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Unit 14 > Molecular Basis of Cancer > Flashcards

Molecular Basis of Cancer Flashcards

1
Q

What are the four different cell fates when considering cell homeostasis?

A

Survival
Growth and divide
Differentiate
Die (apoptotic cell)

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2
Q

What is the process of normal cell proliferation?

A
  1. Binding of a growth fractor to its specific receptor
  2. Transient and limited activation of growth factor receptor
  3. Activates several signal transducing proteins on the inside of the plasma membrane
  4. Transmission of signal through cytosol via second messenger or by cascade of signal transduction molecule
  5. Induces and activates nuclear regulatory factors - initiate DNA transcription
  6. Entry and progression of the cell into the cell cycle, leads to cell division
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3
Q

What processes need to occur in order for a cell to multiply successfully?

A

Extracellular signals
For cell-cycle progression - mediated by mitogens binding to cell membrane receptor
For cell growth - mediated by growth factors binding to cell membrane receptors for nutrient uptake and utilization.

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4
Q

What signalling process leads to cell devision from the binding of a mitogen?

A

Mitogen binds to cell surface receptor (TKR).
Triggers auto and transphosphrylation of intracellular domain
Now active receptor - adaptor protein DRB2 and SOS
SOS is a GEF results in activation of Ras (GTPase)
Activated Ras binds to Raf which autophosphorylates and activates a MAPK signalling cascade - in which MEK and ERK are phosphorylated and activated.
MAP kinase translated into the nucleus - acts as a transcription factor for gene needed for cell division,
Immediate early gene expression of Myc (also a transcription factor) resulting in cyclin D production.

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5
Q

What is the role of NF1 in mitogen activated signalling cascade?

A

Is a tumour suppressor gene
Negativly regulates the activity of Ras through GTPase activity.

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6
Q

How does growth factor lead to increased growth of the cell?

A

Binds to cell membrane-bound receptor. (TKR).
Intracellular domains are phosphorylated and activated.
Results in activation of PI-3 kinase
Activation of Akt
1) activates mTOR - results in increased protein synthesis, increased glucose transport through cell membrane transporter, increased glycolysis.
Increased glycolysis means increased pyruvate to enter the mitochondraite for the TCA cycle, results in increase citirete in cytosol
2) activates ATP citrate Lyase - converts citrate to Acetyl CoA - inc lipid synthesis
Results in increased membrane biosynthesis required for cell growth

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7
Q

What is meant by the cell cycle block?

A

A molecular circuitry in the nucleus, processes and integrates multiple afferent intracellular and extracellular signals to decide if the cell should enter the cell cycle or remain in a non-proliferate state.
Regulates biochemical process responsible for cell division.
Outcomes are - programming cell cycle phases, enter into a quieceint state or enter into active cell cycle.

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8
Q

What is the cell cycle control system?

A

Regulation of the progression of the cell through the cell cycle - mainly mediated through cyclins and CDK which vary in concentration through the cycle.
Influenced by intracellular and extracellular signalling processes,
Ensures all processes are completed and correct.
Acts as checkpoints

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9
Q

What are the four different classes of cyclins?

A

G1/S cyclins
S-cyclins
M-cyclins
G1 cyclins

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10
Q

What is the role of G1/S cyclin?
How does its concentration vary throughout the cell cycle?

A

Activate Cdks in the late G1 and help trigger progression and commitment to the cell cycle
Levels rise in mid G1 and decline rapidly in S phase.

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11
Q

What is the role of S cyclins?

A

Binds CDKs soon after porgression through Start and help stimulate chromosome duplication.
Elevated from late G1 to mitosis, can control some early mitosis events.

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12
Q

What is the role of M cyclins?
How do their levels vary through the cell cycle?

A

Activate CDks that stimulate entry into mitosis at G2/M transition.
Increase steadly during G2 and decrease mid mitosis

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13
Q

What is the role of the G1 cyclins and how does their levels vary through the cell cycle?

A

Govern G1/S cyclins
Help progress through Start in late G1.

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14
Q

Draw a diagram to represent how the level of cyclins and CDKs vary across the cell cycle?

A
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15
Q

What are the pairs of CDKs to cyclins?

A

Cyclin D to CDK4/6
Cyclin E to CDK2
Cyclin A to CDK2 or CDC2
Cyclin B to CDC2.

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16
Q

How do cyclin levels fluctuate through the cell cycle?

A

Mammalian cyclin levels fluctuate dramatically as cell progress through the cell cycle.
Tightly coordinated by cell cycle process as progresses.
heavily influenced by extracellular signals - influence cyclin D which then influcnes other cyclin levels (these other cyclins are considered cell-autonomous)

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17
Q

How are cyclin D activity regulated?

A

Activity increased by EC ligand binding to receptor, normally mitogens to TKRs.
Highest during G1
At G1/S transition - is exported from the nucleus to the cytoplasm where it can no longer have an effect on cell cycle progression.

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18
Q

What type of signalling can increase cyclin D expression?

A

RANK receptor - via NFKB
Estrogen receptor - via AP-1 TF
NEr2
Wnt-Frizzled
BcrAbl
And many more

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19
Q

What is the role of Rb in the regulation of activity through the cell cycle?

A

Rb - TSG
Norm unphosphrylated - binds to and inactivates E2F1
Cyclin D CDK4/6 - phosphorylate - becomes partially active hypophosphorylated - E2F1 - expression of cyclin E.
Cyclin E CDK2 - phosphorylate - becomes hyperphospharylated - inactive TSG - EF2R unbound and able to act as a transcription factor - cyclin A for S cycle.
Cell cycle progression
M to G1 transition - removal of phosphate groups

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20
Q

What is meant by the R point in the cell cycle?

A

The point of commitment in the cell cycle
Where mitogen signalling is no longer required for progression through the cycle.
Point at which sufficient cyclin E for completion of G1 phase - no longer require increase in Cyclin D.
May also be called to as Start point.

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21
Q

What is the role of E2F1 in the cell cycle?

A

Is a proto-oncogene
Negativly regualted by Rb, when Rb is hyperophospharylated and inactive
EF21 - acts as transcription factor for genes involved in progression through the cell cycle
Binds to E2F site on DNA, may also recuit epigenetic changes aka histone deactylase and histone methyltransferase to increase gene expression of cyclin A

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22
Q

What cancers does an Rb mutation relate to?

A

Childhood retinoblastoma - relatively rare - heterozygous congenital mutation.
More common cancers that arise later in life - carcinomas of the lung, breast and bladder - are spontaneous.

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23
Q

What are CDK inhibitor?

A

Bind to CDK, distort the cyclin binding site and the ATP binding site - reduce catalytic activity of the CDK - limits progression through the cell cycle.

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24
Q

What is the role of p27Kip1?

A

p27Kip1 is a CDKi
Blocks Cyclin A/ CDK2 function - obstructs ATP binding site in CDK - prevent progression through S phase

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25
Q

What is the role of p16INK4A in the cell cycle?

A

Is a CDKi of the INK4 class
Distort the cyclin binding site of CDK6, reduce affinity for Cyclin D.
Distores CDK6 ATP binding site - reduce catalytic activity
Prevents progression through G1.

26
Q

Why is the p16 locus important in cancer genetics?

A

Locus contains thee TSG - hence mutation very likely to lead to cancer
Contains:
p16 and p15 - type INK4 CDKi - inhibit G1/ CDK4/6 and cyclin D interaction
p14ARF - ARF protein controls stability of TSG p53
Note ARK promote is upstream of INK4a exon and shares exons.
Therefore mutations in these pathway can inhibit both Rb and p53 pathways.

27
Q

What is the role of p53 in the cell cycle?

A

Located on chromosome 17
Guardian of the genome - TSG
Prevent division of genetically damaged cells.
Influences G1/S and G2/M checkpoints.
Can cause quiescence (temporary arrest of cell cycle), sensencce (permanent arrest of the cell cycle) and apoptosis.

28
Q

How is p53 related to cancers clinically?

A

Homzygous mutation in alomst all cancers
Breast, lung and Colon.

29
Q

What are some of the different check points at different stages in the cell cycle?

A

End of G1 - is the environment favourable
G2/M transition - is all DNA replicated, only once, is the environment facouable
Mid M - are all the chromosomes attached to the spindel?

30
Q

What are some of the roles of p53?

A

Cell cycle arrest - senescens or quiescence
DNA repair,
Block of angiogenesis
Apoptosis

31
Q

What are some factors that can cause mutation of p53?

A

Lack of nucleotides
UV radiation
Ionizing radiation
Oncogene signalling
Hypoxia
Blockage of transcription factors.

32
Q

What is the role of P53 when DNA damage occurs in cancers?

A

Iosnising radtions, carcinogens and mutagens - mutated p53.
DNA damage occurs
p53 dependent genes not activated
No cell cycle arrest, no DNA repair, no senescenes
Mutant cell persist, expand, proliferate and acquire additional mutations.
Forms a malignant tumours.

33
Q

What is the role of p53 in healthy cells when DNA damage occurs?

A

DNA damage or hypoxia
p53 activated and binds to DNA.
Transcription-dependent and independent effects on targets.
Activate BAX genes for apoptosis
Activates CDKI, and DNA repair mechanisms - results in normal cells or senecnsecnes

34
Q

What is the link between cancers and infection?
what are the most common viruses related to cancer?

A

WHO - 15% cancers linked to infection, 9% viruses
The most common viruses associated with cancer are:
H.pylori, HPV, Hep B, Hep C, EBV.
Contribute to multistep oncogenesis.

35
Q

How can viruses lead to cancer?

A

Have oncoproteins that are designed to inactivate Rb and p53/
Viruses evolved to deregulate these in order to ensure own replication within host genome.
Parasitize the host cell DNA replication machinery available in G1 and S - cause initially quiscenit cells to advance into the S phase.
Human cell tends to respond to increase Rb activity -> inc E2F activity - activates p53.

36
Q

How does HPV lead to cancer?

A

Is a dsDNA virus -> papillomaviridae family virus
Oncogenic genes E6 and E7.
E6 - degrades p53 and BAX (prevents apoptosis), activates telomerase (allows rapidly progressive genome replication)
E7 - bind to Rb and displaced E2F, promotes progression through R block.
High risk strains of HPV have E6/7 with higher affinity for targets.

37
Q

What types of cancers of HPV related to?

A

Low risk strains - squamous papilloma - (being warts)
High risk strains - 16,18 - cervical cancer

38
Q

How does Human T-cell Leukemia Virus Type 1 relate to cancer?

A

HTLV-1 - forms a type fo T cell leukemia/lymphoma common in Japana and Caribbean.
Retroviridae family
Viral DNA is integrated into the host chromosome
Tax protein inactivates p53, p16/INKA4.
Activates cyclin D
Monoclonal T cell cancer - one T cell has multiple mutations

39
Q

General theory of how viruses can lead to cancer.

A

Insert their DNA into host genome proteins, regulate host cell gene expression or protein functions.
Regulate host cell progression into cell cycle to increase own replication, often inactive endogenous TSG such as Rb and P53, and activate endogenous oncogenes such as Cyclin D - encourage host cell to progress through cell cycle and prevent apoptosis.
Chronic expression of protein interfering with TSG function
Expression of viral proto-congenes

40
Q

What is viral integration in relation to viruses causing cancer?

A

Permanent insertion of viral DNA into host genome, viral DNA is broken down, created from RNA and inserted or recombined with host genome.
Either due to recombination events or part of natural retrovirus life cycle.

41
Q

How are proto-oncogenes implicated in cancer?

A

Norm - promote cell survival or proliferation
Produce - antiapoptotic proteins, transcription factors for cyclins, signalling molecules
Mutation - gain or function, dominant
Origin - point mutation, chromosomal translocation, amplication

42
Q

How are TSG implicated in cancer?

A

Norm - inhibit cell sruvuval or proliferation
Prodcue - apoptosis promoting proteins, checkpoint inhibitors, DNA repair etc
Mutation - loss of function, genetically recessive
Often deletion, point mutation, methylation

43
Q

How are genome maintenance genes implicated in cancer?

A

Norm - DNA repair or prevent damage
Example - DNA-repair enzymes
Mutation - loss of function mutation, genetically recessive, arise by deletion, point mutation, methylation
Enables more mutation to accumulate

44
Q

What are the different types of proteins that can have mutants forms in cancers?

A
  1. EC and IC signalling mocluesl
  2. signal receptors
  3. Signal transducing protein
  4. transcription factors
  5. Cell cycle control proteins
  6. DNA repair proteins
    7, Apoptopic proteins
45
Q

What are meant by cancer-critical genes?

A

Gene heavly implicated in cancer when mutated includes TSG and proto-oncogenes
TSG - Apc, p53, TGFbeta, MLH1
PO - Ras, beta-catenin
Note mutation must also occur in the correct cell type at the correct stage in development

46
Q

What are the different types of activating mutations?

A

Deletion or point mutation in coding sequences - hyperactive protein
Regulatory mutation - norm protein, over expressed
Gene amplification - promoter mutation
Chrosome rearrangement - hyperactive fusion protein or overly expressed under different promotor

47
Q

What is the two hit hypothesis related to retinoblastoma?

A

Rb mutation - TSG - recessive - require homozygous mutation to cause cancer
Hereditary Rb - mutated one allele congential - occasional cell mutates only good copy of Rb - develop many tumours in both eyes often in childhood
Non - heridary - occasional cell muttes one gene, one of its descents mutation in remaining good allele - rarer, norm one tumour in one eye in adulthood.

48
Q

What are the different ways of elminating the one remaining Rb gene in hereditary retinoblastoma?

A

Non-disjunction - chromosome loss (may be followed by duplication of mutated chromosome)
Mitotic recombination event
Gene conversion during mitotic recombination
Deletion
Point mutation
Epigenetic changes in expression

49
Q

Why are not all TSG consider recessive in the classical sense?

A

BRCA1 gene - checkpoint activation and repair
BRCA2 gene - core mechanism of homologous recombination.
TSG - involved in DNA repair - homozyoug mution is cancer causing.
Heterozygous mutation also increases the risk of cancer, reduced DNA repair function - more likely for mutation to accumulate as age - risk increases as age

50
Q

What is meant by mutation penetrance?
Give an example of a cancer mutation with a high and low penetrance

A

The proportion of people with a mutation who express the disease in their phenotype.
High - Neurofibroblastoma - almost 100%
Low - BRCA1 - 65% penetracne in over 70yrs.

51
Q

What factors can affect penetrance?

A

Age
Sex
Environment
Modifier genes
Promotor or enhancer/silencer mutations
Tissue where mutations occurs - somatic.

52
Q

What is neurofibromatosis type 1?

A

Von Recklingshausen syndrome
Mutation of NF1 gene on chromosome 17 - loss of function of TSG - autosomal dominant.
Causes tumours along the nervous system throughout the body
100% penetrance
Variable severity
Common genetic disorder - not limited by sex or race.
NF1 gene encodes for neurofibromin - GTPase activity of Ras.

53
Q

What is meant by epigenetics?

A

A stably heritable change in gene expression, resulting from a change in the chromosome that does not alter the DNA nucleotide base sequence

54
Q

Why is gene expression important to cancer?

A

Majority of eurkoryote genes are functionally silent.
Internal and external signals are responsible for turning these genes on/off, permanent changes can help differentiate tissue.
This is heavily regulated by chromatin structure altering if the gene is available for transcription.
Dysregulation of transcription of genes can cause cancer.

55
Q

What is DNA methylation and its role as an epigenetic change?

A

Most commonly occuring epigentic change
Heritable, reversible and common thereaputic target.
Pattern is determined mostly in embryogenesis to help differentiate cells and is maintained through generations of cells.
Base methylation.

56
Q

Where does the process of DNA methylation occur?

A

The addition of a methyl group to C-5 position of cytosine residues.
Mostly in CpG (5’-CG-3’) context in nucleotide sequence.
Mostly cytosine followed by a Guanine-CpG dinucleotide

57
Q

How does DNA methylation occur?

A

Reversible reaction from cytosine to 5-methylcytosine
Methy group is addition is catalysed by DNA methyltransferase (simultaneous converts AdoMet to AdoHcy.
DNA demethylase can remove the methyl group from 5-methylcytosine.

58
Q

What are the different types of methyltransferases and how are their roles different?

A

DNMT3a/b/L - add methyl group to previously unmethylated dsDNA, this re-establishes the methylation process aka during embryogenesis

DNMT1 - maintains pattern of methylation after DNA replication, requires a hemi methylated DNA substrate, mirrors methylation on base pairs in daughter stand ‘an automatic semi-conservative mechanism’/

59
Q

What is the function of DNA methylation?

A

Long term silencing of genes
X-chromosome inactivation
Establishment and maintenance of imprinted genes
Silencing of repetitive elements e.g transposons
Suppression of expression of viral genes and other delterious insertion into host genome.
Carcinogenesis

60
Q

How can abnormal patterns of DNA methylation lead to carcinogenesis?

A

Methylation may be in promotor region in throughout genome
Alters expression of nearby genes.
Cancer tends to have genome wide loss of DNA methylation.
Promotors with CpG islands tend to be hypermethylated and gene silenced - in cancer tends to be TSG
Methylation - decrease expression
Contrasingly a decrease in methylation can increase expression - oncogenes

Unit 14 (17 decks)

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