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Stem cells, Ageing and Cancer > Oncogenes and tumour suppressor genes > Flashcards

Oncogenes and tumour suppressor genes Flashcards

1
Q

what are viral oncogenes?

A
  • Viral genomes are very simple, with a few genes – these genes perturb the normal regulatory signals of cells and can induce cancer
  • tumour viruses have developed extremely potent genes to perturb the complex regulatory circuitry of the host cells that they infect
  • enough to drive the tumour phenotype
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2
Q

in the past, how was cancer considered to be induced?

A

tumour viruses suspected to be the cause of many human cancers – thought cancer was an infectious disease
- Cancer was considered to be an infectious disease which could be transmitted from one animal to another

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3
Q

how was Rous Sarcoma Virus found to cause sarcoma?

A
  • sarcoma from chicken was isolated and homogenised into small chunks of tissue, and then ground up
  • filtrate was collected by passing the tissue through a fine-pore filter
  • the filtrate was then injected into a young chicken
  • this young chicken then developed a sarcoma
  • the time of induction of the sarcoma became predictable when the filtrate was injected into multiple chickens
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4
Q

how can RSV transform cells in culture?

A

chicken embryo fibroblasts infected with RSV show cancerous phenotypes:
- foci appear after infection
- fibroblasts gain a metabolism similar to tumours isolated from animals
- under microscope, the transformed cell resembled the chicken sarcomas

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5
Q

what is cell transformation?

A

conversion of a normal cell into a cancer cell; it can be accomplished into a Petri dish

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6
Q

why was cell transformation useful in studying RSV?

A
  • provided a chance to study the consequences of RSV infection in cultured cells
  • Cancer is caused by cells that can’t function correctly – don’t need an organism to study cancer, can do in vitro
  • Not a disease of abnormally developing tissues & can be studied at the level of individual cells
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7
Q

is the continued presence of RSV required to maintain cell transformation into a sarcoma?

A

RSV particle transforms the progenitor cells and all their descendants - the virus must be present all the time to maintain the transformed phenotype

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8
Q

what evidence proves that RSV must be present at all times to maintain the transformed phenotype?

A

Temperature-sensitive (ts) RSV mutant-partially defective proteins, can function at the permissive temperature:
- Chicken embryo fibroblasts at 41 degrees cells lost the transformed shape and reverted to the shape and growth of cells that have never been infected with RSV
- transformed state is lost when the cells are kept at the non-permissive temperature (41C)
- ts RSV capable of transforming cells at 37 but not 41 degrees.
- The continued actions of the viral ts protein is required to maintain the transformed phenotype – virus must always be present to induce cancer
-The viral transforming gene was required to both initiate and maintain the transformed phenotype of the infected cells

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9
Q

what are the 9 key phenotypes of transformed/cancer cells?

A
  1. Altered morphology (rounded shape)
  2. Loss of contact inhibition (ability to grow over one another to form foci)
  3. Ability to grow without attachment to substrate (anchorage independence)
  4. Ability to proliferate indefinitely (immortalisation)
  5. Reduced requirement for mitogenic growth factors
  6. High saturation density (large number of cells grow in culture dish) – can form packed tumours
  7. Inability to halt proliferation in the absence of growth factors
  8. Increased uptake of glucose
  9. Tumorigenicity
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10
Q

what is the genome of the RSV?

A

3 genes coding for viral components:
- gag (virion nucleoprotein core)
- pol (reverse transcriptase & integrase)
- env (glycoprotein spikes of the virion) required for viral replication
- + 1 additional gene (unknown).
o Gag, pol, env = viral constituents

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11
Q

how were the functions of the RSV genes discovered? what were the functions of the genes?

A

Use of mutant viruses to reveal the functions of the genes:
- When the 3 viral constituent genes are abolished, there is no viral replication, but can still transform the infected fibroblast
- When the unknown viral gene was removed, there is normal viral replication, and no cancer transformation of the infected fibroblast

The unknown RSV gene is cancer-inducing: this gene was called src

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12
Q

do only RSV-infected cells contain a src-related sequence in their genome?

A

NO: src is present in the genome of normal organisms:
- c-src (cellular-src) and the viral src (v-src) are closely related and act as a potent oncogene = a gene capable of transforming a normal cell into a tumour cell.
- c-src is a proto-oncogene = a precursor of an active oncogene

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13
Q

what is a proto-oncogene?

A

Proto-oncogene: the genomes of normal vertebrates can carry a gene that has the potential, under certain circumstances, to induce cell transformation and thus cancer

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14
Q

do viruses cause the vast majority of cancers?

A

no, mutagens do

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15
Q

how is cancer caused?

A

cancer is induced by mutagens

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16
Q

what are mutagens? give examples:

A

physical or chemical agents that induce cancer through their ability to mutate growth-controlling genes
- Examples: UV light, X-rays, base analogs, DNA intercalating agents

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17
Q

why do chemically transformed cells become cancerous?

A

chemically transformed from mutagens cells carry mutated genes - the mutated genes responsible for the aberrant growth of these cells

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18
Q

how were mutated genes identified in cancers?

A

transfection:
- If a transforming gene is present in the donor DNA, it may become incorporated in the genome of one of the recipient cells and transform the latter
- these will form foci
- . Tumour formation in mice to confirm the transformed state of these cells.
- As a control, DNA from normal, non-transformed cells does not induce transformation
- Donor tumour DNA carried one or several genetic elements able to convert a normal cell into a tumorigenic one

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19
Q

are one or more genes mutated in cancer?

A

Only ~0.1% of the donor DNA became established in the recipient cell genome
- Very low probability of 2 independent, genetically unlinked, donor genes both being introduced into a single recipient cell - 1 in a million
- therefore only 1 gene is responsible for the transformation

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20
Q

what is the term used to describe the mutated gene in cancer?

A

oncogene

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21
Q

what did the transfection experiments detect?

A

Oncogenes detected by transfection were derived from pre-existing normal cellular genes lacking oncogenic function (proto-oncogenes) - similar scenario to the viral oncogenes

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22
Q

can viruses and mutagens activate the same proto-oncogenes?

A

Yes:
DNA probes for retroviral-associated oncogenes on cells transfected with tumour cell DNA:
- A number of proto-oncogenes were found in activated, oncogenic form in human tumour genomes

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23
Q

how can a proto-oncogene be activated to become an oncogene?

A
  • by a mutation in the genetic sequence
  • the sequence is identical between the 2 genes, except for one single codon which had been mutated in the oncogene
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24
Q

how were the changes in genetic sequences between proto-oncogenes and oncogenes discovered?

A

Normal gene and oncogene were cleaved by restriction enzymes & recombinant genes made by ligation:
- transforming activity using transfection-focus assay
- mutation responsible for oncogene activation localised to a 350bp fragment.
- Sequence was determined
- 1 single nucleotide difference, resulting in the substitution of a Gly to a Valine at the 12th codon
- Sequence is identical between the 2 genes, except for one single codon which had been mutated in the oncogene

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25
Q

how do mutagens and viral proteins cause cancer?

A

they induce mutations
- they do not directly cause cancer themselves

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26
Q

what is Ras?

A

Ras is a small GTPase
- Ras cycles between active GTP-bound and inactive GDP-bound

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27
Q

what accessory proteins regulate Ras GTPase?

A
  • GEF = guanine nucleotide exchange factors – catalyses exchange of GDP to GTP
  • GAP = GTPase-activating proteins – hydrolyses GTP to GDP
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28
Q

what is the normal function of Ras is normal cells?

A

In normal cells, under growth factor influence, Ras promotes cell division and proliferation when active, and when there are no growth factors, Ras will be bound to GDP and inactive, so proliferative signalling will be off

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29
Q

what does a mutation in Ras result in?

A

Ras G12V or G12C (mutation at G12 position) = Ras unable to hydrolyse GTP to GDP, so is constitutively active and cannot be turned off

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30
Q

how is the function of Ras changed when it is in its oncogenic form?

A

If Ras is in its oncogenic form, then it is always bound to GTP and therefore proliferative signalling is always on, even in absence of growth factors

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31
Q

what are the 3 ras proto-oncogenes present in the human genome?

A
  1. H-ras
  2. K-ras
  3. N-ras
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32
Q

in which codons may point mutations in Ras occur to induce cancer?

A

point mutation in one of three codons: 12 most frequent, than 13 and 61

~20% of all tumours have undergone an activating mutation in one of the RAS genes

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33
Q

which ras mutation is most commonly mutated in tumours?

A
  • Mutations in K-ras are the most frequent drivers of tumour development across the spectrum of human cancers
  • K-RasG12C mutation is most prevalent in lung cancers
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34
Q

what is the name of the K-ras inhibitor?

A

AMG 510

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35
Q

how does the AMG 510 KRAS inhibitor effect K-ras?

A

AMG 510 inhibitor forms a covalent bond with GDP-bound KRASG12C  high specificity for the mutant protein
- Prevents K-rasG12C from binding to GTP
- AMG 510 is specific for G12C Ras mutation only

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36
Q

why does AMG 510 not affect normal cells?

A

as normal cells do not have the Ras G12C mutation
- AMG 510 is specific for G12C Ras mutation only

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37
Q

what effects does AMG 510 KRAS inhibitor have on cancers?

A
  • AMG 510 inhibits downstream signalling and cell proliferation in lung cancer cell lines in vitro
  • AMG 510 inhibits tumour growth in mice - tumour regression in 8/10 mice
  • AMG 510 efficiency improves in combination with standard chemotherapy (carboplatin) or a drug that inhibits MEK, which acts downstream of Ras
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38
Q

in what situations is the AMG 510 KRAS inhibitor not effective?

A

AMG 510 is not effective on mice lacking an immune system – Ras-inhibitor requires an immune system

39
Q

how does the AMG 510 KRAS inhibitor used in cancer immunotherapy?

A
  • AMG 510 in combination with an immunotherapy called anti-PD1
  • harnesses the immune system to combat cancer - complete tumour regression in 9/10 immunocompetent mice
  • AMG 510 boosts the expression of pro-inflammatory cytokines in tumour-bearing animals
  • Increase infiltration of the tumours by T cells and dendritic cells
  • When KRASG12C cancer cells are reintroduced in animals cured by the combination therapy, there was no tumour formation - long term T-cell response to KRAS tumour cells induced by the treatment
40
Q

how is the AMG 510 KRAS inhibitor limited?

A

adaptive resistance to the treatment occurred rapidly
- Multiple mechanisms of resistance identified in 41% of patients during clinical trials
- in the 41% of patients, there were more than one potential mechanism of resistance

41
Q

what mechanisms do cancers use to resist the AMG 510 KRAS inhibitor?

A
  • On-target mutations disrupting the binding site – AMG 510 can no longer bind to KRASG12C
  • Drug-resistant mutations on KRAS
  • KRAS downstream effector mutations
  • Amplification of KRASG12C
42
Q

how may treatments be developed to combat cancer AMG 510 resistance?

A
  • Need second-generation inhibitors to against drug-binding mutants
  • Combination therapies are essential
43
Q

what is Myc?

A
  • Myc is an proto-oncogene which is activated and overexpressed in >70% of human tumours
  • myc is a transcription factor which promotes growth
44
Q

what are the 3 members of the myc family?

A
  1. C-myc
  2. N-myc
  3. L-myc
45
Q

where are myc proteins localised?

A

they are localised in the nucleus

46
Q

how is myc implicated in cancer?

A
  • Many times higher than the 2 copies present in the normal human genome.
  • The increased gene copy numbers results in corresponding increases in the level of the gene product, myc protein.
  • When expressed at excessive levels, myc drives uncontrolled cell proliferation
47
Q

in what 3 ways may the myc oncogene arise?

A
  1. expression is driven by its normal promoter, but the gene is amplified, resulting in an elevated copy number
  2. chromosomal translocation
  3. pro-virus integration - insertional mutagenesis
48
Q

how does gene amplification induce myc to become oncogenic?

A

N-myc amplification occurs in 30% childhood neuroblastoma
- increased levels of the N-myc gene product due to more gene copies
- therefore more N-myc protein to promote cell growth and proliferation

49
Q

what is chromosomal translocation?

A

chromosomal translocation = a region of one chromosome is fused with a region from a second, unrelated chromosome

50
Q

how does chromosomal translocation induce myc to become oncogenic? give an example:

A

c-myc is under the control of a foreign transcriptional promoter:
- Myc gene is translocated from one chromosome to another
- Burkitt lymphoma: myc gene becomes under the control of the promoter of an immunoglobulin gene = very active
- Immunoglobulins are expressed at high levels, so the myc gene will be expressed highly as well, leading to high proliferation
- Structurally normal myc protein, but abnormally high amounts = relentless proliferation of lymphoid cells
- T8:14 most common translocation = highly active Ig promoter = relentless proliferation of lymphoid cells.

51
Q

using an example, how does pro-virus integration (insertional mutagenesis) induce myc to become oncogenic?

A

ALV = avian leukosis virus - the viral transcriptional promoter disrupted the mechanisms normally controlling the expression of myc, causing increased expression, extremely high levels of myc protein
- In >80% ALV-induced leukaemia, integration of ALV provirus in the chromosomal DNA is seen immediately adjacent of the myc proto-oncogene
- This means that myc is now under the control of the ALV promoter, which is very active – myc becomes oncogenic
- this leads to uncontrolled cell proliferation, resulting in the aggressive cancer that constitutes a leukaemia

52
Q

how may structural changes in EGFR lead to oncogene activation and cancer?

A

The formation of many tumours is linked to deregulation of the epidermal growth factor receptor (EGFR):
- Normally, EGFR recognises the presence of its ligand (EGF) in the extracellular space - downstream signalling upon binding
- In 1/3 glioblastomas, cancer has a truncated form of EGFR that is constitutively active, lacking most of the extracellular domain
- Extracellular domain deletion is well documented in lung cancer and glioblastoma - constitutive signalling in the absence of the ligand
- this enables growth-stimulatory signals to be promoted in the absence of EGF

53
Q

what are the two ways in which cancer can be induced?

A
  1. activation of oncogenes
  2. inactivation of tumour suppressor genes (TSGs)
54
Q

what is the cancer phenotype, based on oncogenes and TSGs?

A

for oncogenes, the cancer phenotype is dominant

for TSGs, the cancer phenotype is recessive

55
Q

how do oncogenes have a dominant effect?

A
  • Regardless of the genes already present in the normal cells, the oncogene dominates and turns the cell cancerous
  • Viral oncogenes can dictate cellular behaviour in spite of the continued presence and expression of opposite cellular genes that usually mediate normal cell proliferation

cell transformation = conversion of a normal cell into a cancer cell, despite the continued presence and expression of opposite cellular genes that usually mediate normal cell proliferation

56
Q

what happens when a cancer cell is fused with a normal cell via a cell fusion assay? what does this indicate?

A

a hybrid cell is formed that cannot form tumours
- Therefore the normal cell phenotype dominates, as it has genes which counteract oncogenes
- Normal cells carry genes that constrain their proliferation, which are inactivated during the development of a tumour = TUMOUR SUPPRESSOR GENES

57
Q

what are tumour suppressor genes?

A

genes that constrain proliferation of normal cells, and are inactivated during the development of a tumour

58
Q

what were the arguments in favour of and against the evidence of TSGs?

A

Favour: easier to lose a TSG by mutation than activating an oncogene (specific mutations required for oncogene activation)

Against: 2 copies of TSG must be lost
- 2 genetic alterations/mutations sound complex and improbable to occur in short period of time.
- 2 mutations are needed to lose TSG, one mutation needed for oncogene

59
Q

what are retinoblasts?

A

Retinoblasts = population of cells in the developing eye; normally stop growing during embryogenesis & differentiate
- If cells keep growing, retinoblastoma can arise

60
Q

what is retinoblastoma?

A

Retinoblastoma: tumour of the retina, arising in the precursor of photoreceptor cells (retinoblasts), which fail to differentiate & divide
- ~ 1:20,000 children
- Diagnosed from birth up to the age of 6 to 8 years
- Can be cured with radiation or surgery

61
Q

what are the 2 forms of retinoblastoma?

A
  1. sporadic form - unilateral retinoblastoma
  2. familial form - bilateral retinoblastoma
62
Q

what is the sporadic form of retinoblastoma?

A

Sporadic form: children from family with no history of retinoblastoma, developing a single tumour in one eye
- unilateral retinoblastoma

63
Q

what is the familial form of retinoblastoma?

A

Familial form: children having a parent who suffered from retinoblastoma, developing multiple foci of tumours in both eyes
- bilateral retinoblastoma + elevated susceptibility of developing other tumours

64
Q

what was Knudson’s 1 hit/2 hits hypothesis?

A

Knudson used mathematics to determine whether the data followed a trend associated with a one-hit or two-hit model of gene mutation
- Information from 2 groups: 23 patients with bilateral familial retinoblastoma, & 25 patients with unilateral sporadic retinoblastoma.
- Time is required for mutations to accumulate, Knudson examined the age at which the children in these two groups were diagnosed with retinoblastoma.
- Rate of appearance of familial tumours (bilateral) = a single random event needed to develop the disease – 1 hit - rate of tumour formed is faster
- Sporadic tumours (unilateral) = 2 random events are required – 2 hits needed - takes longer for tumour to develop

65
Q

what gene mutation causes retinoblastoma?

A

a mutation in Rb gene, resulting in an inactive and recessive Rb allele

66
Q

how does sporadic retinoblastoma arise?

A

Children with 2 WT Rb from the parents require 2 successive alteration/mutations in the retinal cell lineage to inactivate the 2 copies of Rb.

67
Q

how does familial retinoblastoma arise?

A

If Rb mutations are present in the family, then the child already has one mutant Rb - the mutation of the other copy in enough to drive retinoblastoma

68
Q

how can 2 copies of Rb be lost in sporadic retinoblastoma?

A

Probability of both random mutations occurring one after the other is 10^-12 per cell generation – very rare

therefore, mitotic recombination is the cause

69
Q

what is mitotic recombination?

A

genetic material is exchanged between 2 homologous chromosomes through the process of genetic crossing over occurring during G2 phase or, less often, in M phase of the cell cycle

70
Q

how does mitotic recombination occur in sporadic retinoblastoma?

A
  • the chromosomal arm carrying WT Rb allele might be replaced with the one carrying the mutant allele.
  • Occurs at a frequency of 10^-5 to 10^-4 per cell generation - far easier way than mutational inactivation
    -Loss of heterozygosity or LOH (observed in the DNA in the vicinity of TSGs)
  • Heterozygous cell with Rb is changed for a cell which is homozygous for mutant Rb – enough to cause retinoblastoma as 2 mutants are present in the DNA
71
Q

what are the 2 mechanisms in which TSGs 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 inhibits proliferation in response to metabolic imbalance and DNA damage
72
Q

what were the first 2 TSGs which were studied, and what are their roles?

A

Rb and p53
- Both have an important role in the control of the cell cycle
- Both are disrupted in most human tumours

73
Q

what is neurofibromatosis?

A

familial cancer syndrome,
- benign tumours in peripheral nervous system = neurofibromas,
- some progress to malignant neurofibrosarcomas

74
Q

what causes neurofibromatosis?

A

LOF mutation in NF1

75
Q

what is NF1?

A

NF1 (neurofibromin) is a Ras-GAP = GTPase activating protein
- it is a negative regulator of Ras signalling

76
Q

how does NF1 function in a normal cell?

A

In a normal cell, when cell is stimulated with growth factors, NF1 is degraded, enabling Ras signalling to proceed.
- After 60-90min, NF1 levels return to normal, shutting down Ras signaling.
- NF1 is activated when needed

77
Q

what happens when a LOF mutation in NF1 occurs?

A

Mutations in NF1 result in a protein with 1000-fold decrease in GTPase stimulating activity and cannot inactivate Ras
- When NF1 is lost, Ras remains activated for longer and loss of NF1 function in a cell mimic the hyperactivation of Ras observed in the presence of mutant ras oncogenes

78
Q

what cellular pathways does ras activate? what does NF1 inhibit?

A

Ras activates:
- Raf-Erk pathway which leads to proliferation,
- P13K-Akt-mTOR pathway which inhibits apoptosis

In WT, NF1 is present, so there is less Akt and less mTOR, so apoptosis in induced

79
Q

how are signalling pathways altered when a LOF mutation in NF1 occurs?

A

NF1 null cells show overactivation of AKT and the mTOR target S6K
- NF1 null cells have an enhanced ability to form colonies in anchorage independent conditions
- When NF1 is lost, Akt and mTOR is upregulated, leading to lack of apoptosis and uncontrolled growth

80
Q

how can neurofibromatosis and loss of NF1 be treated?

A

overactivation of Akt pathway is blocked by the mTOR inhibitor called Rapamycin:
- Rapamycin inhibits mTOR, thus inhibiting the growth of the cancer
- mTOR inhibition could be a potential strategy to target NF1 null tumours

81
Q

what is adenomatous polyposis coli?

A
  • inheritable colon cancer
  • susceptibility to develop polyps in the colon, prone to develop into carcinomas.
  • The gene responsible is APC (Adenomatous Polyposis Coli)
82
Q

how does the loss of APC gene lead to colon cancer?

A

*Loss of APC gene = first step in colon cancer progression by formation of benign polyps, followed by oncogenic mutations of Ras and mutations or loss of p53 forming larger polyp and then a malignant tumour

83
Q

how are colonic crypts regulated in normal cells?

A
  • stem cells are found at the bottom of crypts, and Wnt signalling triggers the stem cells to proliferate
  • When the cells proliferate, they migrate upwards, so lose Wnt signalling, stop self-renewing and differentiate
  • They localise at the top of the crypt, undergo apoptosis and die before any mutations can give rise to cancer
  • out-migration and death takes only 3 to 4 days - effective defence mechanisms: even if cells sustain mutations, they die within days without causing damage to the intestine.
84
Q

how are colonic crypts altered under APC mutation?

A

Mutations in APC lead to the formation of cancer:
- block of the out-migration of cells from the crypt
- mutated cells accumulate in the crypt rather than being apoptosed

85
Q

what is the role of APC in normal cells?

A
  • Functional APC = part of the destruction complex, responsible for mediating the degradation of b-catenin, mediated by the proteasome
  • APC negatively controls levels of beta-catenin in cytosol
  • APC is not expressed in the cells at the bottom of the crypt - b-catenin can accumulate and move in the nucleus and promote proliferation
  • As the cells move upward, APC expression is increased, which blocks b-catenin TF and inhibits proliferation, promoting differentiation
86
Q

what is the molecular mechanism of APC inactivation in cancer?

A
  • Inactivation of APC - b-catenin cytosolic accumulation and nuclear translocation -> transcription of growth-promoting genes, including myc
  • Accumulation of b-catenin = most important consequence of APC inactivation (90% of sporadic carcinomas) – beta-catenin is a transcription factor, so can target its growth-promoting downstream targets
87
Q

how do colonic crypts vary between WT mice and APC-negative mice?

A

Wild-type mice have small defined crypts in the small intestine with little nuclear β-catenin at the bottom of the crypt.

The small intestine of APC-/- show the crypt-progenitor cell (CPC) phenotype with increased crypt size and nuclear β-catenin

88
Q

what is von hippen-lindau syndrome?

A
  • Hereditary predisposition to the development of a variety of tumours, including clear cell kidney carcinomas, pheochromocytomas (adrenal gland cell tumours) & hemangioblastomas (blood vessel tumours) in the CNS & retina
  • Caused by germline mutations in the tumour suppressor VHL, coding for pVHL protein
  • VHL gene also inactivated in ~ 70% of sporadic kidney carcinomas
89
Q

what is the normal function of pVHL?

A

pVHL main function = promoting the destruction of the transcription factor HIF-1a (hypoxia-inducible factor 1a)
- If oxygen is present, HIF-1a is hydroxylated, and pVHL binds to HIF to mediate ubiquitination and degradation of HIF
- If oxygen is absent in hypoxic conditions, hydroxylase is inactive, so HIF isn’t degraded by pVHL, accumulates and mediates transcription of downstream growth-promoting target genes

90
Q

what do the expression of HIF-1A target genes result in?

A

Expression of target genes: increase blood flow for uptake of more oxygen
- Angiogenesis
- Erythropoiesis
- Glycolysis & glucose uptake

To enable cells to survive under hypoxia (short term) + to acquire access to oxygen supply

91
Q

how is VHL mutated in tumours?

A

there is a LOF point mutation in the amino acid residues of the hydrophobic pocket of VHL, which recognises the hydroxyproline residues of HIF-1A

92
Q

how does the LOF mutation in VHL lead to cancer?

A

Even in presence of oxygen, HIF is not degraded by VHL, so HIF signalling remains active and cell growth is promoted
- Constitutive activation of HIF-1 transcription factors -> growth promoting genes to stimulate the proliferation of a variety of cell types

93
Q

what 3 tumour suppressor genes have been discussed and what are their roles?

A
  1. NF1 - negative regulator of Ras signalling
  2. APC - negative regulator of b-catenin signalling
  3. pVHL negtaive regulator of HIF-1A transcription factors

Stem cells, Ageing and Cancer (8 decks)

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