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GROWTH FACTORS:
Oncogene:
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Despite the presence of proto-oncogenes in our genome all the time, they
themselves do not cause cancer
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This is because oncogenes are:
• Overexpressed
• Are inappropriately expressed
• Deregulated through mutation
• Have altered specificity or have a novel function – this is often the
case for translocations where new fusion proteins are created
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Many oncogenes are activated versions of the normal genes (protooncogenes) involved in the pathways by which growth factors stimulate
cell division
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Insight into this connection came through a convergence of studies on
oncogenes, growth factors and growth factor receptors
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It is therefore important to study “normal” cells because this provides us
with a better understanding of the “abnormal” changes causing tumour
initiation and progression
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Signals from distant cells are called endocrine signals – they originate
from endocrine cells
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In the body, many endocrine cells are located in endocrine glands,
such as the thyroid gland, the hypothalamic and the pituitary gland
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These types of signals usually produce a slower response, but have a
longer-lasting effect
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The ligands are released in endocrine signalling are called hormones,
signalling molecules that are produced in one part of the body, but
affect other body regions some distance away
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These hormones travel the large distances via the bloodstream to
their target cells
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Signals that act locally between cells that are close together are called
paracrine signals
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Paracrine signals move by diffusion through the extracellular matrix
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These type of responses usually elicit quick responses that only last a
short amount of time
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In order to keep the response localized, paracrine ligand molecules
are normally quickly degraded by enzymes or removed by
neighbouring cells
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An example is the transfer of signals across synapses between nerve
cells
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These are produced by signalling cells that can also bind to the ligand
that is released
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This means the signalling cell and the target cell can be the same or a
similar cell, with the prefix auto- meaning self; a reminder that the
signalling cell sends a signal to itself
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GFs are protein chains, often referred to as polypeptides and are
normally secreted by neighbouring cells
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These factors have a basic protein structure and lack complex tertiary
structure but still maintain specificity
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These GFs are major mitogens (substance that stimulates mitosis in a
cell) for many cell types of mesenchymal origin, e
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fibroblasts and
smooth muscle cells, and for some cell populations of
neuroectodermal origin, like oligodendrocytes
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There are four different PDGF genes that encode polypeptides
chains:
§ PDGF-A
§ PDGF-B
§ PDGF-C
§ PDGF-D
3
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All the PDGF polypeptide chains have a common region called the
growth factor domain, which is about 100 aa long that contains a
conserved cysteine residue
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The four PDGF chains assemble into disulphide-bonded dimers via
homo- or heterodimerization, and five different dimeric isomers
have been discovered so far: PDGF-AA, PDGF-AB, PDGF-BB, PDGF-CC,
and PDGF-DD
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One important difference in the processing mechanisms of the PDGFs
can be noted, however – the classical PDGFs are cleaved and activated
in the exocytic pathway, whereas, the novel PDGFs are cleaved and
activated extracellularly
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After dimerization of the PDGF-A and PDGF-B chains in the ER of
producing cells, the dimers are proteolytically cleaved in the transGolgi network during protein maturation and secretion
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sis, the oncogene of Simian sarcoma virus, is derived from the gene for
the B chain of PDGF
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Cells transformed by sis secrete a functional PDGF-BB homodimer,
however, the virus only transforms cells with the PDGF receptors and
therefore, without the presence of the receptors, the virus is
chemically inert
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This is an example of inappropriate expression
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During embryonic development, PDGF is active in kidney, blood
vessels, lung and CNS development
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In the adult blood vessels, the PDGF is involved in constriction and
relaxation effects
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In wound healing:
§ PDGF stimulates the directed migration (chemotaxis) of
fibroblasts, white blood cells and smooth muscle cells
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Epidermal Growth Factor:
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He found that the eyelids would
open up to 5 days earlier then normal and the incisors would erupt up 4
days than normal
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This was explained as the salivary gland extracts contained a growth
factor – epidermal growth factor – as it stimulated the proliferation of
epithelial cells in skin and cornea
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We now know that salivary gland cells produce and secrete EGF, as do
the cells at the site of a wound, and cells during embryonic development
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This
is an example of cell regulation
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EGF is known to be involved in wound healing responses promoting the
regeneration of the epidermis
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EGF is a strong chemoattractant for fibroblasts and epithelial cells
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In vivo, EGF is known to be involved in embryonic development and
stimulate the proliferation of embryonic cells
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TGF- β is not related to TGF-alpha (a member of the EGF super family)
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The TGF- β super family includes TGF β, inhibins, and Activin A, and
BMPs
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TGF- β exists in at least five isomers: β1 – β5, with TGF- β1 is the most
ubiquitous form of the isomers
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Numerous cell types including platelets secrete this GF
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One of the most potent growth factors – acts on many many cells that
express the TGF- β receptors so in a normal homeostasis condition, you
do not want to be inadvertently generating TGF- β unless it is necessary
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TGF- β is generated when it is covalently linked to the latencyassociated protein (LAP) and then it’s made into a dimer by the
disulphide bonds in the Golgi
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It is then secreted into the extracellular matrix
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In the ECM, this TGF- β complex then binds to another protein called the
latent-TGF β binding protein, and the whole thing is called the large
latent complex
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The biologically active part is shown in pink
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So it’s being held in this inactive form, shielded by these other proteins
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The RGD sequence that combine to integrins
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If the cell wants to release active GF, it generates plasmin, secretes it and
that will cleave out the active TGF β
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When plasmin knockout mouse were generated, it was assumed that they
mice would completely lack TGF-β, so the mice would pheno-copy TGF β
mice but that was not the case
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Instead, it was found that you might be able to release active GF without
the plasmin
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Your LAP protein has a RGD sequence that will bind to an integrin
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The other latency protein has an ECM binding domains, like fibronectin
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Therefore, if you have one part of the large latency protein binding to the
integrin and another to the matrix, if the cell moves, there will be a
mechanical pull
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This mechanical traction is an alternative method to release active TGF
β
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Biological activities of TGF- β:
§ Control of cell proliferation – TGF- β can have a pro- or antiproliferative effect depending on the cell type and growth
environment
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§ Control of cell adhesion – the action of TGF- β on connective tissue
cells, epithelial cells and blood cells generally leads to an upregulation of cell adhesion as a result of increased expression of
integrin (cell adhesion) receptors, increased synthesis of ECM
proteins and inhibition of ECM degradation
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It can also induce cytokine production in
white blood cells
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TGF- β is a
chemoattractant (cells move towards) for white blood cells and
can induce the formation of new blood vessels
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The FGF super family is a group of growth factors that were originally
identified as proteins that are capable of promoting fibroblast
proliferation – a connective tissue cell that makes and secretes
proliferation
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FGFs are polypeptide growth factors
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There are 22 human FGF genes that are grouped into 7 subfamilies based
on sequencing
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The expression pattern of these genes is very variable – FGF2 is expressed
ubiquitously whilst FGF4 is only expressed during embryonic
development
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Most FGFs share a highly homologous “core” sequence of ~100 aa
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Some FGFs contain a signal sequence that directs them for secretion via
the ER/Golgi
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FGF1 and FGF2 are found in the ECM but do not have a signal sequence
and are not secreted via the conventional ER/Golgi route
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FGFs can influence:
§ Cell proliferation,
§ Differentiation
§ And migration
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They are known to play an important role in embryonic development and
tissue homeostasis
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The large number of FGFs result in some redundancy between FGFs –
this suggests that other FGFs can step and take over in knockout
experiments, making it difficult to identify key roles for individual
members
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However, key roles have been identified for some members of the family
through successful knockout mouse experiments
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Insulin-like Growth Factor (IGF):
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Also known as scatter factor, was isolated simultaneously as a factor that
could induce liver cell (hepatocyte) growth and act as a factor that could
induce the dissociation of epithelial cells
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HGF is synthesised as an inactive 728 aa long peptide (pro-HGF), which
is localised on the cell surface or in the extracellular matrix
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The pro-HGF is then cleaved to a mature alpha-beta heterodimer by
serum components
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à The Kringle domains increase receptor and therefore cell specificity due to the
complexity that they add to the HGF proteins
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HGF is secreted by connective tissue cells and acts mainly on cells of
epithelial origin
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§ It is the only growth factor known to induce 3D growth of cells in
culture, i
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induces kidney epithelial cells to form tubules
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Cytokines are growth factors of the haemapoietic system