Biomedical subjects

J E Rowland

Publications and source records attributed to J E Rowland.

6 recordsLinked to original sources

PubMed2004

Mouse cellular cementum is highly dependent on growth hormone status.

Cementum is known to be growth-hormone (GH)-responsive, but to what extent is unclear. This study examines the effects of extremes of GH status on cementogenesis in three lines of genetically modified mice; GH excess (giant), GH antagonist excess (dwarf), and GH receptor-deleted (GHR-KO) (dwarf). Age-matched mandibular molar tissues were processed for light microscope histology. Digital images of sections of first molar teeth were captured for morphometric analysis of lingual root cementum. Cross-sectional area of the cellular cementum was a sensitive guide to GH status, being reduced nearly 10-fold in GHR-KO mice, three-fold in GH antagonist mice, and increased almost two-fold in giant mice (p < 0.001). Cellular cementum length was similarly influenced by GH status, but to a lesser extent. Acellular cementum was generally unaffected. This study reveals cellular cementum to be a highly responsive GH target tissue, which may have therapeutic applications in assisting regeneration of the periodontium.

Animals↗

PubMed2003

Hyperinsulinism and overgrowth without obesity.

We report a 5 year old girl with postnatal overgrowth (height velocity >97th centile), hyperinsulinaemia, and increased insulin-like growth factor 1 for age, without evidence of bioactive or immunoreactive growth hormone excess or pituitary abnormality. Although her overgrowth may be a result of hyperinsulinism, her serum contains a factor (neither insulin nor IGF-1) which is able to stimulate the proliferation of lymphocyte precursors, and this could also account for the overgrowth. Over the course of two years observation she has developed acanthosis nigricans and diabetes mellitus.

Acromegaly↗

PubMed1998

Activation of chimeric and full-length growth hormone receptors by growth hormone receptor monoclonal antibodies. A specific conformational change may be required for full-length receptor signaling.

Signal transduction by the growth hormone receptor (GHR) occurs through growth hormone (GH)-induced dimerization of two GHRs to form a trimeric complex. It is thought that dimerization alone is sufficient for signaling, since monoclonal antibodies (mAbs) against the extracellular domain of the GHR elicit proliferation of FDC-P1 cells transfected with a chimeric receptor comprising the extracellular domain of the GHR and the fibronectin and cytoplasmic domains of the murine granulocyte colony-stimulating factor receptor. We have screened 14 GHR mAbs for proliferative activity against characterized FDC-P1 and BaF-B03 cell lines stably expressing the full-length human, rabbit, or rat GHR, or the chimeric human GHR/granulocyte colony-stimulating factor receptor, and for transactivation of the c-fos promoter and STAT activation. With the chimeric receptor, eight mAbs were able to elicit proliferation, although there was no correlation between inhibition of hormone binding and agonist activity. In contrast, no mAbs were able to act as agonists with the full-length GHR FDC-P1 cell lines, although nine competed with GH for binding. A weak proliferative response was observed in the BaF-B03 cell lines with two of the mAbs (263 and 1C9), and the addition of anti-mouse F(ab)2 resulted in increased signaling in the hGHR BaF-B03 cell line to a plateau of 28 +/- 4% of the GH maximum for mAb 263. These data could indicate considerable stringency in the ability of mAbs to correctly dimerize the full-length GHR. However, the ability of mAb 263 to stimulate a mutant hGHR altered in the F'-G' loop of domain 2 was nearly abolished, concurrent with an increased affinity of this mAb for the receptor. Since the F'-G' loop undergoes a conformational change on GH binding and is necessary for full proliferative signaling, we propose that in addition to promoting receptor dimerization, mAb 263 may induce specific changes in receptor conformation similar to GH, which are required for the biological response.

Animals↗

PubMed1998

Isolation of seven unique biogenic amine receptor clones from the honey bee by library scanning.

The biogenic amine receptor genes constitute an ancient and highly divergent family within the larger superfamily of G-protein-coupled receptors. These receptors play a central role in modulating nerve cell activity and thus behaviour. Because the honey bee offers numerous advantages for behavioural studies we endeavoured to isolate as many members of this gene family as possible from the bee. We compared numerous approaches to gene isolation and found that PCR amplification from small subfractions of cDNA or genomic DNA libraries enabled us to isolate clones that are otherwise undetectable. In total we isolated seven biogenic amine receptor clones and identified five additional related sequences by low-stringency Southern hybridization. Two clones, AmBAR4 and AmBAR6, are 84% and 72% identical to the Drosophila 5-HT2 and D1b receptors, respectively, and probably represent orthologous genes. Phylogenetic analysis indicates that AmBAR5 clusters loosely with a variety of tyramine and octopamine receptors with which it shares <66% identity. The other four clones, AmBAR1, AmBAR2, AmBAR3 and AmBAR7, are weakly to moderately related (28-45% identical) to Drosophila dopaminergic or mammalian adrenergic receptors and probably represent receptors of these classes whose orthologues have not previously been isolated from any insect. The honey bee clones expand the size of the known insect biogenic amine receptor gene family to sixteen members. Therefore the size of the biogenic amine receptor gene family of insects approaches that of vertebrates. This is true despite the reduced behavioural and genetic complexity of the insects relative to vertebrate animals.

Amino Acid Sequence↗

PubMed1997

Aspartate 171 is the major primate-specific determinant of human growth hormone. Engineering porcine growth hormone to activate the human receptor.

It has been known for more than 4 decades that only primate growth hormones are effective in primate species, but it is only with the availability of the 2.8 A structure of the human growth hormone (hGH).hGH-binding protein (hGHBP)2 complex that Souza and co-workers (Souza, S. C., Frick, G. P., Wang, X., Kopchick, J. J., Lobo, R. B., and Goodman, H. M. (1995) Proc. Natl. Acad. Sci. U. S. A. 92, 959-963) were able to provide evidence that Arg-43 on the primate receptor is responsible. Here we have examined systematically the interaction between Arg-43 (primate receptor) or Leu-43 (non-primate receptors) and their complementary hormone residues Asp-171 (primate GH) and His-170 (non-primate hormones) in a four-way comparison involving exchanges of histidine and aspartate and exchanges of arginine and leucine. BAF/B03 lines were created and characterized which stably expressed hGH receptor, R43L hGH receptor, rabbit GH receptor, and L43R rabbit GH receptor. These were examined for site 1 affinity, for the ability to bind intact cells, and for proliferative biopotency using hGH, D171H hGH, porcine GH, or H170D porcine GH. We find that the single interaction between Arg-43 and His-170/171 is sufficient to explain virtually all of the primate species specificity, and this is congruent with the crystal structure. Accordingly, for the first time we have been able to engineer a non-primate hormone to bind to and activate the human GH receptor.

Amino Acid Substitution↗

PubMed1971

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