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Biology of Cancer > Introduction to Oncogenes > Flashcards

Introduction to Oncogenes Flashcards

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1
Q

What are the different stages of the cell cycle?

A
  1. Metaphase (M)
  2. G1 phase (G1)
  3. S phase (S)
  4. G2 phase (G2)
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2
Q

Describe Metaphase

A
  • 1st stage of cell cycle
  • Contains M checkpoint which checks that chromosome spindle attachment was successful
  • Checkpoint is regulated by procto-oncogenes (Ras, Myc)
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3
Q

Describe G1 phase

A
  • 2nd stage of cell cycle
  • Includes G0 which is the resting state of the cycle
  • Contains G1 checkpoint which checks for nutrients, growth factors, DNA damage
  • Checkpoint is regulated by procto-oncogenes (Ras, Myc) and tumour suppressor (pRb)
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4
Q

Describe S phase

A
  • 3rd stage of cell cycle
  • Site of DNA synthesis
  • Contains S checkpoint which checks for cell size and DNA replication
  • Checkpoint is regulated by tumour suppressor p53
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5
Q

Describe G2 phase

A
  • 4th stage of cell cycle
  • Contains G2 checkpoint which checks for cell size and DNA replication
  • Checkpoint is regulated by procto-oncogenes (Ras, Myc)
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6
Q

What is a procto-oncogene?

A

Normal cellular genes which regulate cell growth and/or division and differentiation

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7
Q

What is an oncogene?

A

A procto-oncogene that has been activated by mutation or overexpression

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8
Q

What does an oncogene cause?

A

Deregulated cell division

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9
Q

What was the first oncogene discovered in chicken?

A
  • SCR oncogene was discovered in 1970
  • c-SCR (procto-oncogene) -> v-SCR (oncogene)
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10
Q

How many types of conversion of procto-oncogene -> oncogene are there?

A

2 main types

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11
Q

What is the first way in which a procto-oncogene is converted into an oncogene?

A
  • A mutation in the gene results in a different oncoprotein instead of the normal protein being expressed in the cell
  • This protein produced is abnormal and has a different structure to the normal protein
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12
Q

What is the second way in which a procto-oncogene is converted into an oncogene?

A
  • A mutation in the gene results in the same protein being expressed but at higher levels resulting in more of the protein being produced than normal
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13
Q

What are the 3 different changes that activate an oncogene?

A
  1. Point mutation
  2. Gene amplification
  3. Chromosomal translocation
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14
Q

What is point mutation?

A
  • Mutation within the gene which activates the oncogene
  • Results in a mutant hyperactive growth-stimulating protein being produced in a normal amount
  • eg KRAS in lung cancer
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15
Q

What is gene amplification?

A
  • Multiple copies of the gene results in the normal growth-stimulating protein being produced in excess
  • eg c-myc in breast cancer
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16
Q

What is chromosomal translocation?

A
  • Gene is moved to a new DNA locus and is under new controls
  • normal growth-stimulating protein is produced but in excess
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17
Q

How many pathogenic alterations are required to activate an oncogene?

A

Only one pathogenic alteration on one copy of a procto-oncogene can transform it into an oncogene

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18
Q

How many copies of an oncogene is sufficient to promote tumorigenesis?

A

A single copy

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19
Q

What phenotype do oncogenes that cause cancer have?

A

A dominant phenotype

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20
Q

Are procto-oncogene mutations inherited?

A

They are rarely inherited as they are somatic mutations which occur in non-germline cell types

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21
Q

What are 4 different types of procto-oncogenes?

A
  1. Growth factor
  2. Growth factor receptor
  3. Signal transducers
  4. Transcription factor activators
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22
Q

What is HER2 protein?

A

HER2/neu/ERBB2 gene encodes for part of the human epidermal growth factor response 2 protein (HER2)

23
Q

How is HER2 able to function?

A
  • Receptor dimerisation is required for HER2 function
  • Can be activated by heterodimerisation with HER3/EGFR
  • Or can be activated by homodimerisation with another HER2 molecule
24
Q

What does the heterodimerisation of HER2 achieve?

A
  • When HER2 is bound with a receptor-specific ligand, a signal cascade occurs which results in activation of transcription in genes
  • This allows cell proliferation, survival and motility
25
Q

What does the intracellular tyrosine kinase activity of HER2 achieve?

A

Allows HER2 to use ATP to phosphorylate and activate substrates

26
Q

How is HER2 implicated in breast cancer?

A
  • HER2 is amplified in approx 20% of invasive breast cancers
  • It is associated with aggressive disease and poor prognosis
27
Q

How much is HER2 proteins increased by if activated into an oncogene?

A

20 thousand copies before to 20 million after oncogene activation

28
Q

What is the effect of multiple copies of HER2 proteins?

A
  • Leads to excess activation due to an increase of heterodimers
  • Leads to too much degradation of p27 due to an increase of homodimers
29
Q

How can HER2 oncogene be treated?

A
  • Target therapy through the use of two monoclonal antibodies
  • Trastuzumab and Pertuzumab
  • Only effective in HER2+ cancers (amplified HER2)
30
Q

How does trastuzumab work?

A
  • Binds to HER2 when it is overexpressed to increase p27 to aid the cell cycle
  • Applied to HER2+ breast cancers in combination with chemotherapy
31
Q

How does pertuzumab work?

A
  • Inhibits dimerisation of HER2 with HER3
  • Can be used in combination with trastuzumab
32
Q

What is KRAS protein?

A
  • Belongs to Ras proteins family which are cellular signal transducers
  • Activated downstream of HER2
  • Activated by receptor tyrosine kinases
33
Q

How is KRAS activated?

A
  • KRAS GDP is the inactive form and KRAS GTP is the active form
  • Becomes activated when GTP is converted into GDP
  • Becomes deactivated when the activated form binds with Pi
  • Therefore works like an on/off switch
34
Q

What is the importance of KRAS protein?

A

The signalling pathways control the transcription of genes when regulate cell growth and differentiation

35
Q

What are some of the pathways KRAS activates?

A
  1. MTORC1 pathway = cell survival, growth, migration
  2. PLD pathway = endocytosis
  3. RHO pathway = cytoskeleton, cell migration
36
Q

How is KRAS mutated?

A

Point mutations in hotspots at codons 12/13 and in lower frequencies at 18/61/117/146

37
Q

What does KRAS mutation result in?

A
  • Reduced intrinsic GDP activity which leads to permanent activation of KRAS
  • Leads to downstream signalling pathways causing malignant transformations
  • This results in KRAS being in a permanent ‘on’ position leading to permanent cell growth and proliferation
38
Q

Is the KRAS oncogene treatable?

A

Does not react to target therapy but recent research has promising data on small molecular inhibitors

39
Q

What is the BCR-ABL1 oncogene?

A
  • The fusion of protein making gene BCR and signal transducer gene Abl
40
Q

How is the BCR-ABL1 oncogene formed?

A
  • ABL gene is found in chromosome 9
  • BCR gene is found in chromosome 22
  • The parts of each chromosome containing the gene break off from the chromosome
  • The parts of the chromosomes containing ABL and BCR fuse together through balanced translocation, to create changed chromosome 22, also known as Philadelphia chromosome (Ph’)
  • The parts of the chromosomes not containing either gene also fuse to create changed chromosome 9
41
Q

Why is Philadelphia chromosome (Ph’) important?

A

It appears in 95% of cases of chronic myeloid leukaemia (CML)

42
Q

What does BCR do?

A

Encodes a protein that acts as a guanine nucleotide exchange factor for Rho GTPase proteins

43
Q

What does ABL do?

A

Encodes a protein tyrosine kinase whose activity is tightly regulated

44
Q

What does the BCR-ABL1 oncogene do?

A
  • Produces BCR-ABL oncoproteins which results in unregulated protein tyrosine kinase activity
45
Q

What are the effects of BCR-ABL oncoproteins?

A
  1. Proliferation of progenitor cells in the absence of growth factors
  2. Decreased apoptosis
  3. Decreased adhesion to bone marrow stroma (triggers leukaemia)
46
Q

What therapies inhibit BCR-ABL1?

A
  • Easy to diagnose
  • Drug imanitib specifically inhibits BCR-ABL1 from phosphorylating substrates in order to treat leukaemia
47
Q

What is c-MYC protein?

A
  • Belongs to Myc family which are genes that encode for transcription factors
48
Q

How do MYCs work?

A
  • They function in a complex with Max protein
  • Activates a high number of genes that are involved in many cellular and molecular pathways
49
Q

What are some molecular pathways activated by MYCs?

A
  1. Increased transcription
  2. Increased rRNA and protein synthesis
  3. Increased glycolysis
50
Q

What are some cellular pathways activated by MYCs?

A
  1. Increased cellular proliferation
  2. Increased metabolic transformation
  3. Increased metastatic capacity
51
Q

How does c-MYC become activated into an oncogene?

A

Pathogenic alterations involve gene retrovirus activation, amplifications and translocations

52
Q

What is the retrovirus activation alteration of the c-MYC gene?

A
  • Insertion of a retrovirus between exons 1 and 2 in c-MYC procto-oncogene in the same transcriptional orientation
  • The procto-oncogene becomes activated leading to transcription of c-MYC mRNA which translates to produce c-MYC protein
  • Commonly found in bursal lymphomas in chickens when retrovirus avian sarcoma leukosis virus (ASLV) is inserted
53
Q

What is the translocation alteration of the c-MYC gene?

A
  • Translocation between chromosome 8 (c-MYC procto-oncogene) and chromosome 14 (immunoglobulin heavy chain gene) resulting in their fusion into one gene
  • Commonly observed in 85% of Burkitt’s lymphoma in humans
54
Q

What therapies are there for c-MYC?

A
  • Lack of strategies that directly target c-MYC
  • Inhibitors of the translation caused and MYC protein destabilising drugs do show great promise

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