Growth factors and the control of human teratoma cell proliferation.
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Cell Division↗
Biomedical subjects
W Engström
Publications and source records attributed to W Engström.
Stimulatory effect of insulin like growth factor II on DNA synthesis in the human embryonic cornea.
By using an organ culture technique, corneal endothelial cells in human embryonic eyes could be stimulated to initiate DNA synthesis by exposure to insulin like growth factor II (IGF-II). The thymidine-labelling index doubled after IGF-II supplementation. However, this stimulatory effect was neither augmented nor abrogated by the simultaneous addition of Mannose-6-Phosphate. Nor did Mannose-6-phosphate stimulate DNA synthesis in the absence of IGF II. In contrast, the IGF II effect was partly counteracted by addition of an antibody that blocks binding to the IGF type I receptor. Taken together, this data suggests that IGF II stimulates DNA-synthesis in corneal endothelium by binding to the IGF type I rather than the IGF type II/ mannose-6-phosphate receptor.
Cornea↗
Growth at the cellular level.
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Beckwith-Wiedemann Syndrome↗
Nucleotide sequence of a porcine insulin-like growth factor II cDNA.
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Amino Acid Sequence↗
The expression of the TGF beta 1 gene in the first trimester human eye and other embryonic organs.
We have examined the expression of the transforming growth factor beta 1 gene in a variety of tissues in the developing human embryo. Northern blot analysis revealed the presence of TGF B1 mRNA in the 10-12 week old eye as well as in most first trimester organs with the notable exception of the yolk sack. In an attempt to determine the topographical distribution of TGF B1 transcripts within the eye, we found that messenger RNA levels were higher in the posterior regions of the eye globe.
Embryo, Mammalian↗
Stimulatory effects of basic fibroblast growth factor on DNA synthesis in the human embryonic cornea.
First trimester human embryonic eye globes were micro-dissected so that a passage was opened between the outer environment and the anterior chamber, which rendered free access of tissue culture medium to the endothelial cell monolayer. The dissected eye globes were maintained in organ culture for 24h in the continuous presence of tritiated thymidine. Sections were cut through the whole eye globes and were subject to autoradiographic analysis in order to estimate the mitogenic response of human corneal endothelial cells to externally supplied growth factors and hormones. It was found that the corneal endothelial cells could be stimulated to initiate DNA synthesis by exposure to basic fibroblast growth factor (bFGF). The thymidine labelling index nearly doubled after bFGF addition. Northern blot analysis revealed the presence of bFGF transcripts in the embryonic eye. In contrast we were unable to trace any bFGF transcripts in other first trimester human embryonic organs. In an attempt to determine the topographical distribution of bFGF mRNA within the eye, we found that transcript levels were higher in the posterior regions of the eye globe. Immunostaining with the appropriate antibody showed conclusively that bFGF protein was present in both the anterior and posterior human eye. These results suggest that local production of bFGF may stimulate cell proliferation in vivo.
Blotting, Northern↗
Bradykinin blocks the action of EGF, but not PDGF, on fibroblast division.
Quiescent fibroblasts derived from human fetal lung can be stimulated to reinitiate DNA synthesis by sequential addition of 3 nM IGF-1 and a low concentration (8 pM) of EGF or by continuous exposure to 10% fetal calf serum or 10 ng/ml PDGF. Bradykinin blocks the IGF-1 and EGF-dependent signals without affecting the response to serum or PDGF. It activates protein kinase C and its anti-mitogenic effect is abolished after this kinase has been down-regulated. Bradykinin has no effect on the binding affinity of the EGF receptor whereas phorbol ester induces its 'transmodulation' to low affinity.
Blood↗
The role of N-linked glycosylation in the regulation of activity of 3-hydroxy-3-methylglutaryl-coenzyme A reductase and proliferation of SV40-transformed 3T3 cells.
The effects of glycosylation inhibitors on the proliferation of SV40-transformed 3T3 cells (SV-3T3) were examined in vitro. Whereas swainsonine and castanospermine, which inhibit distal steps in the glycosylational processing, exerted marginal or no effects on cell proliferation, a proximal inhibitor, tunicamycin, efficiently decreased the rate of DNA synthesis and also inhibited the activity of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase. The inhibitory effects of tunicamycin on cell proliferation could be partially reversed by addition of dolichol, a metabolite in the pathway regulated by HMG-CoA reductase. This finding suggests that tunicamycin exerts at least one of its effects on cell proliferation by modulating the activity of HMG-CoA reductase.
Animals↗
Analysis of gene dosage on chromosome 11 in children suffering from Beckwith-Wiedemann syndrome.
The Beckwith-Wiedemann syndrome (BWS) is composed of multiple congenital malformations coupled with a high concurrent risk for the development of specific rare childhood tumours. The syndrome is characterised by a complex mode of inheritance, but recent evidence indicates that it is an autosomal dominant trait with variable penetrance. It has been previously suggested that major rearrangements of the short arm of chromosome 11 are involved in the aetiology of the disease. We undertook to search for rearrangements in 11p in four patients with BWS and their parents and siblings. By using cloned DNA fragments homologous to four genes located on 11p, namely catalase, parathyroid hormone, insulin-like growth factor II and the proto-oncogene c-Ha-Ras, we subjected DNA from the patients to a restriction fragment length polymorphism (RFLP) analysis after digestion with restriction enzymes. We found no evidence for any large scale deletions or amplifications in this chromosomal region. We therefore conclude that altered gene dosage is not, as has been suggested, a requirement for the development of BWS. This raises the question of whether some other molecular mechanism is responsible for the malformations observed.
Adolescent↗
Paraspinal muscle pathology in experimental scoliosis.
Paraspinal muscle biopsies from ten rabbits with experimentally induced scoliosis and from four healthy controls were analyzed histologically and histochemically. Scoliosis was induced by two different methods: six animals underwent unilateral damage of the dorsal column of the spinal cord (mean curve: 22 degrees) and four costotransversectomy (mean curve: 47 degrees). In eight scoliotic animals myopathic changes were detected on the muscles of the concave side. Only those animals which underwent costotransversectomy showed a neuropathic pattern with cronic denervation changes on the convex side. As regards the fiber type distribution, the control group showed a higher percentage of type-I fibers, which were similar on both sides of the spinal cord. No fiber proportion asymmetry could be detected in the muscles on the concave side in normal or scoliotic rabbits. There was a tendency to depart from normal values, in two different ways, on the convex side of scoliotic animals. Thus, in contrast to the medullary damage group, the muscles of the costotransversectomized rabbits showed an increased proportion of type-I fibers. Taken together, our findings support the hypothesis that myopathic changes as observed in human idiopathic scoliosis are a consequence of the postural deformity. Fiber type distribution does not appear to be related to the curvature in the same way.
Animals↗
The effects of tunicamycin, mevinolin and mevalonic acid on HMG-CoA reductase activity and nuclear division in the myxomycete Physarum polycephalum.
The effects of two inhibitors of 3-hydroxy 3-methyl glutaryl-coenzyme A reductase (tunicamycin and mevinolin) on nuclear division in the myxomycete Physarum polycephalum were examined. Tunicamycin exerted a minor effect on division in synchronized cultures, whereas mevinolin delayed the second, third and fourth nuclear divisions with increasing efficiency. Mevinolin also appeared to be the more potent inhibitor of HMG-CoA reductase, which catalyses the rate-limiting step in the biosynthesis of cholesterol and other isoprene derivatives. These effects of mevinolin could be partially reversed by the addition of mevalonate, suggesting that mevinolin exerts its inhibitory effects on Physarum nuclear division by decreasing the activity of HMG-CoA reductase.
Cell Nucleus↗
Wiedemann-Beckwith syndrome.
The Wiedemann-Beckwith syndrome (WBS) comprises an accumulation of multiple congenital anomalies. Exomphalos, macroglossia and gigantism are considered the most common manifestations, hence the alternative designation EMG-syndrome. The syndrome carries with it an increased risk of developing specific tumours. One of the more frequent metabolic changes is transient neonatal hypoglycaemia, the result of increased insulin secretion. Inheritance of the syndrome remains uncertain. Most cases are sporadic, but a number of familial cases have been reported. Present evidence suggests that WBS is an autosomal dominant trait with variable expressivity. This review summarizes the abundant literature on the subject and discusses recent molecular genetic developments that may explain the interrelationship between the clinical abnormalities, metabolic disturbances and development of tumours.
Beckwith-Wiedemann Syndrome↗
Serum levels and urinary excretion of beta-2-microglobulin in patients with urinary bladder carcinoma.
The levels of beta 2-microglobulin in urine and serum were determined in 34 patients with urinary bladder carcinoma. In 22 patients (64%) serum beta 2-microglobulin was elevated and in 11 patients (32%) urinary excretion of the protein was increased. It was also found that all but 1 patient with elevated serum beta 2-microglobulin or urinary beta 2-microglobulin had WHO grade-II or grade-III tumors. In contrast, all patients with grade-I tumors, except 1, displayed normal levels of urine and serum beta 2-microglobulin.
Biomarkers, Tumor↗
The effects of glycosylation inhibitors on the proliferation of a spontaneously transformed cell line (3T6) in vitro.
We have examined the effects of different inhibitors of glycosylation processing on the proliferation of a spontaneously transformed murine cell line (3T6) in vitro. It was found that whereas two compounds that specifically inhibit distal steps in the glycosylation chain (swainsonine and castanospermine) only exerted marginal inhibitory effects on cell multiplication, a proximal inhibitor (tunicamycin) efficiently decreased the rate of DNA synthesis in a dose-dependent fashion. This tunicamycin-induced inhibitory effect on cell proliferation was cell cycle-specific, in the sense that cells in G1 only were blocked in their cell cycle progression. Like others (Volpe & Goldberg, 1983), we found that tunicamycin inhibited the activity of 3-hydroxy-3-methylglutaryl coenzyme-A reductase (HMG-CoA), which constitutes the ratelimiting step in the biosynthesis of cholesterol and isoprenoid derivatives, by catalysing the reduction of HMG-CoA to mevalonate, and it has been suggested that it plays a role in the control of cell proliferation and in tumour transformation. This raises the question as to whether tunicamycin exerts its inhibitory effects on cell proliferation via the isprene-synthetic pathway in addition to its effects on aspargine-linked glycosylation. By adding exogenous mevalonate, the rate-limiting step at which HMG-CoA reductase converts HMG-CoA to mevalonate can be bypassed. We found that addition of mevalonate partially reverses the effects of tunicamycin on cell proliferation. This suggests that tunicamycin exerts different effects, which taken together lead to a cessation of cell proliferation. One of these effects is likely to be mediated via the mevalonate-synthetic pathway.
Alkaloids↗
[Molecular genetics analysis of patients with Beckwith-Wiedemann syndrome].
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Adolescent↗
The effect of factors released from the tumor-transformed cells on DNA synthesis, mitosis, and cellular enlargement in 3T3 fibroblasts.
Quiescent serum-starved 3T3 cells can be stimulated to initiate DNA synthesis after addition of conditioned media from spontaneously tumor-transformed 3T3 cells (3T6-cells) or from SV-40-transformed 3T3 cells (SV-3T3 cells). The conditioned media were found to stimulate both the chromosome cycle (i.e., DNA synthesis and cell division) and the growth cycle (i.e., cellular enlargement). Furthermore, addition of conditioned media to quiescent 3T3 cells increased the activity of HMG CoA reductase--an enzyme previously proposed to exercise some control on cell proliferation in 3T3 cells (Larsson and Zetterberg: J. Cell. Physiol. 129:99-102, 1986. The increased activity of HMG CoA reductase after treatment with tumor cell conditioned media was correlated to the stimulatory effects on DNA synthesis. By treating 3T3 cells stimulated to resume proliferation by addition of conditioned media with mevinolin (a competitive inhibitor of HMG CoA reductase) the activity of HMG CoA reductase as well as the DNA synthesis and cell division were efficiently inhibited. In contrast, HMG CoA activity was not coupled to the cellular enlargement. Therefore, it is proposed that one set of factors present in tumor cell conditioned media preferentially stimulates the chromosome cycle by increasing the HMG-CoA reductase activity, whereas another set of factors is responsible for growth in cell size. Both types of factors are required for balanced growth.
Animals↗
Expression of the insulin like growth factor II gene in the developing chick limb.
We have examined the expression of the insulin like growth factor II gene in the developing chick embryo. It was found that IGF II transcripts were present in abundant quantities in the eye and the heart as well as in the limb bud in the 4 day old chick embryo. A detailed analysis of the limb bud revealed that IGF II transcripts could be detected in the anterior and the posterior regions indicating that this gene is activated in segments covering the apical ectodermal ridge (AER) and the zone of polarizing activity (ZPA) as well as in neighbouring tissue.
Animals↗
Expression of growth regulatory genes in primary human testicular neoplasms.
Seven testicular tumours of different histological type--two seminomas, two teratomas/teratocarcinomas/embryonal carcinomas, one mixed seminoma/teratoma, one Leydig cell tumour and one testicular lymphoma--were examined for the expression of four potentially growth regulatory genes by Northern blotting. Seven out of seven testicular tumours contained transcripts that hybridized with a human insulin cDNA-probe whereas only four out of seven tumours contained IGF II transcripts. One tumour contained high levels of LDL-receptor transcript whereas all seven tumours contained significant quantities of HMG-CoA-reductase mRNA.
DNA↗