Regulation of the Cell Cycle
Molecular Control System
• Normal growth, development and
maintenance depend on the timing and
rate of mitosis
•Cell-cycle control
system consists of a
set of checkpoints
(G1, G2, and M
phases of the cell
cycle)
• Checkpoints integrate a variety of
internal (intracellular) and external
(extracellular) information
• For many cells, the G1 checkpoint is the
“restriction point”
– A go-ahead signal indicates that the
cell will complete the cycle and divide
– In the absence of a go-ahead signal, the
cell may exit the cell cycle and remain in
the non-dividing state called G0 phase
•Many human cells are in the G0
phase until they die—muscle and
nerve cells
External Factors that can Influence
Cell Division
1. Chemical factors-
a. Lack of nutrients inhibit cell division
b. Presence of specific growth factors
are needed for cell division
– Platelet-derived Growth Factor
(PDGF) is required for division of
fibroblasts used in healing
– Receptors on plasma membrane bind
PDGF and trigger pathway to signal
cell division
External Signals
1. Growth factors stimulate cell division
Figure 12.15 The effect of a growth factor on cell division
Figure 12.15x Fibroblast growth
2. Physical factors-
a. Density-dependent inhibition
• Cell division limited by quantities of
nutrients and growth regulators
b. Anchorage-dependent inhibition
• Cells must attach to substratum
(surface)
• Anchorage is signaled to cell-cycle
control system by linkage between
membrane proteins and elements of
cytoskeleton
Figure 12.16 Density-dependent inhibition of cell division
G2 Checkpoint
• Sequence of cell cycle events are
synchronized by rhythmic changes in activity of
certain protein kinases—enzymes that catalyze
the transfer of a phosphate group from ATP
to a target protein (phosphorylation)
• Phosphorylation causes change in shape that
activates/inactivates target protein which
affect the progression through cell cycle
• Changes in kinase activity regulated by
regulatory proteins
– The protein kinase, cyclin-dependent kinase
(Cdks) are regulated by concentration of
cyclin present
Cdk = Cyclin-dependent
kinases
-constant conc. in a
growing cell
Cyclins-activates kinases
-accumulates in G2
MPF = maturation promoting
factor
-triggers M phase to
start by
phosphorylating a
variety of proteins
Example: proteins that
degrade nuclear
envelope
-triggers own break down
Internal Signals
1. Anaphase does not begin until all
chromosomes are attached to spindle at
metaphase plate
2. Proteins at kinetochore signal pathway
to keep Anaphase Promoting Complex
(APC) inactive
• When active the APC contains
proteolytic enzymes which break down
cyclin and thus initiates separation of
sister chromatids during Anaphase
Cancer Cells have Escaped Cellcycle Control
Cancer cells do not respond normally to the
body’s control mechanisms and divide
excessively
1. Density-independent—make their own
growth factors and continue to divide
uncontrolled (“immortal”)
2. Anchorage-independent
Abnormal cells that escape cell-cycle control are
products of mutated or transformed normal
cells
1. May proliferate to form a tumor—an unregulated
growing mass of cells within normal tissue
• Benign tumor—if cells remain at the original site
• Malignant tumor—if mass impairs normal
function of one or more organs of the body
» Excessive proliferation
» Cells with unusual number of
chromosomes
» Aberrant metabolism
» Detaches and migrates through body
(metastasis)
Figure 12.17 The growth and metastasis of a malignant breast tumor
Figure 12-17x1 Breast cancer cell
Figure 12-17x2 Mammogram: normal (left) and cancerous (right)