AP:CELL CYCLE REGULATION

CELL CYCLE

2 crucial factors for normal growth:

Timing and rate of cell division

Cell division frequency depends on cell type:

skin cells: frequently

Liver cells: can divide when needed (eg. Repair a wound)

Mature nerve cells, muscles: do not divide

WHAT DRIVES THE CELL CYCLE?

Hypotheses:

1. Each event in the cycle triggers the next

incorrect

2. Cell cycle is driven by specific molecular signals

Evidence came from experiments with mammalian cells grown in culture

CELL CYCLE IS DRIVEN BY SPECIFIC MOLECULAR SIGNALS

CELL CYCLE CONTROL SYSTEM

A cyclically operating set of molecules in the cell

Triggers and coordinates key events in the cell cycle

Regulated at certain checkpoints

Regulated by both internal and external controls

CHECKPOINTS

Signals transmitted by signal transduction pathways

Built-in stop signals: stop cell cycle at checkpoints

Overridden by go-ahead signals

Signals report if crucial cellular processes completed correctly

Also register signals from outside the cell

3 major checkpoints: G1, G2 and M

G1 CHECKPOINT

Restriction point in mammalian cells

Most important

if pass, usually complete whole cycle

If no go-ahead signal G0 phase

Most human body cells in G0 phase

Can called back from G0 phase by external cues (eg. growth factors)

THE MOLECULAR BASIS FOR THE CELL CYCLE CLOCK

Rhythmic fluctuations

Abundance and activity of cell cycle control molecules

Two main types of regulatory molecules (proteins):

1. Kinases

2. Cyclins

KINASES

enzymes that phosphorylate other proteins to active/inactive them

Specific kinases give the go-ahead signals at G1 and G2 checkpoints

Constant concentration

Inactive unless attached to a cyclin

Thus known as cyclin-dependent kinases

Cdk + Cyclin MPF

MPF

maturation-promoting factor/M-phase promoting factor

Functions:

1. as kinase

Initiates mitosis

Contributes to chromosome condensation and spindle formation

2. Activates other kinases

Phosphorylates a variety of proteins

Eg. Phosphorylates protein of the nuclear lamina

fragmentation of nuclear envelope

SELF-REGULATION OF MPF

During anaphase, MPF initiates destruction of its own cyclin

Cdks persist as inactive form

INTERNAL SIGNAL AT CHECKPOINTS

M phase checkpoint

Kinetochores not yet attached to spindle microtubules send molecular signal

Sister chromatids stayed together, delay anaphase

When kinetochores of all chromosomes are attached

Inactive protein holding sister chromatids

Sister chromatids separate (anaphase)

Ensures right number of chromosomes in daughter cells

EXTERNAL CHEMICAL SIGNAL

Cells in culture cannot divide if missing an essential nutrient

Eg. Growth factor

Mitogen: a growth factor protein that promotes mitosis

Eg. Platelet-derived growth factor (PDGF)

Required for division of fibroblasts

Fibroblast: a type of connective tissue cell with PDGF receptors

Binding allows cell to pass the G1 checkpoint and divide

Injury platelets release PDGF

EXTERNAL PHYSICAL SIGNAL:DENSITY-DEPENDENT INHIBITION

Crowded cells stop dividing

Cultured cells form a single layer on inner surface of container

If cells are removed, cells bordering space will divide to fill in

Reasons:

Physical contact (minor)

Amount of required growth factors and nutrients available (major)

EXTERNAL PHYSICAL SIGNAL:ANCHORAGE DEPENDENCE

Requires substratum

Eg. Inside of culture container or extracellular matrix of a tissue

Signaled through pathways using plasma membrane proteins and cytoskeleton

CANCER CELLS Do not respond normally to body’s control mechanisms

No density-dependent inhibition

No anchorage dependence

Divide excessively

Invade other tissues may kill organism

Stop dividing at random points in the cycle, instead of at checkpoints

Immortal: can divide indefinitely if given continual supply of nutrients

Eg. HeLa cells: a cultured cell line from 1951, Henrietta Lacks’s tumour

Vs normal cells in culture only divide 20-50 times

CANCER CELLS

Hypotheses for NO density-dependent inhibition:

Do not need growth factors to grow and divide

May make a required growth factor themselves

Abnormal signal pathway to convey GF’s signal even in its absence

Abnormal cell cycle control system

CANCER CELLS - TRANSFORMATION

process that converts a normal cell to a cancer cell

Escape destruction from body’s immune system

Forms tumour (a mass of abnormal cells within otherwise normal tissue)

If remain at original site

benign tumour (no serious problem, can be completely removed by surgery)

If becomes invasive to impair functions of one/more organs

malignant tumour (cancer)

MALIGNANT TUMOUR (CANCER)Excessive proliferation

Unusual number of chromosomes (cause or effect?)

Metabolism may be disabled

No constructive function

Abnormal changes on cells’ surfaces lose/destroy attachment to neighboring cells and extracellular matrix

Can spread into nearby tissues

Can secrete signal molecules to cause blood vessels to grow toward the tumour

METASTASISa few tumour cells separate from original tumour

enter blood/lymph vessels

travel to other parts of body

proliferate and form a new tumour

TREATMENTS – LOCALIZED TUMOURhigh-energy radiation

Damages DNA in cancer cells

normal cells can repair damage, cancer cells cannot

TREATMENTS - METASTATIC TUMOURchemotherapy through circulatory system

Interfere with specific steps in cell cycle

Eg. Taxol prevents microtubule depolymerisation

freezes mitotic spindle

stops actively dividing cells at metaphase

Side effects due to drug’s effect on normal cells

Nausea (intestinal cells)

hair loss (hair follicle cells)

susceptibility to infection (immune system cells)

TAKING IT FURTHER

Transformation always involves alteration of genes that affects the cell cycle control system