Unit 4 Beta

Cell Communication and Cell Cycle: the one-page sheet

4.1 Cell Communication

Cells pass information by direct contact, through gap junctions or plasmodesmata or by touching surface molecules, as when a helper T cell recognizes an antigen-presenting cell; by local regulators such as growth factors that reach nearby cells; by neurotransmitters released across a synaptic cleft onto a single target; and by hormones carried in the blood to distant target cells. Only cells with the matching receptor respond. Bacteria use quorum sensing: an autoinducer builds up as cell density rises until it switches the same genes on in every cell.

Cells signal over four ranges: direct contact (touching cells, gap junctions, plasmodesmata), local signaling (local regulators to nearby cells), synaptic signaling (a neuron to one target cell across a synaptic cleft) and endocrine signaling (hormones in the blood).
Distance trades speed and precision for reach: a neurotransmitter acts within a millisecond on one cell, while a hormone takes minutes to arrive but reaches every tissue.
Being exposed to a signal is not the same as responding: only target cells, which have the matching receptor, respond.
Immune cells use contact: a helper T cell is activated by touching an antigen-presenting cell that displays a fragment of a pathogen.
Bacteria signal too. In quorum sensing, each cell releases an autoinducer; when cell density is high, its concentration crosses a threshold and the whole group switches the same genes on together.

The signaling molecules spread out into the fluid around the cell. Only cells close to the source meet a high concentration, so most signals act locally. Cells far from the source are exposed: this is long-distance (endocrine) signaling by a hormone. Only those target cells bind the signal; the rest are unaffected. The target cell's behavior changes: a channel opens, an enzyme switches on, or genes are switched on.

pathogen: A virus, bacterium, fungus or other agent that causes disease. Immune cells recognize pieces of a pathogen's molecules displayed on cell surfaces.
cell communication: The passing of information between cells, usually as a signaling molecule released by one cell and bound by a receptor on or in another. Cells signal by direct contact, to nearby cells, or over long distances through the blood.
direct contact signaling: Signaling between cells that touch: through channels joining their cytoplasms (gap junctions in animals, plasmodesmata in plants) or by molecules on one cell's surface binding receptors on the other's.
gap junction: A cluster of protein channels joining the cytoplasms of two neighboring animal cells, letting ions and small molecules pass straight from one to the other. Plasmodesmata are the plant version: channels through the cell walls that connect the cytoplasms of neighboring cells.
antigen-presenting cell: An antigen-presenting cell displays fragments of pathogen proteins (antigens) on its surface. A helper T cell whose receptor fits the displayed antigen is activated only by touching that cell, and killer T cells recognize infected cells the same way: by contact.
local signaling: Signaling in which a cell releases a local regulator that diffuses through the tissue fluid to cells close by (paracrine signaling). In autocrine signaling the releasing cell responds to its own signal.
synaptic signaling: Signaling by a neuron: an electrical signal reaches the end of the neuron, which releases neurotransmitter by exocytosis. The neurotransmitter crosses the narrow synaptic cleft and binds receptors on one target cell within about a millisecond.
endocrine signaling: Long-distance signaling: gland cells release hormones into the blood, which carries them throughout the body to target cells far away. Slower to arrive than local or synaptic signals, but able to reach many tissues at once.
hormone: A signaling molecule released into the blood (or, in plants, moved through the plant) that acts on distant target cells. Every cell is exposed, but only target cells, which have a matching receptor, respond.
insulin: A protein hormone released by beta cells of the pancreas when blood glucose rises. It binds receptors on muscle, fat and liver cells, which then take up and store glucose.
growth factor: A local regulator that binds receptors on nearby cells and stimulates them to grow and divide, for example near a wound.
quorum sensing: Bacterial signaling that tracks cell density. Each cell releases a small signaling molecule, an autoinducer; when enough cells share a space, its concentration passes a threshold, receptors are bound, and all the cells switch on the same genes at once (for example, light-making genes).

4.2 Introduction to Signal Transduction

Cell signaling runs in three stages. In reception, a ligand binds a receptor and changes its shape: polar and large ligands bind cell-surface receptors, while small nonpolar ones such as steroid hormones cross the membrane and bind intracellular receptors that switch genes on. In transduction, relay molecules pass the signal along, often by protein kinases adding phosphate groups and by second messengers spreading through the cytoplasm; because each step switches on many molecules of the next, the signal is amplified. The response can be a change in enzyme activity, gene expression or even cell death. Phosphatases and the breakdown of second messengers switch the pathway back off when the ligand leaves.

Every signaling pathway has three stages: reception (ligand binds receptor), transduction (a relay of shape changes inside the cell) and response.
Where the receptor sits depends on the ligand: polar or large ligands bind cell-surface receptors; small nonpolar ligands such as steroids cross the membrane and bind intracellular receptors, which often switch genes on.
Protein kinases switch proteins on (or off) by adding phosphate from ATP; phosphatases remove it. Phosphorylation is the most common switch in transduction.
Second messengers are small molecules or ions made or released in large amounts inside the cell; they spread the signal quickly through the cytoplasm.
Because each active enzyme switches on many copies of the next protein, the signal is amplified, so a few ligand molecules can produce a large response.

The receptor protein changes shape (reception). The signal is now inside the cell, carried by proteins rather than by the ligand. Each phosphorylated protein changes shape and switches on (transduction). The signal is amplified: one bound receptor can lead to millions of product molecules. The cell responds: an enzyme turns on or off, a channel opens, genes switch on, or the cell dies by apoptosis (response). The relay proteins switch back off, so the response stops soon after the signal does.

ligand: A molecule that binds specifically to another molecule. In cell signaling, the ligand is the signaling molecule that binds a receptor's binding site, which fits its shape and charges.
reception: The first stage of cell signaling: a ligand binds its receptor, and the receptor protein changes shape.
signal transduction: The second stage of cell signaling: the shape change of a bound receptor is passed along a chain of relay molecules inside the cell, each switching the next on, until it reaches the molecules that carry out the response. The chain is a signal transduction pathway.
cell-surface receptor: A receptor protein that spans the plasma membrane, with its binding site facing outside the cell. It binds ligands that are polar or too large to cross the membrane, such as insulin and other protein hormones.
intracellular receptor: A receptor protein in the cytoplasm or nucleus. It binds small nonpolar ligands, such as steroid hormones, that diffuse across the membrane; the ligand-receptor complex usually binds DNA and switches particular genes on or off.
second messenger: A small, non-protein molecule or ion made or released inside a cell in large amounts when a receptor is activated. It diffuses quickly through the cytoplasm and switches on relay proteins, spreading and amplifying the signal. (The ligand is the first messenger.)
signal amplification: The growth of a signal along a transduction pathway: each activated enzyme switches on many molecules of the next step, so one ligand-bound receptor can lead to millions of product molecules.
protein kinase: An enzyme that transfers a phosphate group from ATP to a particular protein, changing that protein's shape and switching its activity on or off. A protein phosphatase removes the phosphate, reversing the switch.
cellular response: The final stage of cell signaling: the change the pathway produces, such as an enzyme switched on or off, a channel opened, genes switched on or off, or the cell's own death by apoptosis.

4.3 Signal Transduction Pathways

In a G protein-coupled pathway, a ligand such as epinephrine activates a GPCR, which switches a G protein on (GDP swapped for GTP); the G protein activates adenylyl cyclase, which makes the second messenger cAMP; cAMP activates protein kinase A and a phosphorylation cascade that, in liver cells, breaks down glycogen. Calcium ions are a second messenger released through channels. Receptor tyrosine kinases pair up and phosphorylate each other when a growth factor binds, starting a kinase cascade toward growth and division. Pathways switch off through GTP hydrolysis, phosphodiesterase and phosphatases. A mutation, toxin or drug that locks a step on or off changes every step after it: cholera toxin locks a G protein on, antagonists block receptors.

A G protein is a switch: off with GDP, on with GTP. An activated GPCR flips it on; the G protein flips itself off by hydrolyzing GTP.
Adenylyl cyclase makes cAMP from ATP; cAMP switches on protein kinase A; phosphodiesterase breaks cAMP down. The cAMP level reflects a balance between making and breaking.
Ca²⁺ is the other common second messenger: kept very low in the cytoplasm, it floods in when channels open.
Receptor tyrosine kinases pair up when a growth factor binds, phosphorylate each other, and start a kinase cascade that often switches on genes for growth and division.
A mutation or a drug can leave a pathway stuck on or switched off. Steps after the change follow it; steps before it do not. An antagonist blocks a receptor, an agonist activates it.

The receptor changes shape and makes a G protein on the inside of the membrane release GDP and bind GTP, switching it on. Adenylyl cyclase switches on and converts ATP into many molecules of cAMP, the second messenger. Protein kinase A switches on and phosphorylates many molecules of the next kinase, starting a phosphorylation cascade. It breaks glycogen into glucose units; the cell releases glucose into the blood, fuel for fight or flight. cAMP falls, phosphatases switch the kinases off, and glycogen breakdown stops. keeps every step after it running with no signal; one locked in "off" blocks the response even with the signal present.

G protein-coupled receptor: A G protein-coupled receptor: a cell-surface receptor that crosses the membrane seven times. When its ligand binds, its shape change makes a G protein on the inside of the membrane release GDP and bind GTP, switching the G protein on. Epinephrine and many other hormones and neurotransmitters use GPCRs.
G protein: A protein on the inner face of the plasma membrane that works as an on-off switch: off with GDP bound, on with GTP bound. An activated GPCR makes it swap GDP for GTP; the G protein then switches on an enzyme such as adenylyl cyclase, and switches itself off by hydrolyzing its GTP to GDP.
adenylyl cyclase: A membrane enzyme that converts ATP into the second messenger cAMP. An active G protein switches it on, and each active enzyme makes many cAMP molecules.
cAMP: Cyclic AMP, a second messenger made from ATP by adenylyl cyclase. It diffuses through the cytoplasm and switches on protein kinase A. Phosphodiesterase breaks it down to inactive AMP, so cAMP stays high only while adenylyl cyclase keeps making it.
calcium ion signaling: The use of calcium ions (Ca²⁺) as a second messenger. Cells pump Ca²⁺ out of the cytoplasm and into the ER, keeping its cytoplasmic level about 10,000 times lower; when a signal opens Ca²⁺ channels, Ca²⁺ floods in and binds proteins that trigger responses such as muscle contraction or exocytosis.
receptor tyrosine kinase: A receptor tyrosine kinase: a cell-surface receptor whose inside part is a kinase. Ligand binding brings two receptors together (dimerization); each adds phosphate to tyrosines on the other, and relay proteins bind those phosphates and start a kinase cascade. Growth factors act through RTKs.
phosphorylation cascade: A chain of protein kinases in which each kinase, once switched on, phosphorylates and switches on many copies of the next kinase. It relays and amplifies the signal; phosphatases switch each step back off.
epinephrine: A hormone (also called adrenaline) released by the adrenal glands in danger or stress, part of the fight-or-flight response. In liver cells it binds a GPCR, and the cAMP pathway leads to glycogen breakdown and glucose release; in the heart it raises the rate of beating.
signal termination: The switching off of a pathway when the signal stops: the ligand leaves the receptor, G proteins hydrolyze GTP to GDP, phosphodiesterase converts cAMP to AMP, and phosphatases remove phosphates from relay proteins.
mutation: A change in the DNA sequence of a gene. It can change the protein the gene codes for, sometimes making it work differently, work all the time, or not work at all.
pathway stuck on: A pathway can be stuck on or switched off by a mutation in any of its proteins. A protein that can no longer be switched off (such as a G protein that cannot hydrolyze GTP) keeps the response going without a signal; a protein that can no longer be switched on blocks the response even when the signal is present.
signal-blocking drug: Chemicals that act on signaling pathways. An agonist binds a receptor and activates it as the normal ligand does; an antagonist binds without activating it and blocks the normal ligand. Toxins can also act on relay proteins: cholera toxin locks a G protein in its active form.

4.4 Feedback

Feedback loops link a stimulus, a sensor, a control center with a set point, and effectors. Negative feedback opposes a change and returns the variable to its set point: insulin from beta cells lowers blood glucose after a meal, glucagon from alpha cells raises it when it falls, and sweating or shivering hold body temperature near 37 °C. Positive feedback amplifies a change until an outside event ends it: oxytocin and contractions in childbirth, platelets in blood clotting, ethylene in ripening fruit. When a loop fails, as in type 1 diabetes (little insulin) or type 2 (a weak response to insulin), blood glucose is no longer held in range.

A feedback loop has a stimulus (a change), a sensor, a control center that compares with a set point, and effectors that respond.
Negative feedback opposes the change and returns the variable to its set point, then switches itself off. It keeps conditions stable: blood glucose, body temperature.
Positive feedback amplifies the change until an outside event ends it: oxytocin in childbirth, blood clotting, ethylene ripening fruit such as apples and bananas.
Blood glucose is held by two opposing hormones: insulin lowers it, glucagon raises it.
When a loop fails, homeostasis fails. In diabetes, too little insulin (type 1) or a weak response to it (type 2) leaves blood glucose high.

Blood glucose rises above its normal range: this is the stimulus. They release more insulin into the blood. Muscle and fat cells take up more glucose; the liver stores glucose as glycogen (the effectors respond). Blood glucose falls back toward the set point, and the stimulus for insulin release fades. The liver breaks down glycogen and releases glucose, so glucose rises back: the response always opposes the change.

set point: The value a regulated variable is held near, such as about 37 °C for human body temperature or about 70-100 mg/dL for fasting blood glucose. In practice it is a normal range rather than a single number.
stimulus: A change in the internal or external environment that a sensor detects, such as a rise in blood glucose after a meal. In a feedback loop, the stimulus is the change that starts the response.
sensor: The parts of a feedback loop. A sensor detects a change in a variable; a control center compares it with the set point and sends signals; effectors (muscles, glands, organs) carry out the response that changes the variable.
negative feedback: Regulation in which the response opposes the original change, moving the variable back toward its set point; once the variable returns, the response stops. It keeps conditions stable (homeostasis), as in blood glucose and body temperature control.
positive feedback: Regulation in which the response adds to the original change, so the change grows faster and faster until an outside event ends the loop. It drives a process to completion, as in childbirth, blood clotting and the ripening of some fruits.
glucagon: A hormone released by alpha cells of the pancreas when blood glucose falls. It acts on liver cells, which break down glycogen and release glucose into the blood. Its effect opposes insulin's.
blood glucose regulation: The regulation of glucose in the blood by two opposing negative feedback loops: insulin lowers glucose after it rises, and glucagon raises it after it falls, keeping fasting glucose near about 70-100 mg/dL.
thermoregulation: The control of body temperature. In mammals, a control center in the brain compares temperature with a set point near 37 °C and triggers sweating and wider skin blood vessels when hot, or shivering and narrower skin vessels when cold.
oxytocin: A hormone released from the brain during childbirth when the baby's head stretches the cervix. It makes the uterus contract harder, which stretches the cervix more and releases more oxytocin: positive feedback that ends with birth.
ethylene: A gaseous plant hormone that triggers fruit ripening. In fruits such as apples and bananas, ethylene also makes the fruit produce more ethylene, so ripening speeds up by positive feedback and spreads to nearby fruit.
diabetes: A disease in which blood glucose stays too high because the insulin feedback loop fails. In type 1, the beta cells are destroyed, so little insulin is made. In type 2, cells respond weakly to insulin, and the beta cells eventually cannot release enough to make up for it.
blood clotting: The sealing of a damaged blood vessel. Platelets that stick at the injury release chemicals that attract more platelets, and clotting proteins switch on more clotting proteins: positive feedback that grows until the break is sealed.

4.5 Cell Cycle

A dividing eukaryotic cell cycles through interphase and M phase. In G1 it grows; in S it copies its DNA by base pairing, so each chromosome becomes two sister chromatids joined at a centromere; in G2 it prepares to divide. In mitosis the chromosomes condense, spindle fibers from two centrosomes attach to their kinetochores, the chromosomes line up at the middle, and the sister chromatids separate to opposite poles; nuclei re-form and cytokinesis divides the cytoplasm. The two daughter cells are genetically identical to the parent. Cells may leave the cycle for G0. Mitosis supports growth, tissue repair and asexual reproduction.

The cell cycle is interphase (G1 growth, S DNA copying, G2 preparation) followed by mitosis and cytokinesis. Interphase is busy, not resting.
DNA is copied only in S phase. After S, each chromosome is two sister chromatids joined at a centromere; the DNA content is doubled but the number of chromosomes is the same.
Mitosis separates the sister chromatids so each new nucleus gets one copy of every chromosome; cytokinesis splits the cytoplasm (a cleavage furrow in animal cells, a cell plate in plant cells).
Cells can leave the cycle for G0, working but not dividing; most nerve cells stay there for life.
Mitosis makes genetically identical daughter cells, used for growth, tissue repair and asexual reproduction.

It reaches the size and supplies it needs to copy its DNA. Every chromosome now consists of two identical sister chromatids joined at the centromere, and the cell's DNA content has doubled. The chromosomes can be moved without tangling, and the spindle reaches across the cell. The chromosomes line up across the middle of the cell (metaphase), each sister facing a different pole. Each pole receives one copy of every chromosome. Two daughter cells form, each genetically identical to the parent cell.

cell cycle: The repeating series of events in a dividing eukaryotic cell: interphase (G1, S and G2), when the cell grows and copies its DNA, then mitosis and cytokinesis, which split it into two cells.
DNA replication: The copying of a DNA molecule before a cell divides. The two strands separate, and base pairing lets each serve as a pattern for a new partner strand, so each copy has one old and one new strand and the same sequence.
interphase: The part of the cell cycle between divisions, usually about 90% of the time. In G1 the cell grows and does its normal work; in S it copies its DNA; in G2 it grows more and makes the proteins it needs for mitosis.
sister chromatid: One of the two identical copies of a chromosome made in S phase. Sister chromatids stay joined at a region called the centromere until anaphase, when they separate and each becomes a chromosome of its own.
chromosome condensation: The coiling and folding of each chromosome's long DNA into a short, thick, compact form at the start of mitosis, so it can be moved without tangling or breaking.
mitosis: The division of the nucleus in which the sister chromatids of every chromosome are separated and moved to opposite poles, so each new nucleus gets one complete, identical set of chromosomes. Mitosis and cytokinesis together are the M phase.
mitotic spindle: The structure of microtubules that moves chromosomes during mitosis. It grows from two centrosomes at opposite poles (in animal cells each holds a pair of centrioles); spindle fibers attach to the kinetochore, a protein structure at each chromatid's centromere.
prophase: The stages of mitosis: prophase (chromosomes condense, spindle forms), prometaphase (nuclear envelope breaks down, fibers attach to kinetochores), metaphase (chromosomes line up at the metaphase plate), anaphase (sister chromatids separate and move to opposite poles) and telophase (nuclear envelopes re-form).
cytokinesis: The division of the cytoplasm after mitosis. In animal cells a ring of actin filaments pinches the cell in two along a cleavage furrow; in plant cells vesicles fuse in the middle to build a cell plate, which becomes a new cell wall.
G0: A non-dividing state that cells enter from G1. Cells in G0 are alive and working but not preparing to divide; most nerve and heart muscle cells stay there, while some, such as liver cells, can be called back into the cycle.
daughter cell: Each of the two cells formed when a cell divides. After mitosis and cytokinesis the daughter cells are genetically identical to each other and to the parent cell, with the same number and kinds of chromosomes.
somatic cell: Any cell of a multicellular organism's body that is not part of the line of cells that makes eggs or sperm. Body cells divide by mitosis.
asexual reproduction: What mitosis is used for: growth of a multicellular organism, tissue repair (replacing lost or damaged cells), and asexual reproduction, in which one parent produces genetically identical offspring.

4.6 Regulation of Cell Cycle

The cell cycle is controlled at checkpoints: G1 (size, growth signals, DNA damage), G2 (DNA fully copied and undamaged) and M (every chromosome attached to the spindle). Cyclin-dependent kinases are present throughout but active only when bound to cyclins, whose levels rise and fall; active cyclin-CDK complexes, such as MPF, phosphorylate proteins that push the cell into the next stage, and destroying the cyclin resets the cycle. Growth factors push cells forward and contact inhibition holds them back. The tumor suppressor p53 halts the cycle when DNA is damaged and triggers apoptosis through caspases if repair fails. Cancer arises when mutations turn proto-oncogenes into oncogenes and disable tumor suppressors, so cells divide without control and may spread.

Checkpoints hold the cycle until conditions are right: G1 (size, growth signals, DNA damage), G2 (DNA fully copied and undamaged), M (every chromosome attached to the spindle).
Cyclins rise and fall; CDKs are always present but active only when bound to a cyclin. Destroying the cyclin switches the CDK off and resets the cycle.
Outside signals matter: growth factors push cells past G1, and contact inhibition stops normal cells dividing when they are crowded.
p53 is a tumor suppressor: it halts the cycle when DNA is damaged and triggers apoptosis (through caspases) if repair fails.
Cancer comes from several mutations in one cell line: proto-oncogenes turned into overactive oncogenes, and tumor suppressors lost. Malignant tumors invade and spread (metastasis).

The cell makes more G1 cyclin. The active cyclin-CDK complex phosphorylates target proteins that carry the cell past the G1 checkpoint into S phase. p53 switches on a gene for a protein that blocks cyclin-CDK, so the cycle halts in G1 while the DNA is repaired. Caspases take the cell apart, so a cell with damaged DNA does not divide. Anaphase waits until every chromosome is attached, so each daughter cell gets a full set. The cells divide without growth signals, ignore checkpoints and avoid apoptosis: cancer.

DNA damage: Changes or breaks in DNA caused by copying errors, radiation such as X-rays and ultraviolet light, or chemicals. Cells have repair systems that fix most damage; checkpoints hold the cycle while repair happens.
checkpoint: A control point in the cell cycle where the cell checks that conditions are right before going on. The G1 checkpoint checks size, growth signals and DNA damage; the G2 checkpoint checks that DNA is fully copied and undamaged; the M (spindle) checkpoint checks that every chromosome is attached to the spindle from both poles.
cyclin: A protein whose concentration rises and falls through the cell cycle. A cyclin binds and activates a cyclin-dependent kinase; when its stage is over, the cyclin is destroyed, switching the kinase off.
cyclin-dependent kinase: A cyclin-dependent kinase: a protein kinase present at a fairly steady level through the cycle but active only when bound to a cyclin. Active cyclin-CDK complexes phosphorylate target proteins that move the cell past a checkpoint. MPF (maturation-promoting factor) is the cyclin-CDK complex that drives a cell into mitosis.
density-dependent inhibition: The stopping of division when normal cells touch neighbors on all sides (contact inhibition). Most normal animal cells also need to be attached to a surface to divide (anchorage dependence). Cancer cells lose both controls and pile up in layers.
cancer: Disease caused by cells that divide without control because mutations have disabled cell cycle regulation. A tumor is a mass of such cells; it is benign if it stays in place and malignant if its cells invade nearby tissue and spread through the body (metastasis).
proto-oncogene: A normal gene whose protein promotes cell division, such as a growth factor receptor or a relay protein in a growth pathway. A mutation that makes the protein overactive or overproduced turns it into an oncogene; one changed copy can be enough to push division.
tumor suppressor gene: A normal gene whose protein slows or stops cell division or triggers apoptosis, such as p53, which halts the cycle when DNA is damaged. Cancer risk rises when both copies of a tumor suppressor gene in a cell are lost or disabled.
apoptosis signaling: The signals that trigger apoptosis. Severe DNA damage (through p53), missing survival signals, or a signal from an immune cell switch on caspases, protein-cutting enzymes that take the cell apart in an orderly way, and the remains are engulfed by other cells.