Unit 4: Cell Communication and Cell Cycle

CELL COMMUNICATION + APOPTOSIS
Cells communicate with each other via chemical signals
Intro to nervous and endocrine systems
Cell-to-cell communication is essential for all organisms
E.g. flight or fight response is triggered by a signaling molecule (epinephrine)
Signal Transduction Pathway: series of steps that take place when a signal binds to a cell (message delivered) and converts it into a specific cellular response
Ligand binds to receptor → induces series of reactions for cell response
Pathway similarities suggest that ancestral signaling molecules evolved in prokaryotes and were modified later in eukaryotes
Ligand - things that bind to receptors and trigger signal transduction pathways
Neurotransmitters: SYNAPTIC SIGNALING nervous system ligands, how nerves communicate with target cells thru a synapse, enter synapse through exocytosis, doesn’t travel a far distance in synaptic cleft (ergo local)
Bind to receptors like GPCR (epinephrine), RTK (growth factors), or ligand gated
Hormones: ONLY LONG DISTANCE, sent thru bloodstream
Growth Factors: most important ligand PARACRINE SIGNALING trigger cell division, cause growth and repair. Don’t travel a far distance. Fix damaged parts of the body. Large role if cancer occurs
Local Signaling: animal cells may communicate by direct contact, or cell-cell recognition, info not sent very far
Gap junctions: cells are tightly bound and act as one unit (heart pumping)
Plasmodesmata: rigid cell walls make diffusion difficult between plant cells, they have plasmodesmata tubes instead
Cell-to-Cell Recognition: can determine if self or nonself using glycoproteins
Synaptic signaling- use neurotransmitters for neurons to communicate to target cells
Paracrine signaling- use growth factors, can repair wounds
Affect nearby cells, do not enter bloodstream
Long-distance Signaling:
Released in the bloodstream by endocrine system (hormones)
Every cell in body is exposed to hormone, only cells with receptors respond to the hormone
Target cell is the cell being communicated wit
Growth hormone: grow a lot of cells, growth factors only affect nearby cells, hormones in the bloodstream
RECEPTION
Receptors: specific membrane proteins that receive the ligands and trigger transduction, ligands that bind to ion channel, GPCR, RTK has to be polar
(G protein-coupled receptors) GPCR Receptors: largest family of cell surface receptors, include epinephrine
G-protein normally an inactive protein but activated when ligand binds to it (epinephrine and using GTP), sent on a mission by receptor to trigger a cell response
(Receptor tyrosine kinases) RTK Receptors: Growth factors, any broken receptors associated with cancer
Responds to ligands like growth factors
Causes cell division
Malfunctioning RTKs causes cancer
Phosphorylates relay proteins
Ligand-gated ion channel: acts as a gate when the receptor changes shape, e.g. neurotransmitters
In nervous system: e.g. sodium & calcium channels
Have a gate, and the only way to open it is to have a ligand bind to it, K+, Ca+ or Na+ can enter/leave the cell
Intracellular receptors: proteins found in the cytosol or nucleus of target cells, receives NONPOLAR hormones
Small or hydrophobic chemical messengers can readily cross the membrane and activate receptors
E.g. testosterone, or estrogen (steroids)
Binds to protein in nuclear envelope and initiates transcription
Activated hormone-receptor complex can act as a transcription factor, turning on specific genes
TRANSDUCTION
Protein Kinase: 2nd messengers perform transduction where message is relayed throughout the cell. Proteins that are specialized activated thru phosphorylation “Passing the baton” (relay message), causes a chain
Phosphorylation Cascade: series of activated protein kinases that receive and transport the relay molecule (using ATP) often involving 2nd messengers
Message relayed throughout the cell, prompting a cell response
Using a series of protein kinases using phosphorylation
Responsible for passing the message through the cell using a phosphorylation cascade , passing the relay message as a baton
Second Messenger: anything not a protein kinase that performs transduction/relay the message; water-soluble molecules or ions that spread throughout a cell by diffusion. Participate in pathways initiated by GPCR and RTK.
Cyclic AMP (cAMP)
Most common 2nd messenger
Created using Adenylyl cyclase by taking ATP and cutting off two phosphates (becomes adenosine monophosphate)
E.g. epinephrine binds to GPCR and G protein phosphorylates adenylyl cyclase and makes cAMP and cAMP activates a protein kinase
Ca+++ (calcium ions)
Cell can tightly regulate Ca concentration (active transport) in ER and mitochondria
Can activate IP3 or DAG
IP3
Diacylglycerol (DAG)
RESPONSE
Cell Response: depends on the pathway within the cell leads to regulation of transcription or cytoplasmic activities or “output response”
Many signaling pathways regulate the synthesis of enzymes or other proteins usually by turning genes on or off in the nucleus
Other pathways regulate the activity of enzymes rather than their synthesis
Signal pathways can also affect the overall behavior of a cell, for example, changes in a cell shape
Initiate transcription: begin production of proteins within the cell, control what happens in the cell
E.g. testosterone, estrogen, progesterone
Change cell behavior: tell the cell to do something
E.g. yeast (fungus) cells mating (making shmoos, induce change in cell shape) produce actin microfilaments (for cell movement and shape) to form cortex for changing cell shape (shmoo)
Muscle contractions
Pheromones: externally released ligands for organism-to-organism communication
Activate enzymes: control what chemical reactions the cell is able to perform
Apoptosis (1. DNA mutation, 2. Misfolded protein, 3. Death signal)
Active or suppress genes: triggered by growth factors and hormones
Fine-Tuning of the Response
Amplification of the Signal (and response): enzyme cascades amplify the cell’s response the number of activated products is much greater than in the preceding step
Small amount of ligand create a large response
All of the proteins relaying the message can amplify the response, can activate many enzymes
Specificity of the Response: pathway within the cell dictates the response given from that ligand
Cell can only respond if they have the receptor but the pathway determines what that response is
Efficiency of the Response: increased using scaffolding proteins hold many relay proteins in one location. Have proteins associated with pathway close together to make pathway faster
Termination of the Signal: unbound receptors revert to an inactive state
Specific Responses
Apoptosis: controlled cell death using lysosomes’ hydrolytic proteins (proteases, amylases [carbs], nucleases, etc.) cells in a vesicle the vesicles are taken in by white blood cells and digested
Lysosomal enzymes are released in the cell and break everything down, package everything into vesicles and WBC phagocytosis consumes the vesicles
Release of “death-signal” binds to receptor initiation of phosphorylation cascade and activates nucleases (nucleic acids) and proteases (protein) that break down the cell
Activate enzymes mainly caspase
Reasons: normal development, selectively killing particular cells (finger webbing removal, more space between digits) embryonic development
Triggered by DNA damage (mutation) in the nucleus
Extracellular death ligands (signals)
Protein misfolding in the nucleus (e.g. alzheimer's, parkinson's)
Mutations cause cancer and disease so it’s better to destroy the cell → when things go awry apoptosis is the safeguard
Evolved in early animal evolution and is essential for development and maintenance of all animals
Interference with apoptosis may cause cancer
Caspases are the main proteases (enzymes that cut up proteins that carry out apoptosis)

CELL CYCLE
Interphase: any time the cell is not dividing
G1 (Growth 1): cell spends the bulk of its time, the cell grows and begins normal processes
S (Synthesis): cell begins to prepare for division. DNA replicatescritical to mitosis so both new daughtercells get a full set of DNA
****The chromosomes make copies and are held together by a centromere band, the two copies held are called sister chromatids, those chromatids are identical to each other and are still considered one chromosome, one mitotic chromosome, when the cell divides, the sister chromatids separate and are now separate chromosomes, both daughter cells get one copy and have the same chromosomes as the parent.
If DNA replicates it has to divide, a critical point to decide whether or not it will divide
G2 (Growth 2): undergoes more growth, the cell prepares more for division, organelles begin to replicate
Mitosis: process of cell division, occurs after the G2 phase, technically only when the nucleus divides
The two daughter cells are identical does not produce variation, purpose = cloning
Cytokinesis: when the rest of the cell (cytosol) divides after mitosis nuclei divide
In animal cells:
Cleavage furrow (groove in cell) is formed using a ring of actin microfilaments (for movement)the ring gets tighter until it cuts through the cytoplasm into two daughter cells
In plant cells:
Can’t pinch plant cells into two because of the rigid cell wall
Creates cell plates (produces new membrane and cell wall) the vesicles containing new material form a plate and build new structures to be separated in two through growth
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REGULATION
Checkpoints: points at which the cell checks its function to determine if it will undergo mitosis or not, using analysis of internal conditions
If things go wrong at these checkpoints, the cell will undergo apoptosis
If something goes wrong and goes unregulated/undetected, cell will divide out of control, and this is cancer
G1 “Restriction Point”: to replicate or not replicate DNA, ultimatum either to divide or not divide
If the signal is not reached at the restriction point for the go-ahead, the cell enters:
G0 Stage: a perpetual state of G1, like neurons and heart cells
In order to enter the S Stage, the restriction point go-ahead needs to be reached using the chemical ligand of growth factors
After checkpoint you are committed to divide
G2 Checkpoint: point at which cell decides if they should leave interphase
Uses internal factors ; chemical messengers in side of the cell
Cyclin: levels increase and decrease in a cycle, but at G2, its levels are at its highest and combines with CDK
Cyclin-dependent Kinase (CDK): levels remain constant
Cyclin + CDK come together and form the Maturation Promoting Factor (MPF) which triggers the end of interphase
M Checkpoint (Metaphase Checkpoint): checks if all of the chromosomes are lined up in the middle of the cell, if they aren’t lined up properly, causes apoptosis
Conditions: detected using proteins
Anchorage Dependence: in order for a cell to divide it needs to be attached to something
Density-dependent Inhibition: if cells get crowded, they stop dividing
***cancer cells do not exhibit either of these conditions, that’s why they keep dividing out of control.

CANCER

Cells are unable to regulate mechanisms going thru the process of the cell cycle
→ cells divide out of control
Cancer: unregulated and uncontrolled cell division
Cancer cells do not require growth factors to grow and divide
They can make their own growth factors
Convey a growth factor signal without the presence of a growth factor
***Abnormal cell cycle control mechanism
CDK, cyclin, receptors, growth factors, condition proteins, are all proteins, which are created using DNA, which codes specifically for proteins
If a gene mutates, the protein changes, and when you change a shape of a protein you change its function, and improper regulation begins
Proto-oncogenes: genes that code for all of the proteins used in the cell cycle
If a gene mutates it causes transformation: proto-oncogenes become, oncogenes which are cancerous
Causes proteins to change shape and no longer work
One oncogene is not enough to cause cancer, need 6-9 genes to get cancer
Cannot directly inherit cancer, can’t pass down 7 oncogenes, but could pass down a couple oncogenes, so you’re predisposed
Tumor suppressor genes: group of genes that stop cancer from developing, can also mutate
Can code for proteins that correct mutations and proofread DNA
*P53 Gene: codes for p53 protein which triggers apoptosis
If the gene mutates, bad cells cannot be stopped from living
We normally undergo many mutations on a daily basis, P53 gene prevents these cells from manifesting
50% of cancers involve a mutation to the P53 gene
BRCA1 and BRCA2 genes: genes related to ovarian cancer and breast cancer
HER2 gene: codes for growth factor receptors in breast tissue, if it mutates, cells would divide out of control
Found in high concentration in breast/ovarian cancer patients
Ras gene: codes for G-protein which relays the signal from growth factors
Carcinogens: cause proto-oncogenes to mutate (radiation (x-ray), UV light, Nicotine, e.g.)
***Each cancer is caused by a different set of mutated genes, so there is no possible cure-all
Can only treat certain cancers using specific methods, they have to be tailored to that specific type of cancer
Tumors:
Major difference between the two is a number mutations
Benign: have 5 mutations about, generate a mass but do not spread stays at original site, abnormal cells but are not cancerous
Malignant: impairs the functioning of whatever organ it’s in, this is cancerous so about 7 mutations,
can metastasize: part breaks off, enters the bloodstream, divides and creates a tumor elsewhere in the body
Release their own growth factors, and cause blood vessels to grow towards it so it can nourish and spread
Radiation: high dosage of energy generated to a specific part of the body (lasers) to kill tumor at location (using an MRI)
Usually done in part of chemotherapy
Chemotherapy: toxin that kills all dividing cells
Destroys the spindle fibers that make cells split
Negative Feedback
Set point: an original amount or condition, set by hypothalamus, desired condition
Fever: hypothalamus changes set point to a high temperature to run immune system on hyperdrive (speed reactions) to fight illness
Stimulus: causes you to move away from the set point
Response: attempt to reach back to the set point
NOT FEEDBACK INHIBITION, feedback inhibition is where the final product stops the metabolic pathway, uses allosteric enzymes to control reactions
Negative feedback regulates much larger things (blood-sugar levels, and body temperature)
Positive Feedback
Does not maintain homeostasis
Like cooperativity, where one enzyme binds activating more enzymes
A stimulus pulls you away from the set point, and then your body keeps going away from set point
E.g. breastfeeding, or uterine contractions

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