AP BIOAP BIOUNIT 4:UNIT 4:CELL COMMUNICATION & CELL COMMUNICATION & CELL CYCLECELL CYCLEBig Ideas: ENE, ISTScience Practices: 1, 4, 5, 6

Cell Communication• Cells typically communicate using chemical signals

• These chemical signals, which are proteins or other molecules produced by a sending cell, or secreting cell, are often secreted from the cell and released into the extracellular space

• There, they can float over to neighboring cells.• Not all cells can “hear” a particular chemical message

• In order to detect a signal (to be a target cell), a neighbor cell must have the right receptor for that signal

Cell Communication• When a signaling molecule binds to its receptor, it alters

the shape or activity of the receptor, triggering a change inside of the cell Signaling molecules are often called ligands, a general term for molecules that bind specifically to other molecules (such as receptors).

• The message carried by a ligand is often relayed through a chain of chemical messengers inside the cell

• Ultimately, it leads to a change in the cell, such as alteration in the activity of a gene or even the induction of a whole process, such as cell division• the original intercellular (between-cells) signal is

converted into an intracellular (within-cell) signal that triggers a response.

Cell Communication

Cell Communication• There are four basic categories of chemical signaling found in multicellular organisms: • Autocrine signaling • Paracrine signaling• Juxtacrine signaling• Endocrine signaling

• The main differences between the different categories of signaling are the distance, the source of the signal, and the mode of delivery

Autocrine Signals• A cell signals to itself, releasing a ligand that binds to

receptors on its own surface • Or, depending on the type of signal, to receptors inside of the cell

• This may seem like an odd thing for a cell to do, but autocrine signaling plays an important role in many processes• autocrine signaling is important during development, helping cells

take on and reinforce their correct identities• autocrine signaling is important in cancer and is thought to play a

key role in metastasis • the spread of cancer from its original site to other parts of the body

• In many cases, a signal may have both autocrine and paracrine effects, binding to the sending cell as well as other similar cells in the area.

Autocrine Signals

Paracrine Signals• Cells that are near one another communicate through the

release of chemical messengers • ligands that can diffuse through the space between the cells

• The cells communicate over relatively short distances• Allows cells to locally coordinate activities with their

neighbors• Although they're used in many different tissues and

contexts, paracrine signals are especially important during development• They allow one group of cells to tell a neighboring group of cells

what cellular identity to take on

Paracrine Signals

Paracrine Signals• One example of paracrine signaling is synaptic signaling, in

which nerve cells transmit signals• This process is named for the synapse, the junction between

two nerve cells where signal transmission occurs. • When the sending neuron fires, an electrical impulse moves

rapidly through the cell, traveling down a long, fiber-like extension called an axon

• When the impulse reaches the synapse, it triggers the release of ligands called neurotransmitters, which quickly cross the small gap between the nerve cells

• When the neurotransmitters arrive at the receiving cell, they bind to receptors and cause a chemical change inside of the cell • opening ion channels and changing the electrical potential across the

membrane

Paracrine Signals

Cell Junctions• Cell junctions

• Provide contact between neighboring cells or between a cell and the extracellular space

• Types• Tight junctions

• the membranes of two cells come very close together. • membranes of the contacting cells appear to be

fused. • act as a barrier so that materials cannot pass

between two interacting cells. • the protein components of the tight junction span the

adjacent membranes of each tight junction.

Cell Junctions• Adhesion junctions

• Connects the cytoskeleton of adjacent cells• 2 types

• desmosomes•Connect the intermediate filament•Create a strong bond

• Hemidesmosomes•Connect to the extracellular space

• Gap junctions• Connects the cytoplasm of adjacent cells• Create channels that permit direct cell–cell transfer of ions and small molecules

Cell Junctions

Juxtacrine Signals• Uses the gap junctions in animals

• plasmodesmata in plants have the same function

• These water-filled channels allow small signaling molecules, called intracellular mediators to diffuse between the two cells

• Small molecules and ions are able to move between cells, but large molecules like proteins and DNA cannot fit through the channels without special assistance.

• The transfer of signaling molecules transmits the current state of one cell to its neighbor• This allows a group of cells to coordinate their response to a signal

that only one of them may have received

Juxtacrine Signals

Juxtacrine Signals• In another type of direct signaling, two cells may bind to

one another because they carry complementary proteins on their surfaces

• When the proteins bind to one another, this interaction changes the shape of one or both proteins, transmitting a signal

• This kind of signaling is especially important in the immune system, where immune cells use cell-surface markers to recognize the body's own cells and cells infected by pathogens

Juxtacrine Signals

Endocrine Signals• When cells need to transmit signals over long distances,

they often use the circulatory system• These signals are produced by specialized cells and

released into the bloodstream, which carries them to target cells in distant parts of the body• These signals are called hormones and are released by

the endocrine glands• In humans, endocrine glands that release hormones

include the thyroid, the hypothalamus, and the pituitary, as well as the gonads (testes and ovaries) and the pancreas.

Endocrine Signals

Signal Transduction • The transmission of molecular signals from a cell's

exterior to its interior• Signals received by cells must be transmitted effectively

into the cell to ensure an appropriate response• This step is initiated by cell-surface receptors

• Also known as cell signaling• Steps of Signal Transduction

• Reception• Transduction• Response

Signal Transduction

Signal Transduction • Reception

• The signal molecule is detected by the receptor protein of the target cell• The signal molecule generally comes from outside and is new to the target

cell, where as the receptor molecules/proteins are located inside of the target cell

• Reception can be defined as the target cell detection of a signal molecule that is coming from outside of the cell

• Transduction• The binding of the signal molecule triggers the receptor protein of the

target cell initiating the process of transduction.• Response

• The transduced signal finally triggers a specific cellular response• This response may be in the form of cellular activity

• catalysis by an enzyme • rearrangement of the cytoskeleton• activation of specific genes in the nucleus.

Signal Transduction

Signal Transduction • During signal transduction, a signal may have many

components• Primary messenger

• May be a chemical signal, electrical pulse, or even physical stimulation• Then, the receptor protein embedded in the cellular membrane must

accept the signal. • Upon receiving the signal, this protein goes through a conformational

change• This changes its shape and thus, how it interacts with the molecules around

it.• Receptor proteins are specialized by the type of cell they are

attached to• Each type of cell receives different signals from the body and

environment, and must be specialized so that the body can produce a specific and coordinated response

Signal Transduction • Each of these specialized proteins has a special method of

transferring a signal into the cell• Some proteins activate other molecules, called second messengers,

which carry the message to the nucleus or other organelles• Other proteins use the energy from ATP to activate enzymes, which

carry out metabolic reactions.

• The different routes which signal transduction takes to carry a signal are known as signal transduction pathways

• Examples• Touch and vision • Hormones

Signal Transduction

Changes in Signal Transduction Pathway

• Any alterations in the receptor, proteins, or reactions in a signal transduction pathway can cause changes to the cellular response.

• Many diseases and poisons cause a change or block to a receptor or signaling pathway• Can cause the cell to rapidly multiply and invade other tissues.

• The result is uncontrolled cell growth, often leading to cancer• Cancer can occur in many ways, but it always requires

multiple signaling breakdowns

Changes in Signal Transduction Pathway

• Often, cancer begins when a cell gains the ability to grow and divide even in the absence of a signal.

• Signal transduction inhibitors block signals passed between molecules• these signals are often involved in many functions of the

cells including death, growth, and division• Many drugs have been developed to block particular

signals in the hope of stopping the division of cancer cells

Changes in Signal Transduction Pathway

Feedback• Homeostasis – the maintenance of a stable internal

environment • Also referred to as equilibrium• Maintained by means of feedback mechanisms

• Negative Feedback• A stimulus causes a reaction in the opposite direction• Examples

• Body temperature • Blood pressure• Hunger• Blood sugar regulation• Red blood cell production

Feedback

Feedback•Positive Feedback

•A stimulus causes a reaction in the same direction

•Examples•Childbirth•Blood Clotting

Feedback

Cell Cycle• Cell cycle

• The cell cycle can be thought of as the life cycle of a cell• In other words, it is the series of growth and development steps a

cell undergoes between its “birth”—formation by the division of a parent cell—and reproduction—division to make two new daughter cells

• In eukaryotic cells, or cells with a nucleus, the stages of the cell cycle are divided into two major phases• interphase (G1, S, G2)• mitotic (M) phase

• Stages of the cell cycle• G1 phase - Metabolic changes prepare the cell for division

• During G1, the first gap phase, the cell grows physically larger, copies organelles, and makes the molecular building blocks it will need in later steps.

Cell Cycle• S phase - DNA synthesis replicates the genetic material

• In the S phase, the cell synthesizes a complete copy of the DNA in its nucleus

• It also duplicates a microtubule-organizing structure called the centrosome•The centrosomes help separate DNA during M phase.

• G2 phase - Metabolic changes assemble the cytoplasmic materials necessary for mitosis and cytokinesis• During G2, or the second gap phase, the cell grows

more, makes proteins and organelles, and begins to reorganize its contents in preparation for mitosis

• The G2 phase ends when mitosis begins.

Cell Cycle• M phase - Nuclear division (mitosis) followed by a cell division

(cytokinesis)• produces 2 identical daughter cells

• G0 – resting state• Some types of cells divide slowly or not at all• These cells may exit the G1and enter a resting state called G0• In G0, a cell is not actively preparing to divide, it’s just doing its

job• For instance, it might conduct signals as a neuron or store carbohydrates as a liver cell

• G0 is a permanent state for some cells, while others may re-start division if they get the right signals.

Cell Cycle

Mitosis• Mitosis – cell division that creates 2 genetically identical

daughter cells• Stages of Mitosis

• Prophase• The chromosomes start to condense, making them very compact and

easy to pull apart• The mitotic spindle begins to form

• The spindle is a structure made of microtubules, strong fibers that are part of the cell’s “skeleton”

• Its job is to organize the chromosomes and move them around during mitosis• The spindle grows between the centrosomes as they move apart.

• The nucleolus (or nucleoli, plural), a part of the nucleus where ribosomes are made, disappears• This is a sign that the nucleus is getting ready to break down.

• The nuclear envelope breaks down, releasing the chromosomes.

Mitosis• Microtubules can bind to chromosomes at the

kinetochore, a patch of protein found on the centromere of each sister chromatid. • Centromeres are the regions of DNA where the

sister chromatids are most tightly connected.)• Metaphase

• The spindle has captured all the chromosomes and lined them up at the middle of the cell

• All the chromosomes align at the metaphase plate• not a physical structure, just a term for the plane where the

chromosomes line up• At this stage, the two kinetochores of each chromosome should

be attached to microtubules from opposite spindle poles.

Mitosis• Before proceeding to anaphase, the cell will check to make sure that all

the chromosomes are at the metaphase plate with their kinetochores correctly attached to microtubules.• This is called the spindle checkpoint and helps ensure that the sister

chromatids will split evenly between the two daughter cells when they separate in the next step

• If a chromosome is not properly aligned or attached, the cell will halt division until the problem is fixed

• Anaphase• In anaphase, the sister chromatids separate from each other and are

pulled towards opposite ends of the cell.• The protein “glue” that holds the sister chromatids together is broken down,

allowing them to separate• Each is now its own chromosome• The chromosomes of each pair are pulled towards opposite ends of the cell.

Mitosis• Microtubules not attached to chromosomes elongate and push apart,

separating the poles and making the cell longer.• All of these processes are driven by motor proteins, molecular machines

that can “walk” along microtubule tracks and carry a cargo• In mitosis, motor proteins carry chromosomes or other microtubules as they

walk

• Telophase• The mitotic spindle is broken down into its building blocks• Two new nuclei form, one for each set of chromosomes• Nuclear membranes and nucleoli reappear.• The chromosomes begin to decondense and return to their “stringy”

form• This state is known as chromatin

Mitosis• Cytokinesis

• The division of the cytoplasm to form two new cells, overlaps with the final stages of mitosis• It may start in either anaphase or telophase, depending on

the cell, and finishes shortly after telophase.• In animal cells, cytokinesis is contractile, pinching the cell in two

like a coin purse with a drawstring• The “drawstring” is a band of filaments made of a protein

called actin, and the pinch crease is known as the cleavage furrow

• Plant cells can’t be divided like this because they have a cell wall and are too stiff

Mitosis• Instead, a structure called the cell plate forms down

the middle of the cell, splitting it into two daughter cells separated by a new wall.

• When cytokinesis finishes, we end up with two new cells, each with a complete set of chromosomes identical to those of the mother cell.• The daughter cells can now begin their own cellular

“lives,” and – depending on what they decide to be when they grow up – may undergo mitosis themselves, repeating the cycle.

Mitosis

Regulation of Cell Cycle• External Regulation

• Both the initiation and inhibition of cell division are triggered by events external to the cell• the death of a nearby cell • The release of growth-promoting hormones, such as

human growth hormone (HGH)• A lack of HGH can inhibit cell division, resulting in

dwarfism, whereas too much HGH can result in gigantism

• Crowding of cells can also inhibit cell division. • Another factor that can initiate cell division is the size of

the cell; as a cell grows, it becomes inefficient due to its decreasing surface-to-volume ratio. • The solution to this problem is to divide.

Regulation of Cell Cycle• Whatever the source of the message, the cell receives

the signal, and a series of events within the cell allows it to proceed into interphase• Moving forward from this initiation point, every

parameter required during each cell cycle phase must be met or the cycle cannot progress

• Internal Regulation• It is essential that the daughter cells produced be exact

duplicates of the parent cell• Mistakes in the duplication or distribution of the

chromosomes lead to mutations that may be passed forward to every new cell produced from an abnormal cell

Regulation of Cell Cycle• To prevent a compromised cell from continuing to divide, there are internal control mechanisms that operate at three main cell cycle checkpoints• A checkpoint is one of several points in the eukaryotic cell cycle at which the progression of a cell to the next stage in the cycle can be halted until conditions are favorable.

• These checkpoints occur near the end of G1, at the G2/M transition, and during metaphase

Regulation of Cell Cycle

Regulation of Cell Cycle• G1 Checkpoint

• The G1 checkpoint determines whether all conditions are favorable for cell division to proceed

• The G1 checkpoint, also called the restriction point is a point at which the cell irreversibly commits to the cell division process

• External influences, such as growth factors, play a large role in carrying the cell past the G1 checkpoint

• In addition to adequate protein reserves and cell size, there is a check for genomic DNA damage at the G1 checkpoint

Regulation of Cell Cycle• A cell that does not meet all the requirements will not

be allowed to progress into the S phase• The cell can halt the cycle and attempt to remedy the

problematic condition, or the cell can advance into G0 (resting state) and await further signals when conditions improve.

• G2 Checkpoint• The G2 checkpoint bars entry into the mitotic phase if

certain conditions are not met.• As at the G1 checkpoint, cell size and protein reserves

are assessed

Regulation of Cell Cycle• The most important role of the G2 checkpoint is to ensure

that all of the chromosomes have been replicated and that the replicated DNA is not damaged• If the checkpoint mechanisms detect problems with the

DNA, the cell cycle is halted, and the cell attempts to either complete DNA replication or repair the damaged DNA.

• M Checkpoint• The M checkpoint occurs near the end of the metaphase

stage • The M checkpoint is also known as the spindle checkpoint,

because it determines whether all the sister chromatids are correctly attached to the spindle microtubules

Regulation of Cell Cycle• Because the separation of the sister chromatids during

anaphase is an irreversible step, the cycle will not proceed until the each pair of sister chromatids is firmly anchored to at least two spindle fibers arising from opposite poles of the cell.

• Regulator Molecules of the Cell Cycle• In addition to the internally controlled checkpoints, there are two

groups of intracellular molecules that regulate the cell cycle• These regulatory molecules either promote progress of the cell

to the next phase (positive regulation) or halt the cycle (negative regulation)• Regulator molecules may act individually, or they can

influence the activity or production of other regulatory proteins

Regulation of Cell Cycle• Therefore, the failure of a single regulator may have

almost no effect on the cell cycle, especially if more than one mechanism controls the same event

• Conversely, the effect of a deficient or non-functioning regulator can be wide-ranging and possibly fatal to the cell if multiple processes are affected.

• Positive Regulation• Two groups of proteins, called cyclins and cyclin-

dependent kinases (Cdks), are responsible for the progress of the cell through the various checkpoints

• The levels of the cyclin proteins fluctuate throughout the cell cycle in a predictable pattern

Regulation of Cell Cycle• Increases in the concentration of cyclin proteins are triggered by both external and internal signals.

• After the cell moves to the next stage of the cell cycle, the cyclins that were active in the previous stage are degraded.

• Cyclins regulate the cell cycle only when they are tightly bound to Cdks• To be fully active, the Cdk/cyclin complex must also be phosphorylated (addition of a phosphoryl group – PO3-)in specific locations

Regulation of Cell Cycle• Like all kinases, Cdks are enzymes (kinases) that phosphorylate

other proteins• Phosphorylation activates the protein by changing its shape. The

proteins phosphorylated by Cdks are involved in advancing the cell to the next phase

• The levels of Cdk proteins are relatively stable throughout the cell cycle; however, the concentrations of cyclin fluctuate and determine when Cdk/cyclin complexes form

• The different cyclins and Cdks bind at specific points in the cell cycle and thus regulate different checkpoints

• Since the cyclic fluctuations of cyclin levels are based on the timing of the cell cycle and not on specific events, regulation of the cell cycle usually occurs by either the Cdk molecules alone or the Cdk/cyclin complexes

Regulation of Cell Cycle• Without a specific concentration of fully activated cyclin/Cdk

complexes, the cell cycle cannot proceed through the checkpoints.

• Although the cyclins are the main regulatory molecules that determine the forward momentum of the cell cycle, there are several other mechanisms that fine-tune the progress of the cycle with negative, rather than positive, effects• These mechanisms essentially block the progression of the cell

cycle until problematic conditions are resolved• Molecules that prevent the full activation of Cdks are called Cdk

inhibitors• Many of these inhibitor molecules directly or indirectly monitor a

particular cell cycle event• The block placed on Cdks by inhibitor molecules will not be

removed until the specific event that the inhibitor monitors is completed.

Regulation of Cell Cycle

Regulation of Cell Cycle• Negative Regulation

• The second group of cell cycle regulatory molecules are negative regulators

• Negative regulators halt the cell cycle. • Remember that in positive regulation, active molecules

cause the cycle to progress.• The best understood negative regulatory molecules are

retinoblastoma protein (Rb), p53, and p21• Retinoblastoma proteins are a group of tumor-suppressor

proteins common in many cells• The 53 and 21 designations refer to the functional molecular

masses of the proteins • Much of what is known about cell cycle regulation comes

from research conducted with cells that have lost regulatory control

Regulation of Cell Cycle• All three of these regulatory proteins were discovered to

be damaged or non-functional in cells that had begun to replicate uncontrollably (became cancerous)• In each case, the main cause of the unchecked progress

through the cell cycle was a faulty copy of the regulatory protein

• Rb, p53, and p21 act primarily at the G1 checkpoint• p53 is a multi-functional protein that has a major impact on

the commitment of a cell to division because it acts when there is damaged DNA in cells that are undergoing the preparatory processes during G1• If damaged DNA is detected, p53 halts the cell cycle and

recruits enzymes to repair the DNA

Regulation of Cell Cycle• If the DNA cannot be repaired, p53 can trigger apoptosis, or cell

suicide, to prevent the duplication of damaged chromosomes• As p53 levels rise, the production of p21 is triggered• p21 enforces the halt in the cycle dictated by p53 by binding to

and inhibiting the activity of the Cdk/cyclin complexes• As a cell is exposed to more stress, higher levels of p53 and p21

accumulate, making it less likely that the cell will move into the S phase.

• Rb exerts its regulatory influence on other positive regulator proteins• Chiefly, Rb monitors cell size

• In the active, dephosphorylated state, Rb binds to proteins called transcription factors, most commonly, E2F • Transcription factors “turn on” specific genes, allowing the

production of proteins encoded by that gene

Regulation of Cell Cycle• When Rb is bound to E2F, production of proteins necessary for the G1/S transition is blocked

• As the cell increases in size, Rb is slowly phosphorylated until it becomes inactivated

• Rb releases E2F, which can now turn on the gene that produces the transition protein, and this particular block is removed

• For the cell to move past each of the checkpoints, all positive regulators must be “turned on,” and all negative regulators must be “turned off.”

Regulation of Cell Cycle