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Cell checkpoints and
Cancer
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Introduction
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Catastrophic genetic damage can occur if cells progress to
the next phase of the cell cycle before the previous phase is
properly completed. For example, the attachment of
kinetochores to microtubules of the mitotic spindle during
metaphase. If anaphase is initiated before both kinetochores
of a replicated chromosome become attached to
microtubules from opposite spindle poles, daughter cells are
produced that have a missing or extra chromosome
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The cell cycle proceeds by a
defined sequence of events where
late events depend upon completion
of early events . The aim of the
dependency of events is to
distribute complete and accurate
replicas of the genome to daughter
cells.
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To monitor this dependency, cells
are equipped with the checkpoints
that are set at various stages of the
cell cycle.
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Basic info
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The cell cycle is very basic. It occurs in two phases:
Interphase, Mitosis / Cytokinesis. Mitosis an Cytokinesis are
two separate parts of one phase. Interphase simply is when
the cell is growing and maintaining homeostasis, duplicating
its genetic material and prepping for division.
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Mitosis and Cytokinesis is the splitting of the nucleus and
cytoplasm to create two identical cells with identical genetic
information.
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The average human cell divides about every 24 hours. The
cell cycle is broken down as the following: Interphase – 90%
of the time, mainly in the S phase, and Mitosis and
Cytokinesis – 10% of the time.
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Basic info
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The timing and rate of cell division in different parts of an
animal or plant are crucial to normal growth, development,
and maintenance. The frequency of cellular division varies
with the type of cell.
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The mechanisms that regulate the cell cycle are necessary
for general understanding of cell division but also for
understanding how cancer cells manage to escape the usual
controls.
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The cell cycle control system, triggers and coordinates key
events in the cell cycle.
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The cell cycle is regulated at certain checkpoints by internal
and external signals.
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A checkpoint is a stop-and go-ahead signal that regulates the cell
cycle.
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There are three major checkpoints you need to know!
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G1 Checkpoint
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Known as the restriction point
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Most important
In most cases, if it gets a go ahead here, it will complete the entire
cell cycle
If it doesn’t get a go ahead, it will stop the cell cycle, and goes into
a non-dividing state.
These are usually mature nerve and muscle cells, cells that do not
divide.
Can be “called back” due to external stimuli such as growth
factors
The decision to commit a new round of cell division occurs when
the cell activates cyclin-CDK-dependent transcription which
promotes entry into the S phase.
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G2 Checkpoint
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Known as DNA Damage checkpoint. Prevents cells containing
damaged DNA from entering mitosis (M)
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Following the decision to enter the cell cycle and undergo
division, the cell goes through S phase, in which it replicates
its DNA, and, in most species, G2, in which it undergoes rapid
growth and protein synthesis in preparation for mitosis, the
process of cell division.
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Ensures that the cell underwent all of the necessary changes
during the S and G2 phases and is ready to divide.
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M checkpoint
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The mitotic spindle checkpoint occurs at the point in
metaphase where all the chromosomes should/have aligned at
the mitotic plate.
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The tension that is created by this attachment is what is sensed,
which initiates the anaphase entry. The sensing mechanism
ensures that the anaphase-promoting complex is free to break
down securin, which is a protein, which in turn cuts the
cohesins, the protein composite responsible for cohesion of
sister chromatids.
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After the cell has split into its two daughter cells, the cell
enters G1.
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Kinases
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What causes these control molecules: Proteins
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Protein kinases and Cyclins
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Cyclin dependent kinases (CDKs) control the various checkpoints
that control cell cycle. Different CDKs, control the major steps
between different phases of the cell cycle through
phosphorylation of cell proteins.
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A Cdk is an enzyme that adds negatively charged phosphate
groups to other molecules in a process called phosphorylation.
Through phosphorylation, Cdks signal the cell that it is ready to
pass into the next stage of the cell cycle.
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Cyclins
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Cyclins are another class of regulatory proteins. Cyclins bind
to Cdks, activating the Cdks to phosphorylate other
molecules.
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Cyclins are named such because they undergo a constant
cycle of synthesis and degradation (breakdown) during cell
division. When cyclins are synthesized, they act as an
activating protein and bind to Cdks forming a cyclin-Cdk
complex. This complex then acts as a signal to the cell to
pass to the next cell cycle phase. Eventually, the cyclin
degrades, deactivating the Cdk, thus signaling exit from a
particular phase. There are two classes of cyclins: mitotic
cyclins and G1 cyclins.
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Cell cycle and cancer
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cell cycle checkpoints have been intimately linked with
cancer due to their functions regulating genome stability and
cell progression, respectively.
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In cells that undergo very rapid cell division, G1 and G2 can
be decreased or even eliminated in cells that undergo very
rapid cell division.
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When cancer develops, however, this orderly process breaks
down. As cells become more and more abnormal, old or
damaged cells survive when they should die, and new cells
form when they are not needed. These extra cells can divide
without stopping and may form growths called tumors.
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Genetic mutations causing the malfunction or absence of one
or more of the regulatory proteins at cell cycle checkpoints
can result in the "molecular switch" being turned
permanently on, permitting uncontrolled multiplication of the
cell, leading to carcinogenesis, or tumor development.
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part 1 ppt cell cycle
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part 2 ppt cancer