Transcript Cell Cycle Regulation

Cell Cycle Regulation
Cell Cycle Checkpoints
• Interphase consists of three phases: growth, synthesis of DNA, and
preparation for mitosis (I,M,I,M,I,M,I,M)
• How does the cell make sure, for example, replication has been
completed before moving onto G2?
• CHECKPOINTS – a critical control point to STOP or CONTINUE the cycle
G0– cell cycle arrest.
Not growing.
Importance of Cell Cycle Regulation
• Stem cells: non-specialized cells that differentiate into specialized
cells via external cues
• Out of control cell growth = TUMORS / CANCER!
Important Checkpoints
• G1 checkpoint: cells will be stuck in G0 phase unless
given the go-ahead to start growing in G1. Most cells
(unlike muscle and nerve cells) are in the G1 phase
• S/G2-phase checkpoint: makes sure all DNA is
replicated before moving on and preparing for
mitosis. That would be bad if a cell ended up with
only a partial genome!
• M-phase checkpoint: makes sure all kinetochores are
attached to spindle fibers before going on to
anaphase (Apart). This is important because we can’t
have a cell in the body that’s missing a chromosome!
What if that cell needs to transcribe a gene located
on it!
• If cells are told to STOP they are usually terminated
via apoptosis (programmed cell death)
Cell Cycle Regulation
• The timing and rates of cell division in different parts of an animal or
plant are crucial for normal growth, development, and maintenance
• The frequency of cell division varies with cell type
• Skin cells divide twice a day sometimes
• Many liver cells kept in G0 phase as a reserve
• Muscle cells & nerve cells don’t divide once fully differentiated (always in G0)
• We must understand molecular regulation and cues for each cell type
if we are to understand and stop cancer growth
Internal & External Cues
• Internal and external signals provide stop-and-go signs at the
checkpoints
• External: if there are not enough nutrients in the cell medium than the
cell will not divide and visa-versa.
• Internal: remember, surface-area to volume ratio has to be kept small. If
the cell grows to big in the G1 phase, than the cell can’t get things in and
out of the cell because the volume is too it get’s the internal signal to
start synthesizing it’s DNA to soon divide.
• There must be factors…specific things…that help identify these cues….
The ‘Stuff’ of Cell Cycle Regulation
• Located in the cytoplasm of the cell
• How do we know this? Fusion of a cell in M-phase with a cell in G1-phase
will activate the non-mitotic cell to start undergoing mitosis
• These molecules trigger & coordinate key events in the cell cycle and
they ‘decide’ whether or not it can continue. Who are these ‘bouncers’?
INTERNAL:
Cyclins and CDK’s
• Cyclins and ‘cyclin-dependent kinases’ control the cell cycle
• The CDK’s are kinases, which means they are enzymes and give the cell the go-ahead to
continue through cycle
• CDK’s not active unless bound to a cyclin molecule
• Different cyclin concentrations vary dramatically at different stages in the cell cycle. Each type
of cyclin controls a different checkpoint.
• By binding to the CDK available, this cyclin/CDK pair say GO AHEAD!
• Active Cdks function by phosphorylating proteins
Control of Cyclin Expression
• Our body molecularly controls (transcription) the expression of these
cyclin proteins throughout the cycle
• Remember, if the right cyclin isn’t available at the right time, it’s a no-go!
• Oftentimes In cell signaling, phosphorylation is a way to activate a
protein.
Regulation overload
• Cyclin/CDK pairings control the
cell cycle checkpoints, but lots
of other proteins control the
cyclin’s and CDKs!
• AHHH!!!!
• Don’t worry, you don’t have to
memorize this 
Mitosis-Promoting Factor (MPF)
• A type of cyclin that gets the cell through the M-phase checkpoint
• MPF also promotes disintegration of the nuclear envelope
• AP suggested you know this one 
External Signals
• Growth factors: proteins released
by one group of cells that
stimulate other cells to divide
• Ex. Platelet-derived growth factor
(PDGF) – produced by platelet
blood cells, travel through
circulatory system and bind to
tyrosine kinase receptors on
fibroblasts, causing a signaling
cascade within the fibroblast that
causes it to undergo mitosis
• In a living organism, platelets
release PDGF in the vicinity of an
injury for wound healing
P53 – cell cycle regulator
• Think of P53 as the judge, jury, and
executioner.
• Once DNA is damaged in a cell,
there are four fates
• 1. repair of that DNA  save cell
• 2. Apoptosis  kill that cell!
• You get a mutation in your p53
gene, you are definitely getting
cancer 
RAS – signal transduction
• If you get a mutation that could
lead to increased cellular
signalling, you are very likely to get
cancer
• Overstimulation of the RAS protein
is a common form of cancer
• Point is, all cancers are different!
That’s why they are so hard to
treat. Your DNA can be damaged
anywhere!
Cause of Cancer
• Cancer ALWAYS starts with DNA
• ANYTHING that damages the DNA is a cell
can cause that cell to transform into a
cancer cell
• This damaged cell bypasses all cellular
control systems
Pathophysiology of Cancer
• Cancer cells have bypassed the checkpoints and cells grow
uncontrollably
• Excessive transcription of growth factors (PDGF)
• Abnormalities in cell signaling
• Mutations in cell cycle regulators (p53, RAS)
• Normal cells have a lifespan of 20-50 divisions but come cancer cells
are immortal. One cell line from 1951 is still reproducing in culture!
Pathophysiology of Cancer
• All it takes is ONE damaged cell
• Normally the immune system would
catch it, but if not, it can divide
uncontrollably
• Benign tumors are unable to metastasize
(invade neighboring tissue) and are not
considered cancer
• Malignant tumors are able to
metastasize
BRCA Genes
• People who carry the mutated forms of
these genes are more likely to develop
breast cancer, ovarian cancer, and
prostate cancer in the case of men
• These genes are, therefore, biomarkers
for cancer predisposition
• HOWEVER, only 10% of all breast
cancers are caused by this mutation
Embryonic Stem Cells
• What makes these cells different from
other cells in our body?
• Most cells in our body are fully and
differentiated specialized.
• ESC’s can be either:
• Totipotent: can become any type of cell,
tissue, organ, or entire organism.
• Pluripotent: can become many types of
cells, tissues, or organs
• Undifferentiated: has the ability to follow
any differentiation pathway.
• Unspecialized: can give rise to specialized
cell types
Stem Cells
• Every cell in our body came from one
of three cell lineages that originated in
the blastocyst stage of development
• Ectoderm
• Mesoderm
• Endoderm
• Even in our bodies now, we have cells
that can differentiate into different
types of cells
Medical Uses of Stem Cells
•Repair of brain and spinal tissues.
•Treatment of diseases such as leukemia, str
oke, Alzheimer’s, Parkinson’s, diabetes, cystic
fibrosis.
•Therapeutic cloning of human cells, tissues, and
certain organs (e.g., bone, cartilage, muscle).
•Reprogramming of diseased cells.
•Testing of new drugs.
•Storage of umbilical cord stem cells.
One day, doctors treating a cancer patient with
chemotherapy may be able to replace his or her
damaged blood or marrow cells with new ones
grown from ES cells.
Ethical Considerations
• Is it ethical to use embryonic stem cells?
Different
external cues
(growth factors)
Possible alternatives
WHAAATTT!?