Chapters 11-13

•Cell Communication

•Cell Division (mitosis and meiosis)

•Cancer, Stem Cells and other health applications

Epigenetics- "Above the Genome"•Why is it important to understand how cells communicate and regulate DNA expression?•How do we possess cells with the same genome, but they can look and behave so differently?•How can one "identical" twin suffer from cancer and the other doesn't?

Answers....

•Epigenetics holds the key to understanding these questions as well as many mysteries surrounding inheritance and disease expression.•Epigenetic refers to the long-term alterations of DNA that don't involve changes in the DNA sequence itself.

Case Studies•1) Al and Bo- Monozygotic Twins (no longer considered "identical")- Kallman Syndrome

•2) Dutch Studies of children of mothers pregnant during famine of WWII (1944-1945)

Conclusions....•Epigenetic alterations from environmental influences can result in higher susceptibility of:•obesity, diabetes, heart disease, atherosclerosis and auto-immune diseases as well as depression, anxiety, and schizophrenia.

•

Conclusions...DNA is NOT our Destiny!•Epigenetic inheritance can be passed from grandparent to grandchild!•Epigenetics will substantially alter the way we think about genes, what they are, and what they do, particularly with respect to our development from a fertilized egg (and onward).•--executive function resides at the cellular level, not the DNA level

Cell Communication

•Hello…is anyone there?•Chapter 11

Overview

•Cell signaling evolved early in evolution

•Communicating cells may be close together or far apart

•The three stages of cell signaling are: reception, transduction, and response•http://science.nhmccd.edu/biol/ap1int.htm

Cell Signaling Evolved Early

•Yeast identify their mates by chemical signaling.•There are 2 sexes: mating type a and mating type alpha•“a” mating types release a factor that can bind to specific receptors on alpha cells (vice versa)•This causes “schmooing!” (Cells grow towards one another and fuse!)…example of a signal transduction pathway (See p.198)•Genetic advantage that is conserved!

Figure 11.0 Yeast

Figure 11.1 Communication between mating yeast cells

Communicating Cells….

•May be close together or far apart•Transmitting cells secrete molecules of a local regulator, a substance that influences cells in the vicinity (ex. Growth Factor)•GFs are compounds that stimulate nearby target cells to grow and multiply (Paracrine Signaling…See p.199)

Figure 11.2 Communication among bacteria

Communication Continued(See handout- Types of Signaling)

•Synaptic Signaling: a nerve cell releases neurotransmitter molecules into a synapse…allowing a nerve cell signal to travel long distances without causing unwanted responses•Long Distance Hormonal Signaling: Specialized endocrine cells secrete hormones into body fluids (blood). Hormones can reach virtually all body cells. (See p. 199)•Examples: Insulin (regulates sugar levels in the blood) and ethylene (fruit ripening hormone)•Direct Contact: cell junctions and cell surface molecules

Figure 11.3 Local and long-distance cell communication in animals

Figure 11.4 Communication by direct contact between cells

What happens when a cell encounters a signal?

•The Signal must be recognized by specific receptor molecules

•The information it carries must be changed into another form (“transduced”) inside the cell

•Response (chemical pathway…leading to DNA expression or some cellular activity)

The Three Stages of Cell Signaling

•Reception: the target cell’s detection of a signal coming from the outside…detected when ligand-receptor binding occurs•Transduction: binding changes 3-D shape of receptor; transduction converts the signal to a form that brings about a specific cellular response (usually a series of steps…chemical pathway)•Response: the transduced signal triggers a specific cellular response such as enzyme catalysis, rearrangement of cytoskeleton, activation of specific genes.•Activities occur at the right place, time and are coordinated! (See p. 200)

Figure 11.5 Overview of cell signaling (Layer 1)

Figure 11.5 Overview of cell signaling (Layer 2)

Figure 11.5 Overview of cell signaling (Layer 3)

Signal Reception

•Most signal receptors are plasma membrane proteins•Examples: G-protein-linked receptors (works with the help of cytoplasmic G-protein); Tyrosine-kinase receptors (react by forming dimers and then adding phosphate grps to tyrosines); Ligand-gated ion channels; Intracellular receptors (cytosolic and nuclear proteins); Signal molecules (readily cross the membrane such as steroid hormones and nitric oxide)

G-Protein-Linked Receptors

•A plasma membrane receptor that works with a G-protein•Examples: yeast mating factors, epinephrine, neurotransmitters, and other hormones•Vary in binding sites and for recognizing signal molecules as well as recognizing different G-proteins inside the cell

Figure 11.6 The structure of a G-protein-linked receptor

Figure 11.7 The functioning of a G-protein-linked receptor

G proteins and the Body

•Specific G-proteins are found in the retinal rods and cones•1. G proteins in our sense organs translate environmental information into a language that the G proteins in the brain can understand.•2. G proteins in the nose are activated by olfactory stimuli.•3. G proteins of the tongue register taste.

G Proteins Respond to Hormones

•When in a rage our adrenals release adrenaline into the blood. When it reaches the liver glucose is formed, giving energy for fight or flight. The heart and the blood vessels also become prepared.

Cholera and G Proteins

•Cholera is caused by a comma-shaped bacterium, Vibrio cholerae, which is ingested in contaminated water and food.•The bacteria multiply enormously in the intestine, where epithelial cells allow fluid to leak into the intestine with intense diarrhea as a result.•Cholera is endemic in India and other parts of the third world.

                                                                                 

Cholera and G Proteins

•The bacterium discovered by Robert Koch in 1884, can be killed by antibiotics, but the disease is caused by a bacterial toxin, which irreversibly activates the G proteins of epithelial cells in the intestine.•This results in an often life-threatening loss of water and salts. From Koch's discovery of the cholera bacterium in 1884 it took researchers about 100 years to expose the real cause of the disease - the effect of the bacterial toxin on G proteins.

Cholera and G Proteins

•1. The bacterium produces a toxin that is the cause of the cholera. The toxin molecule is composed of several parts, one of which penetrates the cell membrane.•2. The toxin acts as an enzyme that changes the G protein so that it can no longer switch itself off (unable to hydrolyze GTP to GDP…continually stimulates adenylyl cyclase)•3. The activated G protein changes the function of epithelial cells in the intestine, with enormous loss of water as a result. Cholera affects the intestine because this is the place which the toxin reaches.

•

Villi affected by Cholera

•Intestine villi (left), the minute projections from the mucous membrane of the small intestine, which are primarily affected by the toxin.

Tyrosine-Kinase Receptors

•Growth Factors stimulate cells to grow and reproduce (see Cell Clock ppt)•GFs help the cell regulate and coordinate protein synthesis, DNA replication, and rearrangement of cytoskeleton (mitosis)…specialized for triggering more than one signal-transduction pathway at once!•The receptor is usually a tyrosine-kinase, which catalyzes the transfer of a phosphate group from ATP to a tyrosine on a protein (See p. 203)

Figure 11.8 The structure and function of a tyrosine-kinase receptor

Function of Tyrosine-Kinase Receptor

•Ligand bonding causes 2 receptor polypeptides to aggregate (dimer)•This activates the tyrosine-kinase parts of the polypeptides, each of which adds phosphates to the tyrosines on the tail of the other polypeptide•Once activated, the receptor is recognized by specific relay proteins inside the cell…each protein binds to a specific phosphorylated tyrosine, changing its structure•One tyrosine-kinase receptor can activate more than 10 relay proteins simultaneously…triggering many pathways and cellular responses!•Abnormal tyrosine-kinase receptors cause some kinds of cancer (breast, ovarian, prostate) (See p. 203)

Growth Factors

Ligand-Gated ion Channels

•The receptor is a transmembrane protein that opens to allow the flow of a specific kind of ion across the membrane when a specific signal molecule binds to the extracellular side of the protein receptor (See p. 204)

Ligand-Gated Ion Channel Examples

•Channel proteins bind a specific ligand→shape change→change in [ion]→affects cell functioning•Nervous System: electrical signal propagation

Figure 11.9 A ligand-gated ion-channel receptor

Intracellular Receptors

•Proteins dissolved in the cytosol or nucleus of target cells•A chemical messenger must be permeable to the target cell (hydrophobic properties)•Examples: Steroids and thyroid hormones and Nitric Oxide (NO)•Transcription factors regulate which genes are turned on and are transcribed into mRNA in particular cells at specific times…the chemical messenger carries out the complete signal-transduction process by itself•Common structural evolutionary link! (See p. 205)

Figure 11.10 Steroid hormone interacting with an intracellular receptor

Cancer Inhibition•Cell growth, differentiation and death are essential parts of life.•It is also important that certain cells die when they have outlived their function.

•All of these processes are regulated by proteins that turn on and off of specific genes at specific times.•When this regulation process goes awry, the growth of certain cells is no longer regulated, and cancer often results.

•Designer molecules intervene in unregulated cell growth. These agents function by inhibiting the dimerization of oncogenic transcription factors, or DNA binding proteins. Since the dimerization of these proteins is linked to their activity, the design of such agents may potentially regulate gene expression implicated in cancer.

How are signal-transduction pathways turned off?

•Protein kinases are rapidly reversed by protein phosphatases, enzymes which remove phosphate groups from proteins•Balance between phosphorylation (active kinases) and active phosphatases…concentrations shift!

Figure 11.11 A phosphorylation cascade

Cyclic AMP (cAMP)

•Earl Sutherland discovered that binding of a ligand (epinephrine in liver cells)→elevated cyclic AMP.•An enzyme, adenylyl cyclase, converts ATP to cAMP in response to an extracellular signal•Hormone binds to receptor→G protein receptor activated→specific G protein activated→adenylyl cyclase activated→cAMP is made→signal is broadcast to the cytoplasm (protein kinase A activated)→ hormone destroyed → cAMP inactivated into AMP•Some G proteins inhibit adenylyl cyclase (See Cholera example)

Figure 11.12 Cyclic AMP

Figure 11-12x cAMP

Figure 11.13 cAMP as a second messenger

Other Signal Chemicals

•Calcium is a common second messenger•Increase in [calcium] causes muscle contraction, secretion of certain substances, and cell division (animal cells); coping with environmental stresses (plant cells)…active transport (ER, mitochondria, chloroplasts)•Signal-Transduction pathway of calcium also involves diacylglycerol (DAG) and inositol trisphophate (IP3) (See p. 208-209)

Figure 11.14 The maintenance of calcium ion concentrations in an animal cell

Figure 11.15 Calcium and inositol triphosphate in signaling pathways (Layer 1)

Figure 11.15 Calcium and inositol triphosphate in signaling pathways (Layer 2)

Figure 11.15 Calcium and inositol triphosphate in signaling pathways (Layer 3)

Amplification and Specificity

•Each catalytic protein in a signaling pathway amplifies the signal by activating multiple copies of the next component in the pathway (exponential!)•The particular combination of proteins in a cell gives the cell great specificity in both the signals it detects and the responses it carries out! (Scaffolding protein increase efficiency; pathway branching and cross-talk help coordinate signals and responses) (See p. 210 –212)

Figure 11.16 Cytoplasmic response to a signal: the stimulation of glycogen breakdown by epinephrine

Figure 11.17 Nuclear response to a signal: the activation of a specific gene by a growth factor

Figure 11.18 The specificity of cell signaling

Figure 11.19 A scaffolding protein

Bibliography

•Campbell Biology•Google images•Francis, Richard C., The Ultimate Mystery of Inheritance- Epigenetics, W.W. Norton and Company, 2011•ISBN-978-0-393-07005-7