Download Lecture 8

Leicester Warwick Medical School
Cellular Adaptations
Dr Gerald Saldanha
Department of Pathology
Email: [email protected]
Introduction
• This presentation will ….
– Focus on adaptive responses in cell growth
& differentiation
– Describe cell signalling pathways
– Introduce the cell cycle
Control of cell growth
• Cells in a multicellular organism
communicate through chemical signals
• Hormones act over a long range
• Local mediators are secreted into the
local environment
• Some cells communicate through direct
cell-cell contact
Control of cell growth
• Cells are stimulated when extra cellular
signalling molecules bind to a receptor
• Each receptor recognises a specific protein
(ligand)
• Receptors act as transducers that convert the
signal from one physical form to another.
Signalling molecules
• Most signalling molecules
cannot pass through the cell
membrane
– Their receptors are in the cell
membrane
• Small hydrophobic signal
molecules can diffuse directly
into the cell cytoplasm
– Their receptors are cytoplasmic
or nuclear
Signalling molecules
• Hormones
– Insulin,
– Cortisol
– etc
• Local mediators
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Epidermal Growth Factor (EGF),
Platelet Derived Growth Factor (PDGF)
Fibroblast Growth Factor (FGF)
TGF
Cytokines, e.g. Interferons, Tumour necrosis factor (TNF)
Receptors
• There are three main classes of
receptors….
• Ion-channel-linked receptors
• G-protein-linked receptors
• Enzyme-linked receptors
Receptors
• Ion channel-linked receptors
are important in neural
signalling
• G-protein and enzyme
linked receptors respond by
activating cascades of
intracellular signals
• These signals alter the
behaviour of the cell
G-protein-linked receptors
• G-protein-linked receptors activate a class
of GTP-binding proteins (G-proteins)
• G proteins are molecular switches
• They are turned on for brief periods while
bound to GTP
• They switch themselves off by hydrolysing
GTP to GDP
G proteins
• Some G proteins directly regulate ion
channels
• Others activate adenylate cyclase, thus
increasing intracellular cyclic AMP
• Some activate the enzyme
Phospholipase C, thus increasing
intracellular inositol triphosphate (IP3)
and Diacylglycerol (DAG)
Enzyme-linked receptors
• Many receptors have intracellular
domains with enzyme function
• Most are receptor tyrosine-kinases
• They phosphorylate tyrosine residues in
selected intracellular proteins
• These receptors are activated by growth
factors, thus being important in cell
proliferation
Receptor tyrosine kinases
• Receptor tyrosine kinase activation results in
assembly of an intracellular signalling complex
• This complex activates a small GTP-binding
protein, Ras
• Ras activates a cascade of protein kinases that
relay the signal to the nucleus
• Mutations that make Ras hyperactive are a
common way of inducing increased proliferation in
cancer
Signalling: cytoplasm to nucleus
• Many signalling cascades culminate in
activation of nuclear transcription factors
• Transcription factors alter gene
expression
• C-jun and c-fos ( that form an AP1
complex) and c-myc are three important
transcription factors
Signalling pathway interactions
• There are many signalling molecules and
receptors
• A given cell expresses only a subset of
receptors
• Different intracellular signalling pathways
interact
• This enables cells to respond appropriately
to complex combinations of signals
Cell signalling and proliferation
• Animal cells proliferate when stimulated by growth
factors
• These bind mainly to receptor tyrosine kinases
• These signalling pathways override the normal
brakes on proliferation
• These brakes are part of the cell cycle control
system
• This ensures that cells divide only under
appropriate circumstances
The cell cycle
• The eukaryotic cell cycle consists
of distinct phases
• The most dramatic events are
nuclear division (mitosis) and
cytoplasmic division (cytokinesis)
• This is the M phase
• The rest of the cell cycle is called
interphase which is, deceptively,
uneventful
• During interphase the cell
replicates its DNA, transcribes
genes, synthesises proteins and
grows in mass
Phases of the cell cycle
• S phase – DNA replicates
• M phase – nucleus divides
(mitosis) and cytoplasm
divides (cytokinesis)
• G1 phase – gap between
M and S phase
• G2 phase – between S and
M phase
Cell cycle control
• Cell cycle machinery is subordinate to a
cell cycle control system
• The control system consists mainly of
protein complexes
• These complexes consist of a cyclin
subunit and a Cdk subunit
• The cyclin has regulatory function, the
Cdk catalytic function
Cell cycle control
• Cdk expression is constant, but cyclin
concentrations rise and fall at specific
times in the cell cycle
• The Cdks are cyclically activated by cyclin
binding and by phosphorylation status
• Once activated, Cdks phosphorylate key
proteins in the cell
Cell cycle control
• Different cyclin-Cdk complexes trigger
different cell cycle steps
• Some drive the cell into M phase, others into
S phase
• The cell cycle control system has in-built
molecular breaks (checkpoints)
• The checkpoints ensure that the next step
does not begin until the previous one is
complete
The G1 checkpoint
• The G1 checkpoint has been widely studied
• The retinoblastoma (Rb) protein plays a key
role at this checkpoint
• The Rb protein function is determined by its
phosphorylation status
• S phase cyclin-Cdk complexes
phosphorylate Rb
The G1 checkpoint
• This checkpoint is influenced by the
action of cyclin-dependant kinase
inhibitors (CKIs, e.g. p21, p16)
• E.g. p53 senses DNA damage and
induces p21 expression
• CKIs inactivate cyclin-Cdk complexes
Cellular adaptations of growth and
differentiation
• Cells must respond to a variety of
stimuli that may be hormonal, paracrine
or through direct cell contact
• These stimuli may arise under
physiological or pathological conditions
• The way that cells adapt in terms of
growth and differentiation depends in
part on their ability to divide
Cellular proliferative capacity
• Tissues can be classified according to
the ability of their cells to divide
• Some tissues contain a pool of cells that
move rapidly from one cell cycle to the
next. These are labile cells
Cellular proliferative capacity
• Some cells dismantle their cell cycle
control machinery and exit the cell cycle
• These cells are said to be in G0.
• Some of these cells can re-enter the cell
cycle when stimulated, e.g. by growth
factors. These are stable cells
• Others are unable to re-enter the cell
cycle. These are permanent cells
Growth and differentiation
responses
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Hyperplasia
Hypertrophy
Atrophy
Metaplasia
Hyperplasia
• Increase in the number of cells in
an organ or tissue, which may then
have an increased size
Hyperplasia: causes
• Hyperplasia can only occur in tissues
containing labile or stable cells
• Hyperplasia may occur under
pathological or physiological conditions
Physiological Hyperplasia
• Hormonal e.g. endometrium
• Compensatory, e.g. partial hepatectomy
– TGF alpha, HGF
– TGF beta
Pathological hyperplasia
• Excessive hormone/growth factor
stimulation
• Often occurs alongside hypertrophy
• Associated with increased risk for
cancer
• E.g. Prostate, endometrium
Hypertrophy
• An increase in cell size, and
resultant increase in organ size
Hypertrophy: causes
• Occurs in permanent cells
• Due to synthesis of more cellular
structural components
• Physiological or pathological causes
Physiological hypertrophy
• Increased functional demand, e.g.
skeletal muscle
– Mechanical
• Hormonal, e.g. Uterus in pregnancy
– Usually a combination of hypertrophy and
hyperplasia
Pathological hypertrophy
• Increased functional demand e.g.
cardiac muscle
– Hypertension
– valvular heart disease
Atrophy
• Shrinkage in cell size by loss of cell
substance
– Term is often used loosely to describe
reduced organ size that may be
related to cell loss rather than
shrinkage
Atrophy: causes
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Reduced workload
Loss of innervation
Reduced blood supply
Inadequate nutrition
Loss of endocrine stimulation
Ageing
Metaplasia
• Reversible change of one adult cell
type to another adult cell type
Metaplasia: causes
• An adaptive response to various stimuli
• New cell type is better adapted to
exposure to the stimulus
• The stimulus that induced metaplasia
may, later, induce cancer, e.g. squamous
cell carcinoma of the bronchus
• Metaplasia in mesenchymal tissues is
often less clearly adaptive
Hypoplasia
• Incomplete development of an organ
with reduced cell numbers
Summary
• Cells communicate through signalling
pathways
• Signalling pathways influence the cell
cycle control system
• This determines a cells ability to divide
• A cells replicative capacity influences its
adaptive responses to changes in the
tissue environment