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Summary SSA8 Rb and the cell cycle
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Summary and WG answers of SSA8 Rb and the cell cycle of the course MBO (molecular biology and oncology) at Leiden University
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SSA8 Rb and the cell cycleChapter 8 Weinberg
A cell does not proliferate unless there are mitogenic
factors. TGF-beta can overrule the mitogenic signal to halt
proliferation. Other signals are involved in making the cell
go into a post-mitotic differentiated state. There is a cell
cycle clock which operates in the nucleus. It is a network
of interacting proteins that receive signals and integrates
these and then decides the cell's fate.
8.1 Cell growth and division is
coordinated by a complex array of
regulators
Absence of growth factors leads to a quiescent state of
cells called G0. Withdrawel from the cell cycle can also be actively encouraged by growth
inhibitory factors like TGF-beta. Some cells leave the cell cycle irreversibly and are then also
post-mitotic.
If a cell after division remains active in the growth-division cycle,
there must be immediate preparation for the next division. The G1
phase is the phase between the last division and the next DNA
replication. The S phase is around 6 to 8 hours but depends on
the cell type. In the S phase there is DNA replication. Between
the S and the M phase there is a gap, the G2 phase which takes
3-5 hours. In this phase the cells prepare themselves. The M
phase consists of the prophase, metaphase, anaphase and
telophase.
In the cycle there are checkpoints. A cell cannot go from G1 to S if
there is DNA damage. During the replication S phase, there is
also control for damage. From G2 to M there is a checkpoint to
see if all DNA is actually replicated. The anaphase can also be
blocked if the chromatids do not properly assemble on the mitotic
spindle.
As tumor progression proceeds, cancer cells benefit from certain combinations of mutations
that give the proliferative advantage. There is often increased mutability; genomic instability.
Because of this, normal cells could not proceed in the cell cycle due to the checkpoints.
However, cancer cells inactive the checkpoint control and the growth-controlling genes.
In early embryonic stem cells, there is no pRb-imposed growth control and no p53 pathway.
This indicates that they also do not require growth signals. They thus also seem to have cell-
autonomous behavior. The cells can also form weird, but benign, tumors called teratomas.
8.2 Cells make decisions about growth and quiescence
during a specific period in the G1 phase
A cell is responsive to mitogenic growth factors and growth-inhibitory factors like TGF-beta
from the onset of the G1 phase until around 2 hours before the onset of the S phase. If in this
period, cells are depleted from all growth factors, they will likely go into the G0. The point after
, which the cells are unresponsive is the R point (restriction point). If there have been
mitogenic factors, the cell will definitely go into the S phase. The S phase has a quite set
duration as the cell will just complete it unless there are major damages. The R point is a
critical determinant for the whole proliferation as cells, even though there are control
mechanisms, will then often just complete the whole cycle. In cancer there is often
deregulation of the R-point decision-making machinery. However, there can also be
deregulation of decision points like the attachment to ECM (mediated by integrins). Without
the integrin signaling, there can normally be no cell cycle progression and when there is no
attachment at all there is often activation of aniokis. Tumorigenic cells are anchorage-
independent probably by mimicking attachment via oncoproteins like Ras and Src. There are
also some checkpoints still after the R point; for example, are there enough nutrients?
8.3 Cyclins and cyclin-dependent kinases constitute the core
components of the cell cycle clock
Signals are often emitted via protein kinases. Phosphorylation of the centrosome-associated
proteins at the G1/S boundary allows their duplication for the M phase. Phosphorylation of
other proteins allows for DNA replication. Phosphorylation of histones makes the chromatin
in such a configuration that the S and M phase can take place. Phosphorylation of the
nucleus membrane forming proteins causes them to dissociate during the early M phase.
The kinases that are used in the cell cycle machinery are the cyclin dependent kinases
(CDKs). They have a regulatory subunit; the cyclin proteins. CDKs are serine/threonine
kinases. The cyclins activate the enzymatic activity of the CDKs. So only cyclin-CDK
complexes can drive the cell cycle.
During the G1 phase there are CDK4 and CDK6 which
act quite similarly. They can associate with cyclin D1,
2 or 3 (D-type cyclins). After the R point, E-type cyclins
(E1 and E2) associate with CDK2 to phosphorylate the
substrates necessary for entry to the S phase. As the
cell goes into the S phase, A type cyclins (A1 and A2)
replace the E cyclins on CDK2 so that the S phase can
progress. Later in the S phase, the A cyclins switch
from CDK2 to CDC2. The A cyclins are then in the M
phase replaced by B cyclins (B1 and B2). Cyclin C and
CDK3 is involved in making a cell go from G0 to G1
phase.
The modulation of the cyclin-CDK complex activity is
dependent on the levels of the cyclins. The levels of the CDKs are quite constant. At the end
of the M phase, the B cyclins are degraded and then it accumulates gradually again. Cyclin E
levels are low during most of the G1 phase, but rise abruptly after the R point. Cyclin A levels
increase when the cell goes into the S phase.
The collapse of cyclins in the
next phase is triggered by
ubiquitin ligases which attach
polyubiquitin chains so that they
are broken down by the
proteasome. This breaks down if
important so that cells cannot
slip back into the previous
phase.
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