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Cancer > Intro to tumour suppressors and oncogenes > Flashcards

Intro to tumour suppressors and oncogenes Flashcards

1
Q

Define a neoplasm

A

“new growth”/ tumour, can develop from any normal tissue.

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2
Q

Carcinoma effects…

A

In epithelial cells (ectoderm/endoderm)

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3
Q

Sarcoma effects…

A

Muscle, bone, blood vessel, fibroblasts (mesoderm)

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4
Q

Leukemia/lymphoma effects..

A

circulating cells of the blood and lymph systems (mesoderm)

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5
Q

Describe a benign tumour

A

Non-envasive, encapsulated, non-metastatic, eg a mole.

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6
Q

Describe a malignant tumour

A

Invades and destroys surrounding tissue, metastatic, cancer.

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7
Q

Describe the sequence of events in the development of cancer

A

normal cells, hyperplasia, benign tumour, carcinoma in situ, invasive cancer, metastasis.

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8
Q

How many mutations to cancer cells have and how many are relevant to the disease?

A

thousands, between 10 and 100.

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9
Q

How was it discovered that tumours arise from one cell?

A

Studying glucose-6-phosphate dehydrogenase in heterozygous females, is an X linked gene so cells express either type A of Type B. In the tumours cells expressed only one type so must have come from one cell of a highly mosaic tissue.

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10
Q

Describe two approaches to producing a cancer cell line for in vitro studies.

A
  1. Take normal cells, dish and culture, introduce and oncogene, cells now immortal, mutate a further proto-oncogene or tumour suppressor, now cells are transformed and look like cancer.
  2. Take cancerous cells, mutate further, able to grow in culture.
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11
Q

Describe general approaches to in vivo cancer studies.

A

Normally mouse models. A. transgenics or knock downs. B. application of cancer causing agents to the skin (nude mice).

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12
Q

What fraction of cancer deaths are related to smoking?

A

1/3

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13
Q

What percentage of cancers are familial?

A

10-15%

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14
Q

What percentage of cancers are linked to viruses?

A

15-20%

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15
Q

What percentage of cancers are linked to diet?

A

30%

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16
Q

Describe the approach taken for painting mice with carcinogens.

A

First apply DMBA ( a polycyclic hydrocarbon) as the initiator and then TPA ( a phorbol ester) as the promoter. DMBA causes random point mutations and TPA causes high cell proliferation. Cancer progresses from papillomas to carcinomas. H-Ras is activated in 99% of cases.

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17
Q

How may growth factors act as oncogenes?

A

Over expression, conformational change.

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18
Q

How may growth factor receptors act as oncogenes?

A

mutate and become constitutionally active.

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19
Q

How to membrane associated proteins act as oncogenes?

A

May be ser/thr kinases which pass on the signal.

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20
Q

Which protein bind D-CDK4/6 to prevent its action in cell cycle progression?

A

p16, p18, p15, p19

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21
Q

Which other cyclin/CDK complexes and proteins interact to prevent cell cycle progression?

A

E-CDK2, A-CDK2, A-CDC2, B-CDC2 with p57, p27 and p21

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22
Q

Where were Ras oncogenes first identified?

A

Retro-viruses.

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23
Q

Name the three ras oncogenes and how did they arise?

A

H, K and N ras: paralogues resulting from whole genome duplication.

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24
Q

Which area of RAS is highly conserved and which is not?

A

The N-terminal shows 85% homology. C-terminal is highly variable bar the CAAX terminal (recognised by enzymes).

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25
Q

What percentage of tumours contain activated Ras?

A

10-15% but 95% in pancreatic carcinomas so can be tumour specific.

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26
Q

Which ras gene is associated with lung carinoma?

A

Kras

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27
Q

Which ras gene is associated with melanoma?

A

Nras

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28
Q

Which ras gene can be mutated in replacement of DMBA in painting mouse experiments?

A

Hras

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29
Q

What is the downstream event of MAPK signalling pathway?

A

Movement of transcription factors to the nucleus (and other interactions with cellular substrates)

30
Q

What is the function of the ERK signalling pathways?

A

To transduce mitogenic signals (proteins like growth factors), encourages mitosis.

31
Q

What is Raf? How is it activated?

A

The downstream signalling protein of Ras. A ser/thr kinase. Binds to active RAS at the membrane via the regulatory domain which causes a conformational change. This frees the kinase domain, which is often already bound to a substrate, to perform phosphorylation.

32
Q

What does raf activate?

A

MEK.

33
Q

What does MEK activate?

A

ERK

34
Q

What is the function of ERK?

A

Movement of transcription factors (including EIK and SAP) to the nucleus. Also interacts with other cytoplasmic substrates.

35
Q

What happens to the GF receptor when it binds a mutagen?

A

Dimerises and autophosphorylates, generally.

36
Q

What are Shc and Grb2?

A

Bridge proteins; src homology 2 domain containing (Shc) protein binds a phosphorylated site of the activated GFR and becomes phophorylated. Grb2 then binds Shc by the SH2 domain OR to the GFR directly. The 2 SH3 domains can then bind the two proline-reach sequences of Sos.

37
Q

What is Sos?

A

Son of sevenless. Functions as a guanine nucleotide exchange factor. Once it has bound GRB2 is is teathered as the membrane and able to interact with Ras.

38
Q

Describe the Ras activation cycle.

A

Sos releases GDP from Ras which is then free to bind GTP which is much more abundant in the cell. This increases Ras’ binding affinity for Ras effectors (e.g. Raf) via the activation loop, activating the protein. Ras has an endogenous GTPase domain which slowly converts the bound GTP to GDP, deactivating the protein.

39
Q

What is the function of adaptor and scaffold proteins?

A

Regulate the ERK pathway by binding components of the signalling pathways and supporting their interactions ( hsp90 and 14-3-3) or disrupt/prevent the signalling protein interaction (e.g. RKIP prevents Raf and MEK interacts stopping MEK activation).

40
Q

Where was the v-myc oncogene orignally found?

A

In avain myelocytomatsosis virus MC29 in 1979,

41
Q

How much c-myc linked to tumours.

A

c-myc expression is dysregulated in every human tumour, many of which it is overexpressed.

42
Q

In which cancer is c-myc typically amplified?

A

small-lung-cell carcinoma

43
Q

In which cancer is c-myc typically translocated?

A

Burkitt’s lymphoma. in T cell is a receptor promoter, in B cells if an Ig promoter.

44
Q

In which cancer are there found to be mutations in c-myc control sequences?

A

acute myloid leukemia

45
Q

Which cancer developed in mice models over expressing c-myc?

A

Lymphomas.

46
Q

Which 3 out of 7 myc genes are closely related and oncogenic?

A

c-myc, n-myc and L-myc (3 exons and 30% a.a. sequence identity)

47
Q

What does myc do?

A

Is a TF, either luciene zipper or helix-loop-helix. Binds DNA as a myc:max dimer. induces CYCLINs A and E and cdc25 genes that are involved in cell cycle progression, Also must inhibit differentiation.

48
Q

If there an inflammatory response to apoptosis?

A

No.

49
Q

How was bcl-2 first discovered as an oncogene?

A

Translocation of chr 18 to chr4 with the ig promoter lead to human follicular lymphoma and bcl2 was at the break point (1984)

50
Q

Was is the C. elegans homologue of BCL-2?

A

CED-9, inhibitor of apoptosis.

51
Q

What is the effect of bcl-2 overexpression in haematopoietic cell lines?

A

Extended survival in G0 phase and blockage of c-myc mutation induced apoptosis.

52
Q

What happens in Eu-Bcl-2 mice?

A

B cell extended survival, mice are runted, die young with renal failure and B and T cell lineage failure.

53
Q

How is Bad prevented from binding Bcl-2?

A

By phosphorylation by a MAPK pathway.

54
Q

What do retinoblastoma tumours cause?

A

Displacement of the natural retina and thickening of the optic nerve due to extension of the tumour.

54
Q

What do retinoblastoma tumours cause?

A

Displacement of the natural retina and thickening of the optic nerve due to extension of the tumour.

55
Q

What percentage of retinoblastoma is inherited?

A

40%, rest sporadic. is autosomal dominant and often bilateral.

55
Q

What percentage of retinoblastoma is inherited?

A

40%, rest sporadic. is autosomal dominant and often bilateral.

56
Q

On which chr. is RB?

A

Chromosome 13.

56
Q

On which chr. is RB?

A

Chromosome 13.

57
Q

What is the function of RB.

A

Is increasingly phosphorylated by CDKs during the cell cycle. Starts at the G1 check point by cyclin D/CDK4 (inhibied by p16INK4a). Become hyperphosphorylated by mitosis and then hypophosphorylated after. When unphosphorylated it is able to bind E2F, a TF for S phase genes including cyclin E/CDK2 (inhibited by p21). So when phosphorylated releases E2F to further the cell cycle. There is a positive feedback loop wher cyclin E/cdk2 is able to phophorylate other proteins like p27 which are then degrade to free up for cyclin E/cdk2. S phase genes also further phosphorylate RB.

57
Q

What is the function of RB.

A

Is increasingly phosphorylated by CDKs during the cell cycle. Starts at the G1 check point by cyclin D/CDK4 (inhibied by p16INK4a). Become hyperphosphorylated by mitosis and then hypophosphorylated after. When unphosphorylated it is able to bind E2F, a TF for S phase genes including cyclin E/CDK2 (inhibited by p21). So when phosphorylated releases E2F to further the cell cycle. There is a positive feedback loop wher cyclin E/cdk2 is able to phophorylate other proteins like p27 which are then degrade to free up for cyclin E/cdk2. S phase genes also further phosphorylate RB.

58
Q

How is SV40 oncogenic?

A

Encodes a large T gene which the protein of, CT-Ag, binds RB and sequesters it away from E2F, which is then constitutively active. Also binds p53.

58
Q

How is AV oncogenic?

A

Transforms cells not permissive for viral replication. Oncogenes are E1A, binds p53, and E1B which binds RB

59
Q

What does p53 do?

A

Is a transcriptional regulator, stablized by diverse stimuli including UV, lack of neucleotides, ionizing radiation, oncogene signalling,hypoxia and blocked transcriptions. Once activated by DNA damage it can activate p21 which is a Cdk inhibitor (cdk2) to cell cycle arrest (and other genes), causes expression of DNA repair genes and can activate BAX to cause apoptosis (partly by bcl-2 stabilisation?). It can also block angiogenesis.

59
Q

How is EBV oncogenic?

A

Several potentially oncogenic genes. LMP1 activated signal transduction pathways to promoted cell survival.

60
Q

In what three ways by a virus be oncogenic?

A
  1. Carry additional viral genes which act as oncogenes like HTLV I/II.
  2. Long latency tumours due to the virus inserting next to an oncogene for an extended period (MoMLV)
  3. Acutely transforming retroviruses, gain new info by integrating host genome into its own and now is oncogenic when its ancestor was not. Like Rous sarcoma virus which captures V-src (1.6 kb). V-src then gathered mutations. has no exons. It is able to transform cells in culture.
61
Q

Name 4 DNA tumour viruses.

A

Simian virus 40 (SV40). 5.3KB
Adenovirus 36 kb
Human papilloma virus 8-16 kb
Epstein-Barr virus. 172 kb, around 100 genes.

62
Q

How is SV40 oncogenic?

A

Encodes a large T gene which the protein of, CT-Ag, binds RB and sequesters it away from E2F, which is then constitutively active. Also binds p53.

63
Q

How is AV oncogenic?

A

Tranforms cells not permissive for viral replication. Oncogenes are E1A, binds p53, and E1B which binds RB

64
Q

How is HPV oncogenic?

A

Forms benign warts in the mucosal or cataneous epithelium which regress but can progress to carcinomas. cervial and anogential are associated with HVP16 and 18. Oncogenes are E5 E6 and E7 which target p53 and RB.
In HVP16, E7 binds RB and E6 degrades p53.

65
Q

How is EBV oncogenic?

A

Sereval protentially oncogenic genes. LMP1 activated signal transduction pathways to promoted cell survival.

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