Transcript Slide 1

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 (19441945)
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
the target cell’s detection of a signal
coming from the outside…detected when ligandreceptor 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)
•Reception:
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 signaltransduction pathway at once!
•The receptor is usually a tyrosinekinase, 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