Transcript 6Communication

Cancer, Cell communication and the Cell Cycle
I. Cell Communication – Chapter 16
The major signaling
pathways relevant
to cancer
You will not be responsible for:
Specific downstream
signaling pathways
Questions in this chapter you should be able to answer:
Chapter 16:1 - 10 11all but e, 12,13,16,17,18, 19, 20, 22, 24, 25
Cancer and Cell Communication
1
The life and death of cells
Why do cells eventually die?
-- infection
-- genetic mutation
-- potentially harmful
-- reach replicative limit
How do cells die?
 Apoptosis vs Necrosis
Apoptosis
Cancer and Cell Communication
2
Cancerous cells have two key properties
1)Capacity for perpetual cell division
- Cells replicate through a process
called the Cell Cycle
- Cell replication is carefully regulated
2) Loss of ability to undergo apoptosis
- mutations accumulate over time
Some “oncology”
terminology
Benign tumor
Malignant tumor
Metastasis
Primary vs secondary tumor
Cancer
Cancer and Cell Communication
3
Metastasis requires many cellular changes and is
also an evolutionary process
Metastasis
Cancer and Cell Communication
4
We will focus on mutations that alter 3 key cell
properties and “set the stage” for metastasis
 Mutations that trigger cell proliferation
 activation of “Oncogenes”
 Mutations that disable DNA error detection & apoptosis
 disabling of “Tumor suppressor proteins”
 Mutations that confer immortality
 activation of “Telomerase”
Cancer and Cell Communication
5
How do cells communicate with each other?
Signaling mechanisms
Signaling responses
Cancer and Cell Communication
6
What types of molecules carry
signals to cells?
1) Gases (really small)
NO, H2S, CO
2) ‘Smallish’ organic molecules
steroids
neurotransmitters
[drugs/poisons (nicotine, phytohormones, etc)]
3) Peptide hormones (much bigger)
EGF
Cancer and Cell Communication
7
Where are the receptors?
Intracellular receptors
vs
Cell-surface receptors
Cancer and Cell Communication
8
Oncogenes are mutated genes for proteins that
control when cells divide
For example…
Cell membrane receptors
for hormones that signal
cells to divide
Epidermal Growth Factor (EGF)
binds to HER-receptor
When bound to EGF, the part
of receptor inside membrane
signals cell to divide…. How?
Cancer and Cell Communication
9
Activated receptors cause activation of other proteins
inside the cell
Convey a signal
to nucleus
Activate gene
expression
A cellular response
-- e.g. cell division
Many of these are
potential oncogenes
Receptor Signaling
Cancer and Cell Communication
10
Oncogenes code for mutated receptors or signaling proteins
that are trigger cell division inappropriately
Normal genes code for proteins
that function normally
Mutated genes can code
for abnormal proteins
If “always on” = an oncogene
Cancer and Cell Communication
11
How do cell surface receptors ‘signal’?
FSH & Receptor
Signal transduction
Pathways
Signaling proteins
Secondary Signals
-- cAMP, Ca++, DAG, IP3
Cancer and Cell Communication
12
Signaling pathways can
interact
Multiple signals
Processed simultaneously
Activating or inhibiting
Signal integration
Cancer and Cell Communication
13
What are the three types of cell surface receptors?
= Ligand-gated channel
Cancer and Cell Communication
14
How are G-proteins activated?
“7-pass” receptors
-- Hundreds of different types
-- triggering enumerable different
cytoplasmic processes
Examples
Glucagon – activates glucose release by liver
Lutenizing Hormone (LH) – triggers progesterone
release from ovary
Adrenalin (epinephrine) – increases heart rate
Allergen – mast cell degranulation
G-protein-linked
receptors
Cancer and Cell Communication
15
Acetylcholine acts at a G-protein-linked receptor on heart muscle to make the
heart beat more slowly by the effect of the G protein on a K+ channel, as
shown in this Figure. Which one or more of the following would enhance this
effect of acetylcholine? Explain.
(a) A high concentration of a nonhydrolyzable analog of GTP.
(b) Mutations in the acetylcholine
receptor that weaken the interaction
between the receptor and
acetylcholine.
(c) Mutations in the G protein αsubunit that speed-up the hydrolysis
of GTP.
(d) Mutations in the K+ Channel that
make the βγ-subunit bind tighter
Cancer and Cell Communication
16
How do activated G-proteins
trigger release of ‘secondary
messenger’ molecules?
-- open channels
-- activate enzymes
Secondary messengers include:
cAMP, Ca++, DAG, IP3
Some toxins interfere with G-proteins
Cholera toxin
Inhibits GTPase activity of α-subunit
-- causes Na+ efflux into intestine
-- water flow into intestine
Pertussis toxin
Prevents GDP/GTP exchange
-- GTP locked in off state
-- mucous secretion into lungs
cAMP Signaling
Cancer and Cell Communication
17
Downstream effects can be…
Downstream enzyme activation
(can be very rapid)
-- effect of adrenaline
Changes in gene expression
(slower)
There can be many other
types of responses
Block gene expression
Activate exocytosis
-- allergic responses
-- insulin release
or endocytosis
-- phagocytic cells
Cancer and Cell Communication
18
How do enzyme-linked receptors function?
Receptor Tyrosine Kinases (RTK)
Dimerization
Autophosphorylation
Activated signaling
proteins
Cancer and Cell Communication
19
In 25% of breast cancers,
HER2 receptor is over-produced
HER2/HER2 dimers form
-- activated without hormone
HER2 Signaling
Cancer and Cell Communication
20
RTK Signaling often
occurs through Ras
A “monomeric” GTP-binding protein
RAS activates a kinase “cascade”
(MAP Kinase module)
Cancer and Cell Communication
21
How are complex
signally pathways
‘dissected’?
Genetically engineer cells to
contain…
-- Knockout mutations
-- Constitutive expression mutations
How do these 5 experiment establish
signaling sequence of RAS, X and Y?
Cancer and Cell Communication
22
When activated by the signal, the platelet-derived growth factor (PDGF) receptor
phosphorylates itself on multiple tyrosines (as indicated below by the circled Ps; the numbers next to
these Ps indicate the amino acid number of the tyrosine). These phosphorylated tyrosines serve as
docking sites for proteins (A, B, C, and D) that interact with the activated PDGF-receptor.
Binding of PDGF activates the PDGF-receptor leading to an increase in DNA synthesis.
To determine whether protein A, B, C, and/or D are responsible for activation of DNA
synthesis, you construct mutant versions of the PDGF-receptor that retain one or more
tyrosine phosphorylation sites. In the cells, the various versions of the PDGF-receptor
become phosphorylated on whichever tyrosines remain. You measure the level of DNA
synthesis in cells that express the various mutant receptors and obtain the data shown
below.
A. From these data, which, if any, of these
proteins A, B, C, and D are involved in
the stimulation of DNA synthesis by
PDGF? Why?
B. Which, if any, of these proteins inhibit
DNA synthesis? Why?
C. Which, if any, of these proteins appear to
play no detectable role in DNA
synthesis? Why?
D. What is the effect of the binding of A on
the effect of B?
Cancer and Cell Communication
23