Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

BMS247 - Stem cells > TSG > Flashcards

TSG Flashcards

1
Q

What drives cancer cell proliferation?

A

The activation of an oncogene

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

What did the discovery of the proto-oncogene provide?

A

A simple and powerful explanation of how cell proliferation is driven

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

What does the inactivation of a tumour supressor gene cause?

A

Causes cancer

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Are VIRAL oncogenes dominant or recessive?

How was this shown?

A

Dominant

Infection of normal cells –> transformation
DESPITE the continued presence and expression of opposite cellular genes that mediate normal cell proliferation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

Are NON-VIRAL oncogenes dominant or recessive?

How was this discovered?

A

Recessive

Discovered by cell fusion (comparison of 2 alternative alleles and specified phenotypes when BOTH alleles are forces to coexist):

  • Dominant allele will produce the phenotype
  • Hybrid cells were UNABLE to form tumours –> cancer phenotype is RECESSIVE
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Are the majority of cancers viral or non-viral?

A

Non-viral

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Describe the cell fusion technique

A

1) Grow 2 different cells in the dish in high numbers
2) Add a FUSION agent - fuses the membranes of the cells touching together - producing a cell with a single cytoplasm and 2 nuclei
3) Genetic techniques so that only the cells with nuclei from 2 DIFFERENT cells survive

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

What is the fusion agent added in cell fusion?

A

Sendai virus or PEG

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

What is a cell called that originates from 2 different cells?

A

A heterokaryon

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

What genetic techniques can be used to ensure that only heterokayons survive?

A

Genes that convey antibiotic resistance but only express HALF in each cell type

When combine cell types –> resistance

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

What would happen in the hybrid cell if the cancer phenotype was dominant?

A

The hybrid cell will be TRANSFORMED and become TUMORIGENIC if injected into the mouse

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

What are ‘tumour supressor genes’?

A

Genes that restrain the proliferation of a cell

Are INACTIVATED during the development of a cancer

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

What are the arguments FOR the existence of TSG?

A

It is EASIER to lose a TSG by mutation than ACTIVATE an oncogene:

  • Specific mutations are required to activate an oncogene
    BUT
  • Can make mutations in many places along the DNA sequence to inactivate the TSG
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

What are the arguments AGAINST the existence of TSG?

A

TWO copies of the TSG must be lost for a phenotype:

  • Sounds improbable and complex to do in a short space of time
  • Must have 2 INDEPENDANT mutations (1 in each copy of the gene) to lead to inactivation
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

What is the genetic explanation for the recessive phenotype?

What is this?

A

Retinoblastoma

Tumour of the retina, arising in the precursor of photorecptor cells

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

Who does retinoblastoma effect?

A

CHILDREN

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

What are the 2 forms of retinoblastoma?

A

1) SPORADIC

2) FAMILIAL

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

What is the sporadic form of Rb?

A

Children with the disease come from a family with NOO HISTORY of the disease

SINGLE tumour in ONE eye (UNILATERAL)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

What is the familial form of Rb?

A

Children from a parent who has suffered from Rb

MULTIPLE foci of tumors in BOTH eyes (BILATERAL)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

Which type of Rb increases the susceptibility to other tumours?

A

Familial Rb

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

Who derived the 1 hit/2 hits hypothesis?

What did he do?

A

Alfred Knudson

Studied the kinetics with which the retinal tumours appeared in children affected by the unilateral or bilateral tumours:

  • Rate of appearance of FAMILIAL tumours (bilateral) = SIGNLE RANDOM event
  • Sporadic tumours = 2 random events (2 ‘hits’)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

What did Alfred Knudson hypothesise?

A

That mutations causing Rb are RANDOM, SPORADIC events

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

What causes retinoblastoma?

A

Mutations in the Rb gene

Which form an inactive RECESSIVE Rb allele

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

Why is the sporadic form of Rb suggested to need ‘2 hits’?

A
  • No parents affected
  • Children have 2 x WT alleles
  • 2 mutations needed - to mutate EACH copy of the genome
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Q

Why is the familial form of Rb suggested to need ‘1 hit’?

A
  • Parents affected
  • Child only have 1 x WT allele (other is mutated)
  • Only 1 mutation needed to drive retinoblastoma
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
26
Q

Why must there be a different way for the second allele to be lost (not due to mutation)?

A

PROBABILITY of BOTH mutations occurring one after the other is DOUBLE the probability of most mutational events

Most mutational events - 10^-6
Mutation one after the other - 10^-12

27
Q

What is the second way in which the second allele can be lost in retinoblastoma?

When does this occur?

A

MITOTIC RECOMBINATION (homologous recombination in mitosis)

Occurs during the G2 or M phase of the cell cycle

28
Q

What is the mechanism of homologous recombination in which the second allele is lost in retinoblastoma?

A
  • Chromosomal arm carrying the WT Rb allele might be replaced with the one carrying the MUTANT allele
29
Q

What is the frequency of mutation during mitotic recombination?

What is this compared to the frequency of a second point mutation?

A

10^-5 / 10^-4

Second point mutation = 10^-12

30
Q

What 2 results can occur when the cells divide, after crossing over?

A

1) Heterozygosity RETAINED (one mutant and one WT)

2) Heterozygosity LOST (2 x WT or 2 x MUTANT)

31
Q

What are the 2 mechanisms to stop cancer development?

A

1) Direct SUPPRESSION of cell PROLIFERATION in response to growth-inhibitory and differentiation-inducing factors
2) Components of the cellular machinery that INHIBT PROLIFERATION in response to METABOLIC IMBALANCE (lack of nutrients) and DNA damage

32
Q

What are the first 2 TSGs intensively studied?

What do these genes do?

When are they disrupted?

A

Rb and p53

These genes CONTROL the cell cycle

Disrupted in MOST human tumours

33
Q

What is NF1?

A

A NEGATIVE regulator of Ras signalling

34
Q

What is Neurofibromatosis? Cause?

What is it characterised by?

A

A familial cancer syndrome, caused by LOF in NF1

Characterised by:

  • Benign tumours in the peripheral nervous system (neurofibromas)
  • Some can progress –> MALIGNANT NEUROFIBROSARCOMAS
35
Q

What is NF1?

What does it do?

A

Neurofibromin (a RasGAP gene)

Promotes the INACTIVATION of Ras (GTP–>GDP)

36
Q

What do mutations in NF1 result in?

A

A protein with a 1000-fold decrease in GTPase stimulating activity:

  • Ras activated for LONGER
37
Q

What does loss of NF1 mimic?

A

The HYPERACTIVATION of Ras observed in the presence of mutant rat oncogenes

38
Q

What happens in NORMAL cells that are stimulated with growth factors?

A

NF1 is DEGRADED - enabling Ras signalling to proceed

39
Q

What is the APC gene?

What is it responsible for?

A

Adenomatous Polyposis Coli

Responsible for:
- The exit of cells from the colon crypts

40
Q

What is APC characterised by?

What percentage of colon cancers does this represent?

What type of cancer is this?

A

Characterised by the susceptibility to develop polyps in the colon (prone to carcinomas)

Represents 1% of colonic cancers

Inheritable cancer

41
Q

What % of the colon cancers are sporadic?

A

95%

42
Q

Describe the NORAML cell proliferation control of the colonic crypts

A
  • Stem cells are found at the BOTTOM of the intestinal crypts
  • Some progeny of these cells STAY BEHIND: to maintain a CONSTANT NUMBER of stem cells
  • MOST progenitor cells- dispatched and migrate upwards (out of the crypt), towards the LUMINAL SURFACE of the epithelium
  • These cells eventually DIFFERENTIATE and DIE
43
Q

How long does out migration and death of the progenitor cells take?

A

3-4 days

44
Q

What is the function of out migration and death?

What does this mean?

A

Effective DEFENCE mechanism:

  • Prevent the organ from mutation
  • If sustain mutation - die within days, without causing damage to the intestine

Means:
- The ONLY mutations that can drive the development of cancer in the colon crypt = mutations that block the out-migration of the cells from the crypt

45
Q

What is the movement of cells from the colon crypt upwards controlled by?

How?

A

b-catenin:

  • At the bottom of the crypt, stoma cells secrete Wnt factors –> drive the expression of b-catenin
  • When b-catenin levels = high, cells retain STEM CELL phenotype
  • As progenitors move upwards, don’t receive Wnt stimulation –> b-catenin is no longer expressed
  • Cells shut down and stop proliferating
46
Q

What is the contribution of APC to the movement of the cells from the colon crypt?

How?

A

PROMOTES the movement away from the crypt

By:
- NEGATIVELY controlling the levels of b-catenin in the CYTOSOL

  • APC NOT expressed at the bottom of the crypt - b-catenin levels are HIGH
  • b-catenin move into the NUCLEUS
  • BUT is expressed at higher levels as move upwards out of the crypt - b-catenin levels are LOW
  • b-catenin remains in the cytosol
47
Q

What happens if the expression of APC is lost?

A
  • Cells lose the ability to migrate out away from the crypt

- Mutated cells accumulate in the crypt, rather than being lost

48
Q

How does APC negatively control b-catenin levels?

A
  • APC is part of a DESTRUCTION COMPLEX

- Targets b-catenin for degradation –> cannot localise in the nucleus and drive the proliferative signal

49
Q

What happens when there is a lack of proliferative signal from b-catenin in the nucleus?

A

Cells go onto differentiate

50
Q

What happens in tumours, with regards to APC and b-catenin?

A
  • INACTIVATION of APC
  • b-catenin destruction complex not formed
  • b-catenin not degraded
  • Cytosolic accumulation and nuclear translocation of b-catenin
  • Drives the expression of certain genes
51
Q

What genes does b-catenin drive the transcription of?

A

GROWTH PROMOTING GENES - Myc

52
Q

What is the most important consequence of APC inactivation?

What is 10% of mutations?

A

Accumulation of b-catenin (90%)

10% - mutations in either b-catenin itself or OTHER components of the DESTRUCTION COMPLEX

53
Q

What does small intesting APC -/- show?

A

Cypt-progenitor cell (CPC) phenotype with INCREASED:

1) CRYPT SIZE (more proliferative progenitors)
2) NUCLEAR b-catenin

54
Q

What is Von Hippen-Lindau syndrome?

What causes this syndrome?

A

HEREDITARY PREDISPOSITION to the development of a variety of tumours in MANY locations in the body

Caused by:

  • Germ-line mutations in the TUMOUR SUPPRESSOR GENE (VHL)
  • Inactivating VHL
55
Q

What does VHL code for?

What is this important in?

A

pVHL protein

Important in modulation of the HYPOXIC RESPONSE

56
Q

How does the inactivation of VHL cause Von Hippen-Lindau syndrome?

A

VHL codes for the protein pVHL which is normally involved in:
- Promoting the DESTRUCTION of a transcription factor HIF-1a

  • HIF-1a is usually involved in controlling the response of the cells to hypoxia
57
Q

What is normoxia?

A

NORMAL oxygen tension

58
Q

What happens inside the cell under normoxic conditions? (involving HIF-1a)

A

1) 2 proline residues in HIF-1a are HYDROXYLATED
2) When hydroxylated - can bind to the pVHL and 2 additional proteins - form a complex
3) Formation of this complex leads to the UBIQUITINATION of HIF-1a –> proteosomal degredation

59
Q

What hydroxylates the 2 proline residues in HIF-1a under normoxic conditions?

A

Proline hydroxylase

60
Q

What is hypoxia?

A

SUBNORMAL oxygen tension

61
Q

What happens inside the cell in hypoxic conditions?(involving HIF-1a)

A

1) Prolines are NOT hydroxylated
2) HIF-1a cannot form a complex and is NOT degraded
3) HIF-1a combines with HIF-1b –> activated transcription of HIF target genes, which allow the cells to survive in low oxygen conditions and acquire access to oxygen supply by stimulating the formation of new blood vessels

62
Q

In hypoxia, why are the prolines of HIF-1a not hydroxylated?

A

Proline hydroxylase enzyme requires oxygen to work

63
Q

What are some of the target genes that are upregulated by HIF-1a with HIF-1b in hypoxic conditions?

A

Regualtors of:

  • Angiogenesis (formation of blood vessels)
  • Erythropoiesis (formation of RBCs)
  • Glycolysis and glucose uptake
64
Q

What are the 2 scenarios which cause the tumours in Von Hippen-Lindau syndrome that have been observed?

What do BOTH of these mutations lead to?

A

1) Mutant alleles of VHL –> no pVHL present in the cance cells
2) POINT MUTATIONS in the amino acid residues in the hydrophobic pocket in HIF-1a that normally recognises hydroxyproline residues in HIF-1a –> pVHL cannot bind –> NO degredation

BOTH lead to:

  • CONSTITUTIVE ACTIVATION of HIF-1a TF
  • Activation of growth promoting genes that stimulate proliferation of a variety of different cell types
  • Produce many tumours

BMS247 - Stem cells (15 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions