Growth Factorshormones Proteins

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 Growth Factorshormones Proteins Background

Growth in vertebrates is governed by the integration of genetic, hormonal, and nutritional components. The most significant endocrine influence in body growth is the complex regulation of the growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis, and this mechanism appears to be highly conserved among vertebrates. Growth hormone is involved in regulating numerous physiological processes besides somatic growth in fish including immune function, lipid and protein metabolism, osmoregulation, and feeding behavior. In teleost fish, secretion of growth hormone from the pituitary is regulated by sex steroids along with several hypothalamic factors, which act in concert under the influence of the physiological and nutritional state of the animal.

The primary constituent of the human growth hormone-N gene is the 22 kD growth hormone, also called somatotropin. The most commonly measured form of growth hormone is the pleiotropic, polypeptide, 191-amino acid sequence isoform. The 22 kD isoform contains numerous cleavage sites, and can be structurally distinguished via its positioning of cysteine residues that are responsible for its internal disulfide loop and smaller loop located at the c-terminus. Smaller molecular weight variants of growth hormone also exist that lack specific amino acid residue sequences, such as the 20 kD variant which lacks amino acids 32-46 and the 17 kD variant, which is cleaved form the parent 22 kD isoform at about amino acid residue 40-44.

The measurement and elucidation of its biological properties is complex, as GH does not exist as a single and finite molecule. It has been suggested that over 100 different GH isoforms exist, all arising from one of two genes. These posttranslational processes are thought to take place in the periventricular space prior to entry into the circulation. Such post-translational processes include acetylation, deamination, and hetero- and homo-oligomerization. This ability to form oligomers via either non-covalent or peptide bonds may serve to increase the half-life of the peptide in circulation or may have an undiscovered biological property of GH modulation such as competitive binding to the GH receptor.

Dimerism GH appears to be the most abundant of the post-translationally modified products, although oligomers and pentameric GH have been reported. Homo- and hetero-oligomers have been described in reference to the 22 and 20 kD isoforms. Of particular interest is that small proteolytic fragments and large aggregates are also formed. Thus, the variant nature of these GH isoforms exists in circulation and encompasses a wide range of molecular weights.

The most common circulating variant of GH is the 22 kD monomeric form, which comprises approximately 43% of total GH (unless otherwise noted, measurement of GH in circulation refers to use of an immunoreactive GH assay). The next most prolific variant is the 20 kD, which totals about 8% of circulating GH. The remaining GH is other monomeric forms (5 and 17 kD variants), oligomers, and fragments of the GH polypeptide chain. However, there is some evidence to dispute these ratios. When pituitary extracts and serum analyzed by Western Blotting are compared, the 17 kD isoform is reported to be the dominant GH form in circulation, and that these variants may be released under varying physiological conditions (such as hyperglycemia). Thus, it stands to reason that circulating variants of different molecular weights may be preferentially released in response to a physiological challenge such as exercise.

Growth hormone is synthesized, stored, and secreted by somatotroph cells in the anterior pituitary. The release of growth hormone from the anterior pituitary is pulsatile. The largest peak growth hormone secretion occurs about an hour after the onset of sleep, with subsequent smaller peaks occurring during the night. However, the release of growth hormone is complex, with two somatotroph cells of differing density having been identified. Somatotrophs of lesser density (also called type I) have fewer secretory granules and release primarily the immunoreactive isoform of GH that is commonly studied. Higher density Somatotrophs (type II) have been shown to preferentially release oligomeric isoforms of GH, with molecular weights in the range of 44-60 kD.

Growth hormone acts directly on target tissue by stimulating mitosis, and indirectly by initiating the production and release of IGF-I, a mitogenic factor produced primarily in the liver. The physiological actions of growth hormone are mediated through its binding to the growth hormone receptor (GH-R), located on the surface of cells in target tissue. We have recently identified two GH-R subtypes (GH-R1 and -R2) in the Mozambique tilapia, one of which (GH-R1) we believe to be the putative receptor for somatolactin (SL-R) and the other (GH-R2), the growth hormone-receptor (GH-R). Somatolactin (SL) is a member of the GH/prolactin family of pituitary peptide hormones, which is present in a variety of teleost species as well as the sturgeon and lungfish, but not in tetrapods. The signal transduction by the GH-R leads to the biological actions evoked by GH. Protein restriction during fasting has been shown to reduce circulating IGF-I and liver IGF-I mRNA levels in several teleost species including the tilapia. Alterations in circulating GH and IGF-I due to disruptions in metabolic rhythms in turn alter the number and post-receptor functions of GH-R through changes in the transcription and translation of the GH-R. Insulin-like growth factor-II (IGF-II) shares a high structural homology with IGF-I, and gene expression of both mitogens appears to be regulated in fish in several tissue types by GH. In contrast with mammals which express IGF-II chiefly during embryonic development, IGF-II is expressed widely in both juvenile and adult fish. On the other hand, the metabolic actions of IGF-II in fish are virtually unknown. Both IGFs also activate cell proliferation suggesting that they share several overlapping physiological roles.