Biology · AP Biology
Cell communication and the cell cycle
signals, and the division they trigger
Cells talk to one another with molecules. A signal arrives, a receptor catches it, and a chain of proteins inside the cell passes it on until something changes: a gene switches on, an enzyme starts work, the cell divides.
On the right, one molecule of epinephrine binds a receptor on a liver cell. Inside, each protein switches on several of the next, so one signal at the surface ends as thousands of active enzymes breaking down glycogen.
This chapter follows such signals: how far they travel, how a receptor turns them into a response, what happens when a pathway is broken, and how feedback holds the body steady. Then it turns to the response that matters most for growth and repair, the cell cycle, and to the signals and checkpoints that control it. When those controls fail, the result is cancer.
by contact, locally, and at a distance
A signal is a molecule (a ligand) that one cell releases and another detects. How far it must travel sorts signalling into three kinds.
Direct contact. Animal cells joined by gap junctions, and plant cells joined by plasmodesmata, share their cytoplasm: ions and small molecules pass straight across. Cells can also signal by touch, when a protein on one cell’s surface binds a receptor on another’s. An immune cell that presents an antigen activates a helper T cell this way.
Local signalling. A cell secretes a local regulator that diffuses to nearby cells (paracrine signalling). Growth factors work this way, and morphogens in an embryo tell cells where they are. At a synapse a neuron releases neurotransmitter across a narrow gap to one target. Bacteria release signals too: when enough cells are present, the signal reaches a threshold and the population responds together (quorum sensing).
Long-distance signalling. Endocrine cells release hormones into the blood, which carries them through the body: insulin, human growth hormone, thyroid hormones, testosterone and estrogen. Plants send hormones through their vascular tissue, or, like ethylene, through the air.
A signal reaches many cells but only those with the matching receptor respond. In the figure the hormone passes the cell with no receptor and acts on the one that has it.
reception, transduction, response
Every signalling pathway has three stages. Reception: the ligand binds its receptor. Transduction: the receptor changes shape and passes the signal through a series of molecules. Response: the cell does something.
A receptor is a protein whose binding site fits its ligand’s shape and charges, the way an enzyme’s active site fits its substrate. That is why a signal acts only on cells with its receptor, and why a molecule with a similar shape can block or mimic it.
Where the receptor sits depends on the ligand:
| ligand | examples | receptor |
|---|
| polar or large | epinephrine, insulin, most peptides | in the plasma membrane, binding site outside |
| small, nonpolar | steroid hormones (testosterone, estrogen), thyroid hormone | in the cytoplasm or nucleus |
On the left, a water-soluble ligand cannot cross the bilayer; it binds a membrane receptor whose shape change reaches a relay protein inside. On the right, a steroid diffuses through the bilayer, binds a receptor in the cytoplasm, and the pair enters the nucleus as a transcription factor that switches a gene on.
Responses include changes in gene expression, in enzyme activity, in the cytoskeleton, cell division and cell death. Many pathways get there by protein modification, most often adding phosphate groups, one protein after another.
second messengers, kinases and amplification
Epinephrine (adrenaline) tells a liver cell to release glucose. It never enters the cell; a chain of proteins carries its message inside.
Epinephrine binds a G protein-coupled receptor (GPCR), which crosses the membrane seven times. The receptor changes shape and activates a G protein, which swaps GDP for GTP and switches on the enzyme adenylyl cyclase. That enzyme turns ATP into cyclic AMP (cAMP), a second messenger: small, quick to make and diffusing through the cytoplasm. (Ca2+ and IP3 are second messengers in other pathways.)
cAMP activates protein kinase A. A kinase transfers a phosphate group from ATP to another protein, changing its shape and its activity. Kinase phosphorylates kinase, a phosphorylation cascade, until the last one activates glycogen phosphorylase, which cuts glucose from glycogen. Phosphatases remove the phosphates, so the pathway switches off when the signal stops.
Amplification. Each step activates many copies of the next. With these numbers for each step:
| one epinephrine molecule gives | molecules |
|---|
| epinephrine-bound receptor | 1 |
| active G proteins, each switching on one adenylyl cyclase | 10 |
| cAMP | 1,000 |
| active protein kinase A | 500 |
| active phosphorylase kinase | 5,000 |
| active glycogen phosphorylase | 50,000 |
| glucose 1-phosphate cut from glycogen | 5,000,000 |
The gains multiply: . A cascade of several steps also gives more places to regulate the signal, and lets one signal branch to several responses.
Other receptors work differently. A receptor tyrosine kinase pairs up when its ligand binds and phosphorylates itself, starting several pathways at once. A ligand-gated ion channel opens to let ions through.
mutations, drugs and toxins
A response is only as good as every link in its pathway. Change any component, by a mutation or a chemical, and the response changes with it.
On the right, three copies of one pathway receive the same pulse of ligand (grey trace):
| pathway | what changed | response |
|---|
| normal | nothing | on while the ligand is bound, off after |
| receptor blocked | an antagonist fills the binding site | none, however much ligand |
| relay stuck on | a mutation keeps the relay active | always on, with or without ligand |
Mutations. A change in the receptor’s binding domain can stop it binding its ligand; a change elsewhere can leave it signalling with no ligand at all. A relay protein that can no longer switch off keeps telling the cell to divide; mutated Ras proteins of this kind are found in many cancers.
Chemicals. An antagonist binds a receptor without activating it: beta-blockers occupy epinephrine’s receptors on the heart and lower blood pressure, and antihistamines block histamine receptors. An agonist mimics the ligand. Cholera toxin alters a G protein in intestinal cells so it stays active; cAMP stays high, the cells pump out Cl−, and water follows, causing severe diarrhoea.
Diseases follow the same logic: in type 2 diabetes target cells respond weakly to insulin, so the signal is sent but the response falls short.
a change triggers its own correction
In negative feedback the response opposes the change that caused it, returning the system to its set point. It is how the body keeps blood glucose, temperature and water balance nearly constant: homeostasis.
After a meal, blood glucose rises. β cells in the pancreas detect it and release insulin. Insulin signals liver, muscle and fat cells to take up glucose, and the liver to store it as glycogen, so glucose falls back. When glucose drops below the set point, α cells release glucagon, the liver breaks down glycogen, and glucose rises again.
| minutes after the meal | 0 | 30 | 60 | 90 | 120 | 180 |
|---|
| glucose (mg/dL) | 90 | 139 | 126 | 111 | 101 | 93 |
|---|
| insulin (µU/mL) | 8 | 67 | 59 | 41 | 28 | 14 |
|---|
Glucose peaks about 29 minutes after the meal and is close to 90 mg/dL again by 120 minutes. Insulin rises with glucose and falls once glucose is back: the correction switches itself off.
When the loop breaks. In type 1 diabetes the β cells are destroyed and no insulin is made (grey curve): glucose starts high and stays high. In Graves’ disease, antibodies stimulate the thyroid as its own regulating hormone would; the thyroid makes more and more hormone, which no longer shuts off its stimulus.
a change that drives itself further
In positive feedback the response amplifies the change that caused it, moving the system further from where it started. It is used for events that must be completed quickly, and something outside the loop has to end it.
Labour. The baby’s head stretches the cervix. Nerves signal the brain, and the posterior pituitary releases oxytocin. Oxytocin makes the uterus contract harder, which stretches the cervix more, which releases more oxytocin. In the figure each contraction is 1.45 times the last. Birth removes the stretch, and the loop stops.
Lactation. A baby suckling triggers hormones that release milk, so it suckles more; weaning ends it. Fruit ripening. Ripening fruit makes the gas ethylene, which speeds ripening in itself and in its neighbours. Blood clotting. Platelets at a wound release chemicals that attract more platelets, until the wound is sealed.
| negative feedback | positive feedback |
|---|
| the response | opposes the change | reinforces the change |
| the result | stability about a set point | a rapid, completed change |
| examples | blood glucose, body temperature | labour, lactation, ripening |
interphase, then division
The cell cycle is the life of a cell from one division to the next. Most of it is interphase, when the cell grows and copies its DNA; a short M phase divides it.
| phase | what happens | hours |
|---|
| G1 | growth; the cell makes proteins and organelles | 11 |
| S | DNA synthesis: every chromosome is replicated | 8 |
| G2 | more growth; the cell prepares to divide | 4 |
| M | mitosis, then cytokinesis | 1 |
For a human cell in culture the whole cycle takes about 24 hours, 23 of them interphase. On the graph, DNA per cell doubles from 2C to 4C through S, stays at 4C through G2 and mitosis, and halves when one cell becomes two.
After S, each of a human cell’s 46 chromosomes is two identical sister chromatids joined at the centromere: 46 chromosomes, 92 chromatids. Mitosis gives one of each pair to each daughter, so both get 46 and are genetically identical to the parent. Mitosis builds a growing body, repairs tissue, and is how many organisms reproduce asexually.
G0. A cell that specialises often leaves the cycle and stops dividing. Most mature nerve and muscle cells stay in G0; liver cells can return to the cycle when the liver is injured.
Timing from a snapshot. In a sample of dividing cells, the fraction in each phase is the fraction of the cycle spent there. If 20 of 480 cells are in mitosis, M lasts 20/480 × 24 h = 1.0 h.
replicate, align, separate
Mitosis shares one complete copy of the genome with each daughter. It runs in order: chromosomes already replicated in S condense, align in the middle of the cell, and separate to opposite ends.
The cell on the right has 2n = 4: two homologous pairs, red from one parent, blue from the other. It is a continuous process; the usual names mark its stages.
Prophase. Chromatin condenses into compact chromosomes, each two sister chromatids. The nuclear envelope breaks up, and the two centrosomes move apart, growing the spindle of microtubules between them.
Metaphase. Microtubules from opposite poles attach to each chromosome’s centromere, one to each sister, and the chromosomes line up on the metaphase plate.
Anaphase. The sisters separate and are pulled to opposite poles. Each chromatid is now a chromosome in its own right: for a moment the cell holds 8.
Telophase and cytokinesis. A nuclear envelope forms round each set, and the chromosomes loosen. Cytokinesis divides the cytoplasm: an animal cell pinches in two at a cleavage furrow; a plant cell builds a cell plate across the middle.
| chromosomes | chromatids (DNA molecules) |
|---|
| G1 | 4 | 4 |
| G2 to metaphase | 4 | 8 |
| anaphase | 8 | 8 |
| each daughter | 4 | 4 |
The AP exam asks for the order of these events (replication, alignment, separation) and what each achieves, not the names of the phases.
checkpoints, cyclins and CDKs
A cell divides only when it should. At checkpoints the cycle stops until conditions are right.
| checkpoint | it asks |
|---|
| G1 checkpoint | Is the cell big enough, are nutrients and growth factors present, is the DNA undamaged? |
| G2 checkpoint | Is all the DNA replicated, and is it undamaged? |
| M checkpoint | Is every chromosome attached to spindle fibres from both poles? |
A cell that fails the G1 checkpoint does not enter S; it may enter G0. A cell that fails the M checkpoint holds in metaphase, so no chromosome is lost.
Cyclins and CDKs. A cyclin-dependent kinase (CDK) is present all through the cycle but is active only when bound to a cyclin. Cyclin is made steadily through interphase (red curve) and destroyed in mitosis. Once enough cyclin has built up, cyclin–CDK complexes phosphorylate the proteins that carry the cell into the next stage. The complex that triggers mitosis is MPF (blue). When cyclin is destroyed in anaphase, MPF switches off and the cell can finish dividing.
Signals from outside feed in here. A growth factor, such as platelet-derived growth factor at a wound, binds a receptor and starts a pathway that raises cyclin levels and pushes the cell past the G1 checkpoint.
when the controls fail
Disrupting the cell cycle can end in one of two ways: a cell that divides when it should not, or a cell that is made to die.
Cancer is uncontrolled cell division, caused by mutations in the genes that regulate the cycle. Normal cells in a dish stop dividing when they touch (density-dependent inhibition) and divide only when attached to a surface (anchorage dependence). Cancer cells ignore both and pile up into a tumour.
Two kinds of gene are involved. Proto-oncogenes encode proteins that promote division, such as growth-factor receptors and relay proteins; a mutation that makes one overactive, an oncogene, works like an accelerator held down. Tumour-suppressor genes encode the brakes. The best known, p53, stops the cycle when DNA is damaged and, if the damage cannot be repaired, starts apoptosis. Cancer usually needs several such mutations in one cell line.
Apoptosis is programmed cell death. The cell shrinks, its DNA is cut up, and it breaks into membrane-bound fragments that other cells engulf, without spilling its contents into the tissue. It removes damaged cells, and shapes the body: in a human embryo it removes the tissue between the fingers.
Doubling. A culture of cancer cells that doubles every 24 hours, starting from 1,000 cells:
| hours | 0 | 24 | 48 | 72 | 96 |
|---|
| cells | 1,000 | 2,000 | 4,000 | 8,000 | 16,000 |
|---|
: after 96 h, 4 doublings, 16 times as many cells.
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