8 - The control of G1 progression by oncogenes and tumour suppressor genes

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When do cells enter the cell cycle?
Most cells are quiescent, only those with sufficient proliferation signals enter the cell cycle They are under negative control (anti-proliferative signals) and positive control to drive the cell into cell proliferation
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What happens at the restricton point in the cell cycle?
regulates exit from Go phase - blocks cell cycle progression unless nutrients and mitogens are continuously present
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What causes cells to enter Go phase?
Lack of mitogens: anti-proliferation signals e.g. contact inhibition, TGF-beta telomer damage
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How can oncogenes be identified? first cycle
take DNA from human tumour cells->transfect mouse 3T3 cells->culture for 2 weeks->focuse transformed NIH/3T3 cells growing among untransformed cells-> extract DNA, transform new mouse cells-> second cycle
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How can oncogenes be identified? second cycle
extract genomic DNA->introduce it into phage vector->plate phage on E.coli->replica on filter paper->use Alu probe to see oncogenes
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what causes cancer in mice?
Mice expressing rasD and myc oncogenes get tumours much more quickly than mice only expressing one oncogene
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What are oncogenes?
dominantly active or overexpressed versions of normal signalling components-can drive G0 cells through the G1 / S transition
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What happens when a mitogen receptor is activated?
Ras GTPase is activated->Ras binds and activates Raf->MAP kinase cascade->MAP kinase enters nucleus when activated & phosphorylates & activates a dimeric TF composed of Fos & Jun
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What happens where Fos and Jun are activated?
leads to immediate early gene expression->Myc TF is one of genes induced by Fos/Jun->triggers delayed (early) response gene expression-> one of genes inder control of Myc is Cyclin D (G1 phase cyclin)
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What effect does mitogen stimulation have?
triggers activation of G1/Cdk complexs and entry into the cell cycle
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How does premature entry into the cell cycle occur?
by overxpression or dominantly activated mutation of protooncogenes
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Describe the order in which transcription factors are sequentially activated and why?
Early TF: fos/jun Middle TF: myc Last TF: E2F - to push the cells through this critical point in G1 to traverse the restriction point
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What is unique and tumour suppressor genes?
to push the cells through this critical point in G1 to traverse the restriction point
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Deescribe the 2 ways in which retinoblastoma can occur?
Hereditary: heterozygosity->somatic mutation->homozygous cell gives rise to tumours in retins/ Sporadic retinoblastoma: normal->1st somatic mutation->2nd somatic mutation->homozygous cell gives rise totumours in retina
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Describe mitotic recombination
heterozygous for mutatnt allele->chromosome duplication->recombination between homologous chromatids->normal 2:2 chromosome segregation->1 hmozygous for noral allele & 1 homozygus for mutant allele
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Describe mis-segregation
heterozygous fr mutant allele->chromosome duplication->aberrant segregation 3:1 -> 1 recieves 1 and dies, other receives 3->random loss of extra chromosome->hetero OR homozygous for mutant allele formed
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What role do external signals play in entry into the cell cycle?
activate cyclins-> normal cells can pass restriction point and enter the cell cycle (no singals -> normal cells arrest at restriction point)
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Can cells ever pass restriction point when her are no external signals?
Rb mutant cell passes restriction point & if active oncogene mimics external signal-> cells with active oncogenes pass restriction point
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What happens when Cdk 4/6-p16^Ink4a is inactive/active?
inactive: differentiated cell expressing p16 does not cycle/ Active: differentiated cell mutant for p16 passes restriction point
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What effect does Activation or overexpression of oncogenes (such as rasD, myc or Cyclin D) or loss of tumour suppressors (such as Rb or p16INK4) have?
force cells to enter S phase (DNA replication) before ready->replication stress. Replication forks are initiated but collapse due to insufficient substrate availability->parts of genome are unreplicated/damaged->chrom. rearrangements
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Card 2

Front

What happens at the restricton point in the cell cycle?

Back

regulates exit from Go phase - blocks cell cycle progression unless nutrients and mitogens are continuously present

Card 3

Front

What causes cells to enter Go phase?

Back

Preview of the front of card 3

Card 4

Front

How can oncogenes be identified? first cycle

Back

Preview of the front of card 4

Card 5

Front

How can oncogenes be identified? second cycle

Back

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