Chapter 12. Regulation of the Cell Cycle
Download
Report
Transcript Chapter 12. Regulation of the Cell Cycle
Regulation of Cell Division
AP Biology
2006-2007
Activation of cell division
How do cells know when to divide?
cell communication signals
chemical signals in cytoplasm give cue
signals usually are proteins
activators or inhibitors
AP Biology
Coordination of cell division
Multicellular organisms coordinate cell
division across different tissues & organs
critical for normal growth,
development & maintenance
coordinate
timing of
cell division
rates of
cell division
not all cells may have the
same cell cycle
AP Biology
Frequency of cell division
Frequency of cell division varies by cell type
embryo
cell cycle < 20 minute
skin cells
divide frequently throughout life
12-24 hours cycle
liver cells
retain ability to divide, but keep it in reserve M
metaphase anaphase
divide once every year or two
prophase
mature nerve cells & muscle cells
C
G2
do not divide at all after maturity
permanently in G0
S
AP Biology
telophase
interphase (G1, S, G2 phases)
mitosis (M)
cytokinesis (C)
G1
There’s no
turning back,
now!
Overview of Cell Cycle Control
Two irreversible points in cell cycle
1) replication of genetic material
2) separation of sister chromatids
Checkpoints
process is assessed & possibly halted
sister chromatids
centromere
single-stranded
AP Biology
chromosomes
double-stranded
chromosomes
Checkpoint control system
Checkpoints
cell cycle controlled by STOP & GO
chemical signals at critical points
signals indicate if key cellular
processes have been
completed correctly
3 major checkpoints:
AP Biology
G1, G2 and M
Checkpoint control system
3 major checkpoints:
G1
Can DNA synthesis begin?
G2
Has DNA synthesis been
completed correctly?
Commitment to mitosis
M
Are all chromosomes
attached to spindle?
Can sister chromatids
separate correctly?
AP Biology
Major Checkpoints
1. G1 checkpoint (Most important!)
Controlled by cell size, growth factors,
environment
“Go” completes whole cell cycle
“Stop” cell enters nondividing state (G0 Phase)
2. G2 checkpoint
Controlled by DNA replication completion,
DNA mutations, cell size
3. M-spindle (Metaphase) checkpoint
Check spindle fiber (microtubule) attachment to
chromosomes at kinetochores (anchor sites)
AP Biology
G1 Checkpoint is the most critical!
Primary decision point
“restriction point”
If cell receives a “GO
ahead”signal, it will
divide
If cell does not receive
signal, it exits cycle &
switches to G0 phase
Apoptosis – cell death
AP Biology
G1 Checkpoint
AP Biology
G0 phase
G0 phase
non-dividing, differentiated state
many human cells in G0 phase
liver cells
M
Mitosis
G2
Gap 2
S
Synthesis
AP Biology
in G0, but can be “called
G1
Gap 1
back” to cell cycle by
external cues
nerve & muscle cells
G0
highly specialized
Resting
stopped in G0 & can
never divide
Cell Cycle Control System
Checkpoint = control point where stop/go
signals regulate the cell cycle
AP Biology
“Go-ahead” signals
Protein molecules that promote cell
growth & division
internal signals
“promoting factors”
external signals
“growth factors”
AP Biology
Where is
the P
attached?
“Go-ahead” signals
Protein molecules that promote cell growth & division
internal signals
“promoting factors”
external signals
“growth factors”
Primary mechanism
of control: phosphorylation
Use of kinase enzymes
which either activate or
inactivate cell signals by
adding a phosphate
AP Biology
Where is
the P
attached?
Internal Regulatory Molecules
• Kinases : protein enzyme controls cell cycle; active when
connected to cyclin
• Cyclin-dependent kinase: Cdk
• Cyclins: proteins which attach to kinases to activate them;
levels fluctuate in the cell cycle
• When are cyclin levels highest?
AP Biology
Cyclin & Cyclin-dependent kinases
CDKs & cyclin drive cell from one
phase to the next in cell cycle
proper regulation of cell
cycle is so key to life
the genes for these
regulatory proteins
have been highly
conserved through
evolution
AP Biology
the genes are
basically the same
in yeast, insects,
plants & animals
(including humans)
inactivated Cdk
Cell cycle Chemical signals
Cyclins
regulatory proteins
levels cycle in the cell
phosphorylates
cellular proteins
activates or
inactivates proteins
Cdk-cyclin complex
Forms MPF complex
Triggers movement
into next phase
AP Biology
activated Cdk
Internal Regulatory Molecules
MPF = maturation-promoting factor
•
AP Biology
specific cyclin-Cdk complex which allows cells
to pass G2 and go to M phase
External Regulatory Factors
AP Biology
External Regulatory Factors
Growth Factor: proteins released by other
cells to stimulate cell division
Density-Dependent Inhibition: crowded cells
normally stop dividing; cell-surface protein
binds to adjoining cell to inhibit growth
Anchorage Dependence: cells must be
attached to another cell or ECM to divide
AP Biology
External signals
Growth factors
coordination between cells
protein signals released by
body cells that stimulate other
cells to divide
density-dependent inhibition
crowded cells stop dividing
When not enough growth factor
left to trigger division in any one
cell, division stops
anchorage dependence
to divide cells must be attached to a
substrate or tissue matrix
“touch sensor” receptors
AP Biology
Growth factor signals
growth factor
nuclear pore
nuclear membrane
P
P
cell division
cell surface
receptor
protein kinase
cascade
Cdk
P
P
E2F
chromosome
P
APcytoplasm
Biology
nucleus
M-spindle Checkpoint:
Mitotic spindle at metaphase
Kinetochore =
proteins associated
with DNA at
centromere
AP Biology
M checkpoint
G2 checkpoint
Chromosomes attached
at metaphase plate
• Replication completed
• DNA integrity
Active
Inactive
Inactive
Cdk / G2
cyclin (MPF)
M
Active
C
cytokinesis
mitosis
G2
G1
S
MPF = Mitosis
Promoting Factor
AP Biology
Cdk / G1
cyclin
Active
G1 checkpoint
Inactive
• Growth factors
• Nutritional state of cell
• Size of cell
Cancer & Cell Growth
Cancer is essentially a failure
of cell division control
unrestrained, uncontrolled cell growth
What control is lost?
gene p53 plays a key role in G1 restriction point
p53 protein halts cell division if it detects damaged DNA
options:
p53 is the
Cell Cycle
Enforcer
stimulates repair enzymes to fix DNA
forces cell into G0 resting stage
keeps cell in G1 arrest
causes apoptosis of damaged cell
ALL cancers have to shut down p53 activity
AP Biology
p53 — master regulator gene
NORMAL p53
p53 allows cells
with repaired
DNA to divide.
p53
protein
DNA repair enzyme
p53
protein
Step 1
Step 2
Step 3
DNA damage is caused
by heat, radiation, or
chemicals.
Cell division stops, and
p53 triggers enzymes to
repair damaged region.
p53 triggers the destruction
of cells damaged beyond repair.
ABNORMAL p53
abnormal
p53 protein
Step 1
DNA damage is
caused by heat,
radiation, or
AP chemicals.
Biology
cancer
cell
Step 2
The p53 protein fails to stop
cell division and repair DNA.
Cell divides without repair to
damaged DNA.
Step 3
Damaged cells continue to divide.
If other damage accumulates, the
cell can turn cancerous.
Development of Cancer
Cancer develops only after a cell experiences ~6 key
mutations (“hits”)
unlimited growth
turn on growth promoter genes
ignore checkpoints
turn off tumor suppressor genes (p53)
escape apoptosis
turn off suicide genes
immortality = unlimited divisions
turn on chromosome maintenance genes
promotes blood vessel growth
turn on blood vessel growth genes
overcome anchor & density dependence
turn off touch-sensor gene
AP Biology
It’s like an
out of control
car!
What causes these “hits”?
Mutations in cells can be triggered by
AP Biology
UV radiation
chemical exposure
radiation exposure
heat
cigarette smoke
pollution
age
genetics
Tumors
Mass of abnormal cells
Benign tumor
abnormal cells remain at original site as a
lump
p53 has halted cell divisions
most do not cause serious problems &
can be removed by surgery
Malignant tumors
cells leave original site
lose attachment to nearby cells
carried by blood & lymph system to other tissues
start more tumors = metastasis
impair functions of organs throughout body
AP Biology
Traditional treatments for cancers
Treatments target rapidly dividing cells
high-energy radiation
kills rapidly dividing cells
chemotherapy
stop DNA replication
stop mitosis & cytokinesis
stop blood vessel growth
AP Biology