(ETs) also have vasoconstrictive effects; this is a
family of acidic peptides with 21 amino acids
which includes not only the ET isoforms ET-1,
ET-2 and ET-3 but also the vasoactive intestinal
contractor (VIC) of the mouse and the four sarafotoxins in the venom of the snake Atractaspis
engaddensis. The prepro-ET-1, synthesized in the
endothelial cells, has a length of 202-212 amino
acids according to the species. A pro-ET-1 with 38
(human) or 39 amino acids (pig) is released proteolytically, and this gives rise to the mature ET-1
by the unusual cleavage of a 21-Trp/22-Val bond
[58, 204). The homeostatic control of blood pressure and osmolality is the function of the natriuretic peptides from the cardiac atria (ANP) and
the brain (BNP); these also arise from longer precursors. Whilst the circulating aforms of ANP
vary by at the most one amino acid amongst the
mammals, the related peptides of the chicken, the
frog Rana ridibunda and the eel Anguilla japonica
show sequence differences amongst themselves
and compared with the mammalian ANPs and
BNPs of about 50 %. ANP-like substances have
been detected immunologically in gastropods and
crustaceans [215, 245).
8.6 Calcitonins and Parathormone
Calcitonin and parathormone are involved in calcium homeostasis, with calcitonin depressing the
calcium level in the blood plasma, and parathormone treatment resulting in its elevation. CalcitoDins (CT) are synthesized in the C cells of the
mammalian thyroid gland and in the ultimobranchial bodies of other vertebrates. They have been
detected either immunologically or by functional
tests in all vertebrates except the agnathans. The
CTs consist of 32 amino acids (Fig. 8.21), of
which the 7 N-terminal positions are identical in
the human, bovine, porcine and salmon molecules, but the remaining residues differ widely. In
spite of this, the fish CT has hormone activity in
birds and mammals but not in fish. Thus, the substance itself appears to be older than its function
in some of the vertebrates [169]. In the CT precursor of man, the rat and chicken, the CT sequence lies between long C- and N-terminal
sequences; the cleavage sites here also consist of
pairs of basic amino acids. The CT gene is made
up of six exons, one of which encodes the whole
CT sequence, and a further one codes for a
homologous peptide of 37 amino acids, the calcitonin gene-related peptide (CGRP). The relative
8.7 Growth Factors
303
proportions of these two peptides are regulated in
a tissue-specific manner by alternative splicing in
the two mammals mentioned and in the chicken.
CT predominates in the thyroid and ultimobranchial bodies, and CGRP predominates in the
brain [59]. CT/CGRP-like substances have been
detected immunologically in the brains of all
classes of vertebrate including the agnathans, and
even in the lobster Nephrops norvegicus
[103, 238].
The parathyroid glands (small epithelial
bodies) produce the parathormone (PTH). Of
the 84 amino acids making up this molecule,
there is only 8 % difference between the sequences of cattle and swine, but 33 % difference
between these two mammals and the chicken.
PTH is probably present in all tetrapods but not
in the fish. In bovine prepro-PTH, the PTH
sequence is preceded by a signal sequence of
25 amino acids and a pro-sequence of 6 amino
acids [35].
8.7 Growth Factors
The growth of vertebrate cells in tissue culture
depends upon peptide growth factors (GFs)
which are found, for example, in blood plasma.
For this reason, many tissue culture media contain foetal calf serum. In contrast to the hormones, which are stored intracellularly and secreted
as required, the growth factors are released continuously from cells. These factors bind to specific
receptors on the cell surface. This activates a tyrosine kinase which, via a cascade of further specific
kinases, initiates the cell's growth response
[30, 137, 240]. In many cases, the GF-producing
cells themselves possess receptors and respond to
their own growth factors. It may be that the
evolution of signalling by peptides began with this
autocrine mechanism; this then developed to produce effects on neighbouring cells (paracrine
mechanism) and finally, by transmission in the·
extracellular fluids, to effects on distant cells
(endocrine mechanism). Unlimited cell division
(proliferation) is a characteristic of tumour cells
and, as might be expected, there is a relationship
between growth regulation by GF and carcinogenesis. There exist, for example, transforming
GFs, and some oncogenes code for aberrant
forms of the growth factors or their receptors.
The continuously increasing number of known
growth factors can be divided into families
according to structure, origin and activity. The
family of acidic peptides with 21 amino acids
which includes not only the ET isoforms ET-1,
ET-2 and ET-3 but also the vasoactive intestinal
contractor (VIC) of the mouse and the four sarafotoxins in the venom of the snake Atractaspis
engaddensis. The prepro-ET-1, synthesized in the
endothelial cells, has a length of 202-212 amino
acids according to the species. A pro-ET-1 with 38
(human) or 39 amino acids (pig) is released proteolytically, and this gives rise to the mature ET-1
by the unusual cleavage of a 21-Trp/22-Val bond
[58, 204). The homeostatic control of blood pressure and osmolality is the function of the natriuretic peptides from the cardiac atria (ANP) and
the brain (BNP); these also arise from longer precursors. Whilst the circulating aforms of ANP
vary by at the most one amino acid amongst the
mammals, the related peptides of the chicken, the
frog Rana ridibunda and the eel Anguilla japonica
show sequence differences amongst themselves
and compared with the mammalian ANPs and
BNPs of about 50 %. ANP-like substances have
been detected immunologically in gastropods and
crustaceans [215, 245).
8.6 Calcitonins and Parathormone
Calcitonin and parathormone are involved in calcium homeostasis, with calcitonin depressing the
calcium level in the blood plasma, and parathormone treatment resulting in its elevation. CalcitoDins (CT) are synthesized in the C cells of the
mammalian thyroid gland and in the ultimobranchial bodies of other vertebrates. They have been
detected either immunologically or by functional
tests in all vertebrates except the agnathans. The
CTs consist of 32 amino acids (Fig. 8.21), of
which the 7 N-terminal positions are identical in
the human, bovine, porcine and salmon molecules, but the remaining residues differ widely. In
spite of this, the fish CT has hormone activity in
birds and mammals but not in fish. Thus, the substance itself appears to be older than its function
in some of the vertebrates [169]. In the CT precursor of man, the rat and chicken, the CT sequence lies between long C- and N-terminal
sequences; the cleavage sites here also consist of
pairs of basic amino acids. The CT gene is made
up of six exons, one of which encodes the whole
CT sequence, and a further one codes for a
homologous peptide of 37 amino acids, the calcitonin gene-related peptide (CGRP). The relative
8.7 Growth Factors
303
proportions of these two peptides are regulated in
a tissue-specific manner by alternative splicing in
the two mammals mentioned and in the chicken.
CT predominates in the thyroid and ultimobranchial bodies, and CGRP predominates in the
brain [59]. CT/CGRP-like substances have been
detected immunologically in the brains of all
classes of vertebrate including the agnathans, and
even in the lobster Nephrops norvegicus
[103, 238].
The parathyroid glands (small epithelial
bodies) produce the parathormone (PTH). Of
the 84 amino acids making up this molecule,
there is only 8 % difference between the sequences of cattle and swine, but 33 % difference
between these two mammals and the chicken.
PTH is probably present in all tetrapods but not
in the fish. In bovine prepro-PTH, the PTH
sequence is preceded by a signal sequence of
25 amino acids and a pro-sequence of 6 amino
acids [35].
8.7 Growth Factors
The growth of vertebrate cells in tissue culture
depends upon peptide growth factors (GFs)
which are found, for example, in blood plasma.
For this reason, many tissue culture media contain foetal calf serum. In contrast to the hormones, which are stored intracellularly and secreted
as required, the growth factors are released continuously from cells. These factors bind to specific
receptors on the cell surface. This activates a tyrosine kinase which, via a cascade of further specific
kinases, initiates the cell's growth response
[30, 137, 240]. In many cases, the GF-producing
cells themselves possess receptors and respond to
their own growth factors. It may be that the
evolution of signalling by peptides began with this
autocrine mechanism; this then developed to produce effects on neighbouring cells (paracrine
mechanism) and finally, by transmission in the·
extracellular fluids, to effects on distant cells
(endocrine mechanism). Unlimited cell division
(proliferation) is a characteristic of tumour cells
and, as might be expected, there is a relationship
between growth regulation by GF and carcinogenesis. There exist, for example, transforming
GFs, and some oncogenes code for aberrant
forms of the growth factors or their receptors.
The continuously increasing number of known
growth factors can be divided into families
according to structure, origin and activity. The