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BMS247 Stem Cells > L13 - Tumour Supressor Genes > Flashcards

L13 - Tumour Supressor Genes Flashcards

1
Q

Activation of oncogenes

A

Leads to proliferation

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2
Q

Inactivation of TSGs

A

Leads to proliferation

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3
Q

TSGs are involved in cancer when they are

A

Inactivated or lost

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4
Q

Viral oncogenes have a

A

Dominant effect

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5
Q

The cancer phenotype is

A

Recessive

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6
Q

What is the cell fusion technique

A

Comparison of two alternative alleles and specificed phenotypes when both are forced to co-exist
Dominant allele wins

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7
Q

Growing many nuceli in the same cytoplasm is known as

A

Heterokaryon

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8
Q

Are hybrid cells able to form tumours

A

NO

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9
Q

What were the arguments in favour of there being tumour supressor genes

A

Easier to lose a TSG by mutation than activating an oncogene
SINCE SPECIFIC mutations are required for the gain of funtion

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10
Q

What were the arguements AGAINST the existance of TSGs

A

2 copies of the TSg must be lost through 2 separate genetic alterations
Complex and thoguh to be improbable to occur in such a short spac of time

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11
Q

What cancer provides genetic eveidence for TSGS

A

Retinoblastoma

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12
Q

General retinoblastoma

A

Tumour of the eye
Arrises from photoR precursors
Affects 1:20’000
Diagnosed from birth up to age of 6-8

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13
Q

Two forms of retinoblastom

A

Sporadic and familial

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14
Q

Sporadic Rb

A

Develops in children with no family history
Single eye
UNILATERAL

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15
Q

Familial Rb

A

Children that have a parent who suffered from Rb
Development of multiple foci
BILATERAL RETINOBLASTOMA

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16
Q

Who proposed the two hit hypothesis regarding the formation of retinoblastoma

A

Knudson

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17
Q

Why is familial both eyes and sporadic a single eye

A

Familial - higher only need a single event

Sporadic (single eye) - require two random events

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18
Q

Children with WT Rb from both parents require

A

Two successive alterations in the retinal cell lineage - this is required to inactivate the two functional copies

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19
Q

Children with an Rb mutation inherited from the parents require

A

A single mutation in the other copy - this is sufficient to be able to drive retinoblastoma

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20
Q

Probability of a single mutagenic event occuring in the first place

A

10^-6

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21
Q

Probability of 2 successive mutations occuring in the Rb gene

A

10^-12

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22
Q

How may mitotic recombination be involved with Rb

A

Chr arm containing the WT allele might be replaced with the one containing the mutant allele

23
Q

Why is it more likely that mitotic recombination is involved as oposed to mutational inactivation

A

Occurs at a higher freq (10^-5/4)

24
Q

What are two ways in which TSGs may function

A

Direct supression of cell proliferation in resposne to growth-inhibitory and differentiation-idnucing factors
Compoentents of the cellular machinery that inhibits proliferation in response to metabolic imbalance and DNA damage

25
Q

What were the first two TSGS to be studied

A

Rb and p53

26
Q

NF-1 is a

A

Negative regulator of Ras

27
Q

Mutations in NF1 can cause

A

Neurofibromatosis

28
Q

Neurofibromatosis

A

Familial cancer
Benign tumour in the PNS
Some progress into neurofibrosarcomas

29
Q

NF1 encodes a

A

Ras GAP

30
Q

What is the action of a Ras GAP

A

Causes the hydrolysis of GTP terminating signalling

SO when mutated get a consituitvely active rase

31
Q

What is the result of a mutation in NF1 and the effect on this of the protein produced

A

Mutations in NF-1 leads to a protein which has a 1000 fold decrease in its ability to stimulate GTP hydrolysis

32
Q

What percentage of colon cancers are sporadidc

A

95%

33
Q

APC

A

Adenomatous polyposis coli

34
Q

In the inestinal niche where are stem cells found

A

Bottom of the crypt

35
Q

What are the two fates of the stem cell pool

A

Some remain at the bottom of the crypts to retain the stem cell pool

Most move up as TRANSIT AMPLYIFYING CELLS and are dispatched to the luminal surface of the epithelium

36
Q

What are some of the defence mechanisms in the I crypt

A

Even if cells sustain mutations they die within days - this causes no damage to the intestin

37
Q

Because of the defecne mechanisms what mutation is required to fascilaitate the formation of cancer

A

Mutations which bock the out migration of cells form the crypt

38
Q

What is outmigration controlled by

A

B-catenin which is regulated through Wnt signalling

39
Q

APC mutations block

A

The outmigration of cells so they accumulate

40
Q

APC negatively controls the levels of

A

cytosolic B catening

41
Q

Where is APC expressed

A

Not expressed in the cells at the bottom of the crypt

As cells begin to move upward they express APC

42
Q

What is the effect of APC not being expressed in the cells of the bottom of the crypt

A

B catenin is able to accumulate in the nucelus

43
Q

Molecular consequences of APC inactivation

A

B catenin is able to accumulate in the cytoplasm and then is able to be translocated to the nucelus

Causes transcription of growth promoting genes including myc

44
Q

What is VHL

A

Von Hippen Lindau syndrome

45
Q

pVHL is important in the modulation of the

A

Hypoxic resposnse

46
Q

VHL inactivated in 70% of

A

sporadic kidney carcinomas

47
Q

Normoxia is

A

Normal oxygen tension

48
Q

Hypoxia is

A

Subnormal oxygen tension

49
Q

HIF-1a

A

Promotes the destruction of the transcription factor HIF-1a

50
Q

What is the expression of pVHL in tumours

A

No expression undetectable

51
Q

Where to mutations occur in the VHL protein

A

In the amino acid residues in the hydrophobic pocket recogniseing hydroxyproline residues in HIF-1a

52
Q

The overall consequence of a mutant pVHL at the molecular level is

A

Conistiuitive activation of HIF-1a TFs

53
Q

What is the result of conistiuitive activation of HIF-1a TFs

A

Transcription of growth promoting genes whih stimulate the proliferation of a variety of cell types

BMS247 Stem Cells (14 decks)

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