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

divisionb. 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 Signals1. 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 Signals1. 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 Cell-cycle 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)