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Molecular Basis of Disease > Oncogenes And Tumour Suppressor Genes > Flashcards

Oncogenes And Tumour Suppressor Genes Flashcards

1
Q

What are the main functional changes in cancer?

A

Increased growth (loss of growth regulation and stimulate environment to promote growth - angiogenesis))
Failure to undergo apoptosis
Loss of differentiation
Failure to repair DNA damage

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2
Q

What do proto-oncogenes do normally? and what do they do once they are oncogenic?

A

Normal genes that are involved in growth factor signalling pathways - control growth
Mutated oncogene produce larger amounts of product or have increased activity

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3
Q

What do tumour suppressor genes do?

A

Stop uncontrolled growth and inhibit cell cycle or trigger apoptosis

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4
Q

What happens to the oncogene when they pick up a mutation causing cancer?

A

Gain function - become permanently active

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5
Q

What happens to the tumour suppressor gene when they pick up a mutation causing cancer?

A

Loss of function , mutation switches gene off

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6
Q

How many mutations occur in oncogenes causing cancer?

A

Single mutation in one allele is enough for gain of function in oncogene and uncontrolled proliferation and cancer

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7
Q

How many mutations occur in tumour suppressor genes causing cancer?

A

one mutation in each allele (2 hits) needed to lose function of tumour suppressor gene leading to abnormal proliferation

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8
Q

Name a few tumour suppressor genes commonly involved in cancer?

A

p53 and retinoblastoma

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9
Q

name a few oncogenes commonly involved in cancer

A

MYC oncogene

RAS oncogene

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10
Q

How were oncogenes discovered?

A

Induced sarcoma i chickens lead to understanding sarcoma (some cancers) is transmissable

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11
Q

Why is sarcoma transmissable?

A

Only transmissable cancers transfer through viruses (since small enough to go through filter in experiment so figured it cant be bacteria which is too large so must be a virus)

specifically Rous sarcoma virus causes sarcoma to be transmissable

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12
Q

What type of virus is rous sarcoma virus?

A

retrovirus

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13
Q

Why are retroviruses important experimentally?

A

technological advances
funding
improved tissue culture techniques
discovery of reverse transcriptase

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14
Q

What is v-src?

A

proto-oncogene altered from transduced by retroviruses

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15
Q

Where is v-sarc found?

A

an extra gene found in rous sarcoma virus compared to other retroviruses

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16
Q

What is the oncogene hypothesis?

A

idea that v-src (oncogene) was kidnapped and was originally as cellilar gene not viral gene and become oncogenic

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17
Q

How was c-sarc captured by retrovirus? - steps

A

Central dogma as viral genome becomes dsDNA provirus (after inverse transcription)
C-src in host cell chromosomal DNA
Provirus intergrated in host cell chromosomal DNA accidentally next to c-src.
After transcription of this entire region, results in v-src (which is packaged into virus now carrying c-src as v-src after kidnappin)

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18
Q

Why do viruses cause cancer?

A

due to the v-src oncogene which is expressed at high levels in host cells leading to uncontrolled host cell grwoth and cancer

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19
Q

What is c-src involved in?

A

Found in normal host chromosomal DNA and is involved in positive regulation of cell growth and division

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20
Q

What agents cause a proto-oncogene to become an oncogene?

A

Chemicals
Physical
Viruses

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21
Q

Why does c-src not cause cancer but v-src does?

A

V-src mutates and leads to abnormal proliferation - activated oncogene instead of staying as proto-oncogene (c-src involved is. normal proto-oncogene in humans involved in cell division but is oncogene in chickens)

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22
Q

Which viruses transmit viral oncogenes?

A
  • oncogenes also found in viruses and transmitted through either DNA or RNA viruses
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23
Q

How do DNA viruses cause cancer?

A

Encode various proteins to initiate and maintain cancer

24
Q

How do RNA viruses cause canceR?

A

integrate dna copies into genome of host cells and transform oncogene (cancerous transformation in host)

25
Q

What types of mutations can activate onocgenes?

A

Mutations, insertions, amplifications and translocations - only one allele needs this alteration of the genes captured by animal retroviruses

26
Q

How many oncogenes are therw?

A

Many

for every type of protein involved in the growth factor signal transduction pathway

27
Q

By what different molecules are produced from oncogenes when activated? not as proto-oncogenes

A

Mutated gene codes for protein with altered structure/function
Duplicated genes cause increased synthesis of encoded protein of the specific oncogene
DNA regulatory sequence translocated to alter downstream expression = increased synthesis of encoded protein

28
Q

What types of proteins do proto-oncogenes encode for in the growth factor signal transduction pathway? + example protein of each type

A

Growth factors e.g. EGF
Growth factor receptors e.g. ErbB
Intracellular signal transducers e.g. Ras and Raf
Nuclear transcription factors e.g. Fos

29
Q

Which type of protein does Ras oncogenes code for?

A

Intracellular signal transducer

30
Q

What are ras proteins?

A

small GTPases that normally are bound to GDP in neutral state

31
Q

Why is Ras important in cancer?

A

Most commonly mutated oncogene found in cancer

32
Q

What are the mutations found for ras oncogene mutations?

A

Point mutations in codons 12, 13 and 61

Normally codes for glycine at these positions

33
Q

Give 2 examples of ras point mutations forming oncogenes causing 2 types of cancers and why amino acid is produced due to mutation?

A

Codons 12, 13 and 61 point mutations for glycine to valine - bladder carcinoma
Codons 12,13 and 61 point mutations from glycine to cysteine - lung cancer

34
Q

Describe the pathway for normal Ras gene (not mutated)?

A

1) extracellular growth factor signal binds to receptor
2) Binding promotes Ras protein recruitment to the receptor complex
3) Ras exchnages GDP with GTP (change activates Ras)
4) actiated ras protein initiates signalling cascase
5) kinases phorphorylate targets e.g transcriptions factors to promote expression for growth and survival

NORMALLY RAS THEN HYDROLYSES GTP TO GDP AND RAS BECOMES INACTIVE AGAIN

35
Q

What happens to Ras if point mutations in codons 12,13 and 61 occur (oncogene that produces Ras is activated) to the growth signalling pathway? !!!!

A

Ras becomes hyperactive due to mutated form (since the oncogene that encodes ras is mutated and active - gained function and is always switched on)

  • Loss of GTPase activity so GTP to converted back to GDP and Ras remains active therefore continuously active pathway so protein stimulating cell cycle still expressed and continual progression of cell cycle leads to tumourigenesis
36
Q

What is the MYC oncogene family made of and what do they code for?

A

C-MYC, MYCN and MYCL - MYC oncogene family

c-Myc, N-Myc - protein MYC oncogene encodes

37
Q

Compare how MYC oncogene becomes activated to how Ras oncogene becomes activated?

A

Ras has point mutations in codons 12, 13 and 61 so one amino acid change from glycine to another amino acid

MYC oncogene activated by CHROMOSOMAL TRANSLOCATION

38
Q

What is myc oncoprotein?

A

transcription factor - regulates many processes of cell cycle

39
Q

What effects does MYC oncoproteins have?

A

Ribosome biogenesis
Protein translation
Cell cycle progression and metabolism etc…

40
Q

What structure does the MYC onocoprotein (transcription factor) have? !!!

A

Helix loop helix leucine zipper

which dimerises with partner proteins Max to activate gene expression

41
Q

When do MYC oncogenes become activated?

A

Chromosomal translocations that cause foreign transcriptional promoters to activate oncogene

42
Q

What is Burkitt’s lymphoma and what causes in?

A

Associated to epstein barr virus

  • chromosomal translocations that put MY gene nect to regulation of Ig heavy chain causes c-myc to be regulated = cancer
43
Q

Which chromosome translocations cause Burkitt’s lymphoma?

A

Chromosomal translocations in chromosome 2,14 and 22 (where Ig heavy chain gene regulator is). Any one of these must fuse to section of chromosome 8(where MYC gene is)

44
Q

Name another cancer caused by chromosomal translocation that is not Burkitt’s lymphoma?

A

Chronic myelogenous leukemia (CML)

45
Q

Explain the chromosomal translocation mechanism leading to CML?

A

CML carry philadelphia chromosome (fusion product of chromosomal translocation between chromosomes 9 and 22)

Chromosome 9 has ABL gene (oncogene) and chromosome 22 have BCR gene. Fusion of both lead to enhanced tyrosine kinase activity of oncogene ABL leading to abnormal proliferation

46
Q

How were tumour suppressor genes discovered?

A

Fusion of normal cells with tumour cells, hybrid cell was not tumourigenic so normal cell must have genes that inhibit/suppress tumour development

47
Q

What is the importance of Tumour suppressor genes?

A

Balance growth promoting pathways (proliferation and cell survival) with cell cycle arrest and apoptosis

48
Q

When does a tumour suppressor gene lose its function?

A

Inactivation of both alleles of the gene either due to mutation or deletion

49
Q

What are anti-oncogenes?

A

Tumour suppressor genes

50
Q

What type of gene is a tumour suppressor gene since it needs 2 hits to lose function?

A

Recessive gene

51
Q

Give a few examples of tumour suppressor genes and what is the purpose of each one?

A

RB1 - retinoblastoma gene - regulate cell cycle checkpoints
APC - regulates differentiation
BRCA1 - regulates DNA repair
p53

52
Q

What is retinoblastoma?

A

Rare childhood cancer where immature retinoblasts grow fast without turning into retinal cells forming tumour in back of cell

53
Q

How is retinoblastoma tumour seen?

A

Shine light and it reflects back off of tumour in eye

54
Q

What causes retinoblastoma?

A

Inherited (needs one more HIT of acquired mutation alongside the inherited mutation) or sporadic (needs 2 HITs of acquired mutations on somatic level) mutations in the retinoblastoma gene (Rb) on chromosome 18

55
Q

Why does retinoblastoma need 2 hits?

A

recessive gene since its a tumour suppressor gene, function of gene not lost till both alleles have mutated

56
Q

What is loss of heterozygosity in retinoblastomas?

A

Inherited mutations means one allele is normal, other is mutated. If other also becomes mutated sporadically, loses this heterozygosity , becomes homozygous for mutated gene

57
Q

What is the main function of Rb protein?

A

regulate cell cycle by inhibiting G1 to S phase transition by…….

Molecular Basis of Disease (29 decks)

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