Somatostatin, a cyclic tetradecapeptide, is both a hypothalamic hormone and a paracrine peptide, with effects on many tissues. Despite the fact that somatostatin can inhibit various cellular events in a number of cell lines, somatostatin is a constituent of medium defined for optimal growth of FRTL5, a line of differentiated and nontransformed rat thyroid follicular cells. In the present study we have evaluated the role of somatostatin in the control of DNA synthesis in FRTL5 cells and have investigated the mechanisms of somatostatin interaction with pathways stimulated by TSH and insulin-like growth factor-I (IGF-I). Somatostatin inhibits TSH-stimulated DNA synthesis and cell proliferation in FRTL5 cells. Maximal effects are observed at somatostatin concentrations of 0.1-10 ng/ml, and the effects are diminished at somatostatin concentrations above 10 ng/ml. Somatostatin also inhibits (Bu)2cAMP-stimulated DNA synthesis, suggesting that the loci of somatostatin action are both proximal and distal to activation of adenylate cyclase. Somatostatin also inhibits DNA synthesis stimulated by insulin-like growth factor-I (IGF-I), a pleiotropic growth factor that works through non-cAMP-dependent pathways. The somatostatin analog octreotide is more potent than native somatostatin in inhibiting DNA synthesis stimulated by either TSH or IGF-I. Somatostatin does not alter TSH or IGF-I binding to FRTL5, demonstrating that somatostatin affects the postreceptor signal transduction pathways stimulated by these factors. We conclude that 1) the use of somatostatin in hormone-supplemented medium for FRTL5 is unnecessary and may inhibit cell growth; 2) somatostatin can inhibit the direct effects of IGF-I on peripheral tissues in addition to its ability to interfere with IGF-I synthesis by inhibiting the synthesis and release of pituitary GH; and 3) somatostatin is a useful tool for dissecting the pathways involved in mediating differentiated function and growth of FRTL5 cells.
In a family expressing euthyroid hyperthyroxinemia, an increased association of plasma thyroxine (T4) with transthyretin (TTR) is transmitted by autosomal dominant inheritance and is secondary to a mutant TTR molecule with increased affinity for T4. Eight individuals spanning three generations exhibited the abnormality. Although five of eight individuals had elevated total T4 concentrations, all affected individuals were clinically euthyroid and all had normal free T4 levels. Purified TIR from the propositus had an affinity for 125I-T4 three times that of control 1TTR. Exons 2, 3, and 4 (representing > 97% of the coding sequence) of the TIR gene of DNA prepared from the propositus' peripheral blood leukocytes were amplified using the polymerase chain reaction (PCR) and were sequenced after subcloning. Exons 2 and 3 were indistinguishable from normal. In 50% of clones amplified from exon 4, a substitution of adenine (ACC) for guanine (GCC) in codon 109 resulted in the replacement of threonine-for-alanine, a mutation confirmed by amino acid sequencing of tryptic peptides derived from purified plasma TTR. The adenine-for-guanine substitution abolishes one of two Fnu 4H I restriction sites in exon 4. PCR amplification of exon 4 of TT7R and restriction digestion with Fnu 4H I confirmed that five affected family members with increased binding of 25.I-T4 to TMR are heterozygous for the threonine 109 substitution that increases the affinity of this abnormal TIR for T4. (J. Clin.
We have studied the binding of recombinant human insulin-like growth factor I (hIGF-I), and hIGF-II, and rat IGF-II [rIGF-II (multiplication-stimulating activity)] to the human amniotic fluid IGF-binding protein placental protein-12 (PP12). PP12 displayed a 5- to 10-fold higher affinity for IGF-I compared to hIGF-II or rIGF-II. These differences in binding affinity were confirmed by both saturation binding analysis and competitive binding analysis using 125I-labeled IGF-I, hIGF-II, and rIGF-II and each of the unlabeled ligands. PP12 produced dose-dependent inhibition of IGF-I-stimulated [3H]thymidine incorporation in the rat thyroid follicular cell line FRTL5. Inhibition of IGF-I-stimulated thymidine incorporation paralleled the ability of PP12 to inhibit IGF-I binding to the surface of FRTL5. At a high concentration, PP12 also inhibited TSH-stimulated DNA synthesis but did not inhibit the binding of 125I-labeled TSH to FRTL5. Insulin did not inhibit the binding of 125I-labeled IGFs to PP12, and PP12 did not inhibit the ability of insulin to stimulate DNA synthesis. These data suggest that the ability of PP12 to inhibit TSH-stimulated DNA synthesis is through the inactivation of IGF produced endogenously by FRTL5. Low concentrations of PP12 produced a statistically significant enhancement of TSH-stimulated DNA synthesis; the mechanism by which this occurs remains unclear.
Marked fluctuations in mobility, known as the on-off phenomenon, frequently emerge during the course of chronic treatment with levodopa in patients with Parkinson's disease. Similar fluctuations in mobility and mental status have been observed in a 10-year-old Japanese girl with tetrahydrobiopterin deficiency (BH4 deficiency) while receiving neurotransmitter and biopterin supplement. In order to define the underlying mechanisms for the phenomenon in our patient, we studied the temporal relationship between plasma levodopa levels and clinical status during oral (2.0 mg/kg per day) and continuous intravenous (2.0 mg/kg per 12 h) administration of the drug. Following each oral levodopa dose, the plasma concentration of levodopa peaked at 60-90 ng/ml within 60 min and fell to 5-15 ng/ml within 2 h. The clinical state of the patient varied acutely in parallel with the plasma levodopa concentrations. The clinical swings completely disappeared when the plasma levodopa concentrations were stabilized between 120-150 ng/ml by continuous infusion. Paradoxically, on awakening from sleep, she was invariably ambulatory despite very low plasma levodopa levels (less than 10 ng/ml). These observations indicate that the on-off phenomenon in our patient reflect the fluctuations of plasma levodopa levels as demonstrated in Parkinson's disease, but there may be substantial differences in levodopa transport across the blood-brain barrier and/or striatal dopamine-receptor interaction between Parkinson's disease and BH4 deficiency.
During the past century, Japanese children have shown a most dramatic secular trend toward earlier menarche and accelerated tempo of growth. In order to assess the inter-relationship between these dual secular trends, we analysed the data on height and weight measurements of Japanese children, collected by the Japanese Ministry of Education in the years from 1900 through 1986, with reference to various retrospective studies on the age of menarche among Japanese. Between 1950 and 1983, both the mean height and weight at menarche varied significantly but percentage of the mean height achieved at menarcheal age, as compared with the mature height, remained relatively stable at approximately 95%. The results indicate that the secular trend toward earlier menarche reflects largely, if not solely, the secular change in tempo of physical growth in Japanese children.
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