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THE CELL CYCLE I
Introduction:
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Important analogy: an automobile, which can be switched on & off and also includes
failsafe mechanisms (i
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flashing lights – cell cycle checkpoints) that stop the machine until
the problem at hand is resolved
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The society itself exists with a strong moral code, whereby the reckless
drivers are arrested (apoptosis and necrosis) rather than risking other people’s lives
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In cultured mammalian cells, the entire cell cycle lasts approx
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Interphase is divided further into:
- G1 - gap prior to S phase
- S – the replication of chromosomal DNA during the synthesis phase
- G2 – gap after S phase, both allow for growth and importantly the repaid of DNA
damage and replication errors
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There exist 3 checkpoints within the cycle:
- In G1 – decision to enter S phase
- End of G2 – decision to enter M phase
- Progression through M phase – spindle assembly checkpoint (i
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to prevent
DNA damage)
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In vertebrates, progression through G1 and entry into S phase requires the presence
of growth factors, and without these growth factors, cells exit the cell cycle and
enter a resting or quiescent state – G0
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These cells would remain in G0 until they receive a signal to re-enter the cell cycle
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Differentiated cells such as nerve, T cells or muscle cells enter G0 upon reaching
terminal differentiation, i
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they can no longer differentiate
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Withdrawal of the growth factor causes the cells to enter G0 within hours, and reentry into the cell cycle needs approx
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Mitosis Promoting Factor (MPF) and Mitotic Entry:
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- The M phase cells forced the interphase cells (i
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all other 3 phases of the cell
cycle) into M phase
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These results demonstrated the sequential and unidirectional phases of the cell
cycle, which are controlled by diffusible chemical signals that operate in the nucleus
and cytoplasm
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Furthermore, the M-phase cells contain an inducer of mitosis that is dominant over
all other phases of the cell cycle – MPF
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Scientists further investigated this factor using oocytes from X
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- Whereas protein synthesis is not required to force a G2 to M phase transition –
the mitotic cytoplasm of an egg is sufficient enough to drive an oocyte into
mitosis
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Via biochemical fractionation of X
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Cyclin m-RNA is sufficient to drive frog eggs into mitosis, indicating that it is the key
driver of mitotic entry
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Activation and inactivation of Cdk1 depends upon accumulation and degradation of
cyclin
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Cell cycle genetics revealed that there are additional controls:
- A wee1 mutant (recessive) where the cells divide faster and produced small cells
– negative regulator of mitosis
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Regulation of Cdk/Cyclin Activity:
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Therefore, the cells grow
but do not divide
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Wee1 appends an inhibitory phosphorylation on Cdc2 Y15 (Tyrosine 15), preventing
Cdc2/Cdk1 activation – functions as a negative regulator
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Whereas wee1 mutants are incapable of applying this inhibitory phosphorylation
and therefore division proceeds prematurely
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Wee2 is not due to a mutation in the same gene as wee1, but actually due to a
mutation in Cdc2 Y15F – tyrosine at 15 changed to phenylalanine
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This point mutation causes premature activation of Cdc2/Cdk1 because it cannot be
phosphorylated by Wee1, therefore an inhibitory phosphorylation cannot be
applied
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Consequently, the complex is prematurely activated, leading to premature division
and smaller cells
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Before mitosis, cdc25 is inactive, which ensures that the inhibitory phosphates
cannot be removed and the complex accumulates in its inactive state
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Upon mitotic entry, however, a small amount of active Cdk1/M-cyclin
phosphorylates and activates Cdc25, allowing it to remove the inhibitory phosphates
on the complex for full activation
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Additionally, upon mitotic entry, a small amount of active Cdk1/M-cyclin
phosphorylates and inhibits wee1, thus preventing the addition of inhibitory
phosphates on Cdk1/M-cyclin and allowing full activation
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What determines the timing of MPF activation is still unclear
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Exit from M Phase:
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Exit from M Phase: APC/C Complex
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Cdc20 dissociates from APC/C, and is replaced with Hct1, which:
- Maintains APC/C activity throughout G1, so that any mitotic cyclins that get
produced are degraded
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The Metaphase-to-Anaphase Transition:
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The Spindle Assembly Checkpoint:
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- 3 of which are classed as budding uninhibited by benomyl – BUD genes
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The MAD/BUD gene products are recruited to unattached kinetochores and
generate a diffusible inhibitor known as the mitotic checkpoint complex, MCC,
which is composed of MAD2, BUB3 and BUBR1
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This complex prevents Cdc20 from activating the APC/C complex and securing is not
degraded, thus activating the SAC and mitosis arrest
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This fluidity between the chromosomes is required to inactivate the SAC
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Maloriented partial tension: the spindle grabs the chromatid from the wrong
direction causing aneuploidy (possibly as a result of no SAC activation)
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Aneuploidy is an early and frequent feature of tumour cells, suggesting that missegregation of chromosomes may be a common feature of cancer
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Defects in the SAC may allow these mis-segregations and this allow aneuploidy to
develop and a complete loss of SAC components in lethal
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Mutations or altered expression of BUB1, BUBR1, BUB3, MAD1, and MAD2 have
been reported in many tumours
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Some therapeutic drugs exist which aim to target the SAC, such as:
- Vinca Alkyloids and taxanes – i
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