Leicester Warwick Medical School

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Leicester Warwick Medical School
Cellular Adaptations Dr Gerald
Saldanha Department of Pathology Email
gss4_at_le.ac.uk
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Introduction

• This presentation will .
• Focus on adaptive responses in cell growth
  differentiation
• Describe cell signalling pathways
• Introduce the cell cycle

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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

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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.

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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

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Signalling molecules

• Hormones
• Insulin,
• Cortisol
• etc
• Local mediators
• Epidermal Growth Factor (EGF),
• Platelet Derived Growth Factor (PDGF)
• Fibroblast Growth Factor (FGF)
• TGF?
• Cytokines, e.g. Interferons, Tumour necrosis
  factor (TNF)

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Receptors

• There are three main classes of receptors.
• Ion-channel-linked receptors
• G-protein-linked receptors
• Enzyme-linked receptors

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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

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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

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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)

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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Growth and differentiation responses

• Hyperplasia
• Hypertrophy
• Atrophy
• Metaplasia

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Hyperplasia

• Increase in the number of cells in an organ or
  tissue, which may then have an increased size

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Hyperplasia causes

• Hyperplasia can only occur in tissues containing
  labile or stable cells
• Hyperplasia may occur under pathological or
  physiological conditions

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Physiological Hyperplasia

• Hormonal e.g. endometrium
• Compensatory, e.g. partial hepatectomy
• TGF alpha, HGF
• TGF beta

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Pathological hyperplasia

• Excessive hormone/growth factor stimulation
• Often occurs alongside hypertrophy
• Associated with increased risk for cancer
• E.g. Prostate, endometrium

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Hypertrophy

• An increase in cell size, and resultant increase
  in organ size

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Hypertrophy causes

• Occurs in permanent cells
• Due to synthesis of more cellular structural
  components
• Physiological or pathological causes

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Physiological hypertrophy

• Increased functional demand, e.g. skeletal muscle
• Mechanical
• Hormonal, e.g. Uterus in pregnancy
• Usually a combination of hypertrophy and
  hyperplasia

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Pathological hypertrophy

• Increased functional demand e.g. cardiac muscle
• Hypertension
• valvular heart disease

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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

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Atrophy causes

• Reduced workload
• Loss of innervation
• Reduced blood supply
• Inadequate nutrition
• Loss of endocrine stimulation
• Ageing

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Metaplasia

• Reversible change of one adult cell type to
  another adult cell type

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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

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Hypoplasia

• Incomplete development of an organ with reduced
  cell numbers

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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