

Many tumour suppressor gene products act as a stop signal to uncontrolled growth, may inhibit the cell cycle or trigger apoptosis

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15
Q

What causes carcinogenesis?

A

There are two major types of mutated gene that contribute to carcinogenesis

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16
Q

What is the normal role of oncogenes?

A

Their normal job is to make cells divide, driving cell division forward

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17
Q

How does oncogenes role differ when mutated?

A

In cancer, pick up mutations that mean they are permanently active – a bit like putting a brick on the accelerator. The car approaches the red light and can’t stop

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18
Q

How do tumour suppressor genes counteract oncogene mutations?

A

Even if you have a mutation in an oncogene that pushes cell division forward, if your tumour suppressor genes are strong enough, they should still be able to counteract the oncogene

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19
Q

Describe the effect of mutated tumour suppressor genes

A

Tumour suppressor genes are like the car’s brakes

In cancer, pick up mutations that switch the gene off. This is like cutting the brakes in a car. Even if there is no oncogenic brake on the accelerator, without breaks the car definitely can’t stop

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20
Q

Summarise the effect of mutations on TSG and oncogenes

A

Tumour Suppressor gene: “Loss of function”

Oncogene: “Gain of function”

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21
Q

What is an oncogene?

A

An oncogene is a mutant form of a normal gene (a “proto-oncogene”) involved in the control of cell growth or division

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22
Q

What studies are important n understanding oncogenes?

A

Studies of retroviruses essential in understanding oncogenes

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23
Q

Describe the landmark Frances Peyton Rous experiment

A

Frances Peyton Rous began his work in 1910 that lead to the discovery of Rous sarcoma virus (RSV).
In 1911 when a farmer bought Rous a prized Plymouth Rock hen that had a large tumour growing in the chest muscle, he used the cell free filtrate from the chicken sarcoma and was able to induce sarcomas in healthy chickens

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24
Q

Outline Rous’s protocol for inducing sarcoma in chickens

A
  1. Chicken with sarcoma in breast muscle
  2. Remove sarcoma, break up into small tissue chunks
  3. Grind up sarcoma with sand
  4. Collect filtrate that has passed through fine-pore-filter
  5. Inject filtrate into young chicken
  6. Observe sarcoma in injected chicken
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25
Q

In Rous’s experiment how long did it take for the tumour to develop?

A

Tumours developed weeks later

Taking the new sarcoma, filtrates produced could also induce tumours in other chickens

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26
Q

How often could rous’ carry out the experiment?

A

The cycles could be repeated indefinitely

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27
Q

Describe the filtrate of rous’s experiment

A

The carcinogenic agent was small enough to pass through a filter

Although the filter used excluded bacteria it was not small enough to exclude viruses

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28
Q

What did Rous conclude form his experiment?

A

Rous concluded that a virus must be responsible for the induction of tumour formation

Discovery that this sarcoma was transmissible through viruses- Rous Sarcoma Virus

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29
Q

Does the transmission of cancer occur through viruses?

A

Although some human cancers are thought to be transmissible through viruses, most are confined to other animals

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30
Q

Why were retroviruses experimentally significant in cancer?

A

Retroviruses were important experimentally:

  • technological advances
  • funding
  • improved tissue culture techniques
  • discovery of reverse transcriptase, RNA genome, replicates via

DNA intermediate that are enveloped.

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31
Q

What causes the viral transformation of the oncogenes discovered by Rous?

A

Decades later oncogenic transformation by this virus (retrovirus virion - rous sarcoma virus) was found to be caused by an extra gene contained in its genome an ‘oncogene’ called v-src

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32
Q

What is v-src?

A

v-src proto oncogene altered form transduced by retroviruses

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33
Q

What is c-src?

A

c-src, cellular oncogene

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34
Q

What is the oncogene hypothesis (by Bishop et al.,) of cancer?

A

Discovered that the some genes of cancer causing viruses were mutated forms of the cellular gene not viral genes

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35
Q

What did the Bishop et al., conclude about the oncogene hypothesis?

A

They concluded that the Rous sarcoma viral gene was in fact a host gene that had
been ‘kidnapped’ by the virus (and ‘transformed’ into an oncogene)

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36
Q

How do viruses capture c-src?

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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37
Q

Describe the c-src captured by virus’

A

60kDa Intracellular tyrosine kinase can phosphorylate cellular proteins and effect growth

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38
Q

What did bishop et al., identify about v-src in their study?

A
  • v-src oncogene as responsible for causing cancer
  • Following infection however, v-src oncogene expressed at high levels in host cell
    ==> uncontrolled host cell growth,
    ==> unrestricted host cell division, and cancer.
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39
Q

What did bishop et al., find out about c-src?

A
  • Hybridization experiments: c-src gene present in many
    species genome
  • Host cell c-src gene normally involved in positive
    regulation of cell growth and cell division.
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40
Q

Describe the findings of bishop et al., relating to proto oncogenes

A
  • Proto oncogenes are normal genes that control growth
  • Various agents (radiation, chemical carcinogens,
    exogenously added viruses) may transform cells by
    “switching on” endogenous oncogenic information
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41
Q

How many of all cancers are oncoviruses responsible for?

A

Approximately 15%-20% of all human cancers are caused by oncoviruses

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42
Q

How are viral oncogenes transmitted?

A

Viral oncogenes can be transmitted by either DNA or RNA viruses.

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43
Q

How do DNA Viruses cause cancer?

A

DNA viruses can 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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44
Q

How do RNA viruses promote 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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45
Q

Describe the type of mutations that occur to oncogenes making them cancerous

A

These genes captured by animal retroviruses are altered in human cancer, activation can involve mutations, insertions, amplifications and translocations

→ Loss of response to growth regulatory factors
One allele needs to be altered

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46
Q

What is the effect amplification / duplication

A

Amplification / duplication increases levels of synthesis of gene proteins

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47
Q

What is the effect of translocation mutations?

A

Translocation forms fusion genes activating more proteins

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48
Q

Give examples of oncogenic mutations causing cancer

A

L-myc (amplification), PI3K (point mutation), PML (translocation) etc.

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49
Q

Name the 4 types of proteins involved in the growth signalling pathway

A

Growth factors
Growth factor receptors
Intracellular signal transducers
Nuclear transcription factors

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50
Q

Outline the effect of EGF in cell signalling

A

EGF binds to its receptor ErbB, which causes recruitment of adaptor molecules e.g. Ras and Raf

Signal transduction molecules such as ERK causing the upregulation of ERK MAP kinase pathway

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51
Q

What is the role of Ras and Raf in cell signalling pathway

A

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

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52
Q

How was the ras oncogene family discovered?

A

ras genes were identified from studies of two cancer-causing viruses the Harvey sarcoma virus and Kirsten sarcoma virus, These viruses were discovered originally in rats hence the name Rat sarcoma

53
Q

Describe the normal role of RAS proteins

A

RAS proteins are small GTPases that are normally bound to GDP in a neutral state

54
Q

What RAS mutations cause cancer?

A

Most commonly mutated oncogene

Point mutations in codons 12, 13 and 61 activate RAS

55
Q

Describe the mutations that cause bladder and lung carcinomas

A

Glycine to valine - bladder carcinoma

Glycine to cysteine - lung cancer

56
Q

Outline the RAS Signal Transduction Pathway

A
  1. Binding of extracellular growth factor signal
  2. Promotes 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 
    signalling cascade (mitogen activated protein kinases)
  1. These kinases ultimately phosphorylate targets, such as
    transcription factor to promote expression of genes
    important for growth and survival
57
Q

How does RAS regulate itself

A

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

58
Q

What is the consequence of RAS point mutations?

A

Consequence of each of these mutations is a loss of GTPase activity of the RAS protein normally required to return active RAS to the inactive RAS GDP

59
Q

What is the effect of loss of GTPase activity on RAS?

A

Constitutive activation without undergoing checks from the cell cycle checkpoints

DNA damage not detected or repaired

60
Q

What are the commonly mutated transcription factors?

A

> MYC oncogene family

61
Q

Describe the MYC oncogene family

A

The MYC oncogene family consists of 3 members; C-MYC, MYCN, and MYCL, which encode c-Myc, N-Myc, and L-Myc, respectively

62
Q

Where was the MYC family first identified?

A

Originally identified in avian myelocytomatosis virus (AMV)

63
Q

What is the role of the MYC oncoprotein family?

A

The MYC oncoproteins belong to a family of transcription factors that regulate the transcription of at least 15% of the entire genome

64
Q

What are some of the downstream effectors of MYC oncogenes?

A

Major downstream effectors of MYC include those involved in:

  • ribosome biogenesis
  • protein translatio
  • cell-cycle progression
  • metabolism
65
Q

Describe the result of MYC effectors being activated

A

They orchestrate a broad range of biological functions, such as cell proliferation, differentiation, survival, and immune surveillance

66
Q

Describe MYC oncogene activity in tumours

A

The MYC oncogene is overexpressed in the majority of human cancers and contributes to the cause of at least 40% of tumours

67
Q

Describe the structure and function of the MYC gene

A

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

68
Q

When is MYC activated?

A

Generally MYC is activated when it comes under the control of foreign transcriptional promoters
e.g. chromosomal translocation

69
Q

What is the result of MYC activation?

A

This leads to a deregulation of the oncogene that drives relentless proliferation

Such activation is a result of chromosomal translocation

70
Q

What carcinogenic virus causes Burkitts Lymphoma (BL)?

A

Epstein Barr virus is associated with Burkitt’s lymphoma (BL)

71
Q

What is Burkitts lymphoma?

A

BL is a high grade lymphoma that can affect children from the age of 2 to 16 years

72
Q

What is endemic (classical African) BL?

A

In central Africa, children with chronic malaria infections have a reduced resistance to the virus

73
Q

What causes BL?

A

All 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

74
Q

Which chromosomal translocations occur in BL patients?

A

In BL three distinct, alternative chromosomal translocations occur from chromosomes 2, 14 and 22 onto a section of fused chromosome 8

75
Q

What is the consequence of chromosomal translocations?

A

responsible for activating other oncogenes

76
Q

What % of leukaemias is CML?

A

Chronic myelogenous leukaemia (CML) accounts for 15-20% of all leukaemias

77
Q

What gene mutation is responsible for CML?

A

95% of CML patients carry the Philadelphia chromosome, that is the product of the chromosomal translocation t(9;22)(q34;q11) generating the BCR-ABL fusion protein

78
Q

What is the consequence of the philadelphia gene in CML patients?

A

As a result of this translocation the tyrosine kinase activity of the oncogene ABL is constitutive leading to abnormal proliferation

79
Q

What treatments are available for CML?

A

Therapeutic strategies for CML include Imatinib (Gleevac) a tyrosine kinase inhibitor-96% remission in early-stage patients

80
Q

Describe the cell hybridization experiment carried out by Harris et al., in discovering TSG

A

somatic cell hybridization experiments

Fusion of normal cells with tumour cells yielded hybrid cells containing chromosomes form both parents. These cells were not capable of forming tumours

81
Q

In Harris’ experiment what prevented tumours from forming?

A

Genes derived from the normal parent acted to inhibit or suppress tumour development

82
Q

What tumour was studied to identify TSG?

A

The first tumour suppressor gene was identified by studies of retinoblastoma, a rare childhood eye tumour

83
Q

What is the role of TSG products?

A

Act as stop signs to uncontrolled growth, promote differentiation or trigger apoptosis

They are usually regulators of cell cycle checkpoints (e.g. RB1), differentiation (e.g. APC) or DNA repair (e.g. BRCA1)

84
Q

What is required to occur for TSG inactivation?

A

Loss of tumour suppressor gene function requires inactivation of both alleles of the gene
Inactivation can be a result of mutation or deletion

85
Q

What is retinoblastoma?

A

Retinoblastoma 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

86
Q

Describe how to identify a retinoblastomic eye

A

An eye that contains a tumour will reflect light back in a white colour.
Often called a “cat’s eye appearance,” - leukocoria.

87
Q

What are the 2 forms of the retinoblastoma disease

A

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

The hereditary mutation is on chromosome 13 (13q14),
the retinoblastoma 1 (Rb1) gene

88
Q

When was RB1 discovered?

A

The existence of the RB1 gene was predicted in 1971 by Alfred Knudson

89
Q

Describe knudson’s two-hit hypothesis

A

He proposed:

Development of retinoblastoma requires two mutations, which are now known to correspond to the loss of both of the functional copies of the Rb gene - “two-hit” hypothesis

90
Q

What is meant by loss of heterozygosity

A

The process leading to inactivation of the second TSG copy - a heterozygous cell receives a second hit in its remaining functional copy of the TSG
=> becomes homozygous for mutated gene

91
Q

What type of mutations cause TSG inactivation?

A

called loss-of-function mutations

Often point mutations or small deletions that disrupt function of the protein encoded by the gene

92
Q

Describe the Rb gene family composition

A

The Rb gene family includes three members: Rb/(p105/110), p107 and Rb2/p130
-collectively known as pocket proteins

93
Q

Describe the structure of pRB

A

pRb is a multi functional protein (110kDa) with over 100 binding partners

94
Q

What is Rb protein?

A

Rb is a transcriptional co factor that can bind to transcription factors

95
Q

What is the role of pRB?

A

RB functions in diverse cellular pathways (apoptosis and the cell cycle)
RB regulates these pathways through stimulation / inhibition of interacting proteins activity

96
Q

What is pRB’s binding partner?

A

It’s main binding partner is the E2F transcription factor, interacting with the large pocket

Other viral oncoproteins can bind to Rb

97
Q

What is the main function of Rb?

A

Main function of Rb is to regulate the cell cycle by inhibiting the G1 to S phase transition

98
Q

Name the 2 important proteins of the cell cycle

A

2 important proteins involved in the cell cycle are:

Cyclins and their associated cyclin dependent kinases (cdks)

99
Q

How is the cell cycle regulated?

A

Passage of a cell through the cell cycle is regulated by

cyclins and cyclin dependent kinases (cdks)

100
Q

What is the first cyclin of the cell cycle?

A

Cyclin D is the first cyclin to be synthesized and drive progression through G1 together with cdk4/6

101
Q

What occurs at the G1 checkpoint of the cell cycle?

A

The G1 checkpoint leads to the arrest of the cell cycle in response to DNA damage

102
Q

What causes Rb phosphorylation?

A

Cyclin D and E families and their cdks phosphorylate RB

103
Q

How does Rb regulate the cell cycle?

A

Rb protein regulates the activity of the E2F transcription factor crucial for the expression of genes required for S phase

104
Q

How is Rb activity mediated?

A

Rb activity is regulated by phosphorylation

When the Rb tumour suppressor is active it can inhibit cell proliferation

105
Q

What is the result of dephosphorylation of Rb?

A

When Rb is dephosphorylated/hypophosphorylated it is active and remains bound to E2F
When Rb is active it blocks the progression of cells to S phase

106
Q

What is the effect of hyperphosphorylated rb?

A

When Rb is hyperphosphorylated , in response to extracellular physiological signals it is inactive

107
Q

What happens when Rb is phosphorylated?

A

Upon phosphorylation of RB, E2F is released and migrates to the nucleus to induce transcription => inactive Rb

108
Q

What is the effect of inactive Rb

A

When RB is inactive cell cycle progression from G1 to S occurs

109
Q

Describe the ways Rb can be inactivated

A

Rb can be inactivated by phosphorylation, mutation, or viral oncoprotein binding

110
Q

How is pRb inactivated in retinoblastoma?

A

In retinoblastoma, pRb is functionally inactivated by mutations or partial deletions

111
Q

How does viral inactivation of Rb occur?

A

Viral inactivation found in small DNA tumour viruses

mainly by disrupting E2F binding or destabilisation of Rb

112
Q

Outline different viral inactivations

A

Adenovirus - E1A
Papilloma - E7
Polyoma – Large T antigen

113
Q

Explain how RB activity in cancer causes deregulation of the cell cycle

A

In cancer cells RB phosphorylation is deregulated throughout cell cycle

As a direct consequence E2F transcription factors can induce the deregulation of the cell cycle
=> cells move through G1 into S and are not subjected to usual checks

114
Q

What is the role of the p53 gene?

A

The p53 gene was the first tumour suppressor gene to be identified
It is involved in sensing DNA damage and regulating cell death/apoptosis as well as other pathways

115
Q

What is the p53 mutation rate in cancers?

A

p53 is mutated in 30-50% of commonly occurring human cancers

p53 specializes in preventing the appearance of abnormal cells

116
Q

What is the effect of tumour cells on p53?

A

Frequent mutation of p53 in tumour cell genomes suggests that tumour cells try to eliminate p53 function before they can thrive

117
Q

Outline the p53 gene structure

A

Protein has an amino transactivation domain, a central DNA binding domain, a tetramerization domain and a carboxyl regulatory domain

118
Q

How many substrates can p53 bind to?

A

Can bind to around 300 different gene promoter regions-main role as a transcription factor

119
Q

What is the regular numbe rof p53 protein?

A

Normally levels of p53 protein are low in cells

120
Q

How are p53 levels kept low in cells?

A

These levels are kept low by MDM2 protein, a ubiquitin ligase (also an oncogene)

121
Q

Outline how MDM2 regulates p53 number

A

In unstressed normal cells both p53 and MDM2 move between the nucleus and cytosol

  1. MDM2 binds p53 to form a complex in the nucleus
  2. MDM modifies the carboxyl terminus of p53 and targets it for degradation by the proteasome

WT p53 has a short 20 min half life

122
Q

What causes p53 activation?

A

Stress signals are able to activate p53

123
Q

How are p53 activating signals detected?

A

Signals are sensed by mainly kinases that then phosphorylate p53

124
Q

What is the consequence of phosphorylated p53?

A

Phosphorylation of p53 disrupts the interaction between it and MDM2

125
Q

Give an example of p53 activation

A

e.g. ionizing radiation signals through two kinases ATM/ATR activate oncogenes such as ras induce activity of p14arf responsible for sequestering MDM2

126
Q

What is the main cause of p53 dysfunction?

A

Mutational inactivation is considered to be one of the most common molecular mechanisms behind the dysfunction of p53.

127
Q

Outline the gene therapy strategy for p53 mutations

A

Retroviruses integrate in a stable form into infected cells genome

Retrovirus-mediated gene transfer of the wild-type TP53 gene into both human lung tumour cell lines and xenograft models could lead to the inhibition of tumour cell growth

128
Q

Describe the different inhibitors used for p53 mutations

A

PRIMA-1, Restores mutant p53 by modifying the thiol groups in the core domain of the protein (reverting back to WTp53

Nutlin- is a potent MDM2 antagonist; prevents refolded p53 from proteasomal degradation

RITA binds to p53 and can restore mutp53 activity

Inhibitors of CRM1 result in nuclear accumulation of p53

129
Q

What is genetic analysis and personalised medicine?

A

A detailed readout of the molecular faults in a patient’s tumour, and new generation of drugs that precisely target them

Cellular Pathology (13 decks)

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