Transcript 4923eda23bb2f71

Cell
Cycle
Objectives
• List the four phases of cell cycle.
• Define checkpoints in cell cycle and mention their
importance.
• Define cyclins and cyclin-dependent kinases.
• List their main types and describe their action as
positive regulators for cell cycle.
References:
Harper’s Illustrated Biochemistry, 26th edition, section
IV; chapter 36 (DNA organization, replication & repair)
pages:333-335 & page 339.
The Cell Cycle
The series of events that take
place in a cell leading to its
division
and
duplication
(replication) that produces two
daughter cells.
The cell cycle
phases:
• G1: Gap 1
• S: Synthetic
• G2: Gap 2
• M: Mitosis
has
4
Interphase
• Before a cell can enter cell division, it needs to take in
nutrients. All of the preparations are done during interphase.
• Interphase is a series of changes that takes place in a newly
formed cell and its nucleus, before it becomes capable of
division again. It is also called preparatory phase or
intermitosis. Previously it was called resting stage because
there is no apparent activity related to cell division.
• Typically interphase lasts for at least 90% of the total time
required for the cell cycle.
• Interphase proceeds in three stages, G1, S, and G2, preceded by
the previous cycle of mitosis and cytokinesis.
• The cells nuclear chromosomes are duplicated during S phase.
G1 Phase
• The first phase within interphase, from the end of the previous M
phase until the beginning of DNA synthesis, is called G1 (G
indicating gap). It is also called the growth phase.
•
During this phase the biosynthetic activities of the cell, which are
considerably slowed down during M phase, resume at a high rate.
• The duration of G1 is highly variable, even among different cells of
the same species.
• In this phase, cell increases its supply of proteins, increases the
number of organelles (such as mitochondria, ribosomes), and grows
in size.
• G2 phase :
Is a period of rapid cell growth and protein synthesis during which the
cell readies itself for mitosis
G0 phase
• The G0 is a period in the cell cycle in which cell exist in a
quiescent ( inactive ) state .
• G0 phase is viewed as either an extended G1 phase where
the cell neither dividing or preparing to divide or a distinct
quiescent stage that occurs outside of the cell cycle.
•
G0 is sometimes referred to as a “post-mitotic state “
since cell in G0 are in a non-dividing phase outside of the
cell cycle .
• Some type of cell such as nerve and heart muscle cell
become post-mitotic state when they reach maturity (i.e
when they are terminally differentiated ) but continue to
perform their main function for the rest of the organism’s
life .
S Phase
• The ensuring S phase starts when DNA replication
commences; when it is complete, all of the chromosomes have
been replicated,
• The amount of DNA in the cell has effectively doubled.
Mitosis (M phase, mitotic
phase)
• It is a relatively short period of the cell cycle.
• M phase is complex and highly regulated.
• The sequence of events is divided into phases, these
phases are sequentially known as:
• prophase,
• metaphase,
• anaphase,
• telophase
• cytokinesis (strictly speaking, cytokinesis is not part
of mitosis but is an event that directly follows
mitosis in which cytoplasm is divided into two
daughter cells)
Regulator of cell cycle
• Cyclins :
• Rhythmic fluctuations in the abundance and activity of control
•
•
•
•
•
molecules pace the cell cycle.
Cyclins are family of proteins whose concentration increase and
decrease through the cell cycle.
Cyclin Dependent Kinases (CDKs):
Some molecules are protein kinases that activate or deactivate
other proteins by phosphorylating them.
The levels of these kinases are present in constant amounts, but
these kinases require a second protein, a cyclin, to become
activated.
The complex of kinases and cyclin forms cyclin-dependent kinases
(Cdks).
Cycling Dependent Kinases Regulate the Cell Cycle
Cyclins and cyclin-dependent kinases
involved in cell cycle progression.
Cyclin D:
Activates CDK4, CDK6 which are
needed
for
Progression
past
restriction point at G1/S boundary.
Cyclin E, A:
Activate CDK2 which is needed for
Initiation of DNA synthesis in early
S phase.
Cyclin B:
Activates CDK1 which is needed for
Transition from G2 to M.
Cell Cycle Checkpoints
A number of surveillance systems control the cell cycle and
interrupt its progression when DNA damage occurs or when the
cells have failed to complete a necessary event.
Major
Checkpoint Monitoring Molecules
• p53
• RB ( Retinoblastoma).
Checkpoint molecules are needed to mediate the
cellular response to DNA damage.
That response range from cell cycle delay to allow
time for DNA repair, to cell cycle arrest, to
apoptosis.
p53
P53: protein of molecular weight 53
Kda, suppresses cell replication and
growth when there is DNA damage:
• DNA damage activates p53.
• P53 causes expression of p21.
• P21 is CDK-cyclin inhibitor (CKI).
• Inhibition of CDK halt progression
through cell cycle.
P53 can also trigger apoptosis
especially in response to radiation.
P53 is one of the most commonly
mutated genes in human cancer
Apoptosis
Programmed cell death
RB
Retinoblastom
• RB is a cell cycle regulator because it binds to and
inactivates a transcription factor (E2F) necessary for
the transcription of certain genes (histone genes, DNA
replication proteins, etc) needed for progression from
G1 to S phase.
• The phosphorylation of Rb by CDK4 or CDK6 results
in the release of E2F from Rb-mediated transcription
repression—thus, gene activation ensures and cell
cycle progression takes place.
Loss of RB
– Enables continuous
DNA synthesis
– Found in melanoma
and liposarcoma