05 Cell Cycle Control

A presentation on Cell Cycle Control and the roll of the tumor suppressor protein, Retinoblastoma

“cell cycle clock”
a molecular circuitry operating in the cell nucleus that processes External and Internal signals
decides…
to enter the active cell cycle
or
retreat into a non-proliferating state (G0)

What is the Cell Cycle?
the cell cycle clock is a network of interacting proteins
a signal-processing circuit

Controlling proliferation
cell’s fate is influenced
normal proteins
oncogene proteins
tumor suppressor proteins

Most oncogenes and tumor suppressor genes can be explained in terms of their effects on the cell cycle clock.

checkpoints in the cell cycle
Checkpoints impose quality control
to ensure that a cell has properly completed all the requisite steps of one phase before it enters the next phase.

The operations of these checkpoints also influence the formation of cancers.

Cancer researchers focus largely on the
G0/G1 transition

G1 when a cell is given the license to make decisions about its fate
R point
the R-point decision is a critical determinant of whether cells will grow or not.
deregulation of the R-point is common in nearly all types of cancer cells.
Cyclins and Cyclin-Dependent Kinases (CDK) are core proteins of the cell cycle clock
By phosphorylating multiple proteins a kinase can switch various proteins on or off.
Kinase = addition of a phosphate group to an AA residue of a protein
Cyclin B activity through the cell cycle

The CDKs are serine/threonine kinases
Binding of a cyclin to a CDK
greatly increases the enzymatic activity of CDK

Cyclins help the cyclin-CDK complexes target certain proteins
Growth factor signalling pathways control cyclin levels and thus cell cycle progression

pRb undergoes phosphorylation through the of cell cycle.
pRB is a Tumor Suppressor
It acts like the breaks on a car
(Oncogenes act like an accelerator in a car!)

Therefore its unregulated loss of function contributes to cancer formation

pRb - the guardian of the R-point
When it becomes hyperphosphoylated

pRb loses its growth-inhibitory powers

Allows progress through late G1

and thereafter into the remaining phases of the cell cycle.
E2F transcription factors bind to pRb
pRb control R-point through its effects on transcription factors termed E2Fs.
unphosphorylated pRb bind E2Fs

hyperphosphorylated pRb dissociate from E2Fs

What sort of genes are transcribed?
Promoters of genes important for S-phase entry have for E2Fs binding sites
genes encoding proteins involved in synthesizing DNA
precursor nucleotides
genes involved in DNA replication.

Cancer Genetics
in brief series…
by Mark Temple