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Jean Jiang Nash

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Bens Story case of retinoblastoma
Cancers result when cells lose contact with neighbours, or lose control of cell cycle, or
cannot die because of constant propagation
To combat cancer we must understand what leads to cancer at the level of molecules
Cell cycle
Enlarges, duplicates chromosomes, and separates into two cells
Must be tightly controlled with checkpoints
In yeast, decision to divide or not to divide based on nutrient availability
oIf enough, then divide
In mice, nutritional and cell-cell communication through contact and receptors
and signals that feed into cell cycle clock
oThey include tyrosine kinase receptors, G-protein coupled receptors, TGF-
beta receptors, integrins, nutrient status
oAll feed into molecular machine, used by cell to deicde whether to enter
into G0 or enter into cell cycle
oThis decision is screwed up in cancer
oWhen enter cell cycle, must finish or die
oEntering is the big decision for the cell
G0 = way for cell to exit cell cycle, if it lacks mitogen telling it to divide
Many checkpoints in cell cycle
oQuestions asked include about DNA damage (blocked if DNA damage);
replication doesnt finish if DNA damage, can stop to repair; entrance into
M, DNA must be completely replicated; anaphase blocked if chromosomes
not aligned up on metaphase plate
All are checkpoints
R point is misregulated in cancer
oMitogens gone, cell stops dividing
oBut once cell pases Restriction point, entire process is autonomous
Cell signals, mitogen, no longer matters
Once enter R point, rest of cycle must occur or die
This is checkpoint most usually lost in cancer cells
Cyclin Cdk complexes checkpoints depend on
Are protein kinases, which must be phosporylated and interact with cyclin
Cyclin binding pulls out T-loop, leaving active site of Cdk available so can
Important to know are cyclin-D CDK4/6 (before R point) and cyclin-E CDK2 (after R point)
To pass R point, cell must express E, which brings cell into S-phase
CDK protein levels are stable through out cell cycle
Cyclin D expression is activated by growth factors
oRegulated by mitogens
oMitogen present, cyclin D expressed; if absent, not expressed
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