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Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The functional role of brain insulin and insulinlike growth factor (IGF) receptors is being sought. Recently it has been found that these ligands are members of a newly identified family of neuritogenic polypeptides. We studied the relationship between 125I-insulin and 125I-IGF binding and their capacity to enhance neurite formation in cultured human neuroblastoma SH-SY5Y cells. The binding of 125I-insulin was temperature-dependent and heterogeneous. The Scatchard plot and dissociation rate were both consistent with the presence of two types of sites. There appeared to be about 900 high affinity sites per cell with a Kd of about 3 nM. This compared favorably with the half-maximal concentration of 4 nM for enhancement of neurite formation. The type I IGF sites were also present. Physiologic concentrations of insulin clearly enhanced neurite formation through the insulin sites, whereas physiologic concentrations of IGF-I and IGF-II enhanced through the IGF sites. Cross-occupancy of sites was observed at supraphysiologic concentrations, providing a reasonable explanation for the broad dose-response curves for these ligands. These results support the suggestion that one function of insulin and IGF receptors in neural tissues may be to modulate neurite formation.
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PMID:Insulin and insulinlike growth factor receptors regulating neurite formation in cultured human neuroblastoma cells. 328 62

Insulin-like growth factors (IGFs) regulate the autocrine/paracrine growth of neuroblastomas. The IGFs bind to specific binding proteins (IGFBPs) which modulate their biological activity. We investigated, by Western ligand blotting (WLB), the presence of IGFBPs and their possible modulation by retinoic acid (RA), IGF-I, IGF-II and truncated Des(1-3)IGF-I in conditioned medium (CM) of the human neuroblastoma SK-N-BE(2) cell line. We demonstrated the presence of two IGFBPs, with MW 37 kDa and 25 kDa. Following immunoprecipitation, they turned out to be IGFBP-2 and -4, respectively. The RA-induced differentiation in SK-N-BE(2) cells was accompanied by a marked reduction of the intensity of both IGFBP bands after 48 h (32% and 24% of control, respectively) and 72 h (2% and 0% of control, respectively) incubation. The addition of exogenous IGFs, which did not induce cell differentiation, did not change the IGFBP pattern significantly, except for the truncated form of IGF-I, which induced a marked decrease in both the 37 kDa and 25 kDa bands after 72 h incubation (45% and 18% of control, respectively). These findings suggest that IGFBPs have a role in RA-induced differentiation in human neuroblastoma cells.
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PMID:Expression and down-regulation by retinoic acid of IGF binding protein-2 and -4 in medium from human neuroblastoma cells. 752 70

Hypoglycemia occurred in a 2-year-old girl with neuroblastoma. Initially, growth hormone secretion was suppressed, and she had low levels of insulin-like growth factor (IGF)-I and IGF binding protein-3, but elevated levels of large molecular weight IGF-II. We postulated that the pathogenesis of her hypoglycemia involved production of IGF-II by her neuroblastoma, leading to GH suppression and an abnormally elevated ratio of IGF to IGF binding protein. She was successfully treated with growth hormone; treatment was associated with normalization of the growth hormone-dependent growth factor levels and with euglycemia.
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PMID:Non-islet-cell tumor associated with hypoglycemia in a child: successful long-term therapy with growth hormone. 765 70

Insulin-like growth factor (IGF)-binding proteins (BPs) bind IGF-I and IGF-II with high affinity and modify the activity of IGF peptides in a complex manner. We have characterized the affinities of IGFBP-1-4 for IGF-I and -II by employing 1) purified IGFBP preparations, 2) both [125I]IGF-I and [125I]IGF-II as radioligands, and 3) multiple IGF analogs designed to have altered affinities for IGFBPs. To this end, human (h) IGFBP-1, hIGFBP-2, and rat (r) IGFBP-4 have been purified to homogeneity from human amniotic fluid, human prostate epithelial cell culture, and B104 rat neuroblastoma cells; for human IGFBP-3, the glycosylated recombinant form (rec-hIGFBP-3), produced in Chinese hamster ovary cells, was employed. The IC50 values of IGF-I for hIGFBP-1, hIGFBP-2, rec-hIGFBP-3, rIGFBP-4, and human serum IGFBPs were 0.05 +/- 0.01, 5.0 +/- 0.01, 0.25 +/- 0.20, 0.6 +/- 0.4, and 0.1 +/- 0.01 ng/ml, respectively. While hIGFBP-1 and rIGFBP-4 had virtually equivalent affinities for IGF-I and IGF-II, hIGFBP-2 and rec-hIGFBP-3 demonstrated 2- to 5-fold higher affinities for IGF-II than for IGF-I. Studies with [Gln3,Ala4,Tyr15,Leu16]IGF-I and Des-(1-3)-IGF-I indicate that specific residues in the first 16 amino acids of the B domain of IGF-I appear to be critical for binding to all of the IGFBPs tested, but not to IGF receptors. However, severe modifications in the B domain disrupt binding affinity, not only for IGFBPs, but also for receptors (IGF-I/insulin hybrid and B-chain mutant). Interestingly, modifications in the A domain of IGF-I, which is believed to contain residues critical for binding to IGF-I and insulin receptors, show differential effects on binding affinity to BPs. [Thr49,Ser50,Ile51]IGF-I, which has normal affinity for the type I IGF receptor, shows at least a 500-fold decreased affinity for hIGFBP-1 and recombinant hIGFBP-3, in contrast to 50- to 100-fold reduced affinity for hIGFBP-2 and rIGFBP-4, and 5- to 10-fold reduced affinity for purified human serum IGFBP-3. More significantly, [1-27,Gly4,38-70]IGF-I shows a 30-fold decreased affinity for the type I IGF receptor and 10- and 2.5-fold reduced affinities for hIGFBP-1 and rec-hIGFBP-3, respectively, but no reduction in affinity for hIGFBP-2 or rIGFBP-4.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Characterization of the affinities of insulin-like growth factor (IGF)-binding proteins 1-4 for IGF-I, IGF-II, IGF-I/insulin hybrid, and IGF-I analogs. 767 79

The neuroblastoma cell line SK-ER3, which is stably transfected with the estrogen receptor (ER), was used to study the effect of insulin and insulin-like growth factors (IGF-I and IGF-II) on growth and morphological differentiation induced by estrogens. The data demonstrate that insulin and related growth factors control the growth and morphological differentiation of the cell line expressing the ER, but not of the parental cell line. Effects elicited by the growth factors in SK-ER3 cells can be blocked by ER antagonists. Transient transfection studies further confirm an effect of the IGFs in modulation of ER-activated promoters. The results presented support the hypothesis of the existence of cross-talk between membrane and intracellular receptors and provide evidence for physiological consequences of the activation of such a pathway of communication. The present study is of particular interest with regard to the theory of prenatal involvement of the ER in maturation of nerve cells. It could, in fact, be hypothesized that IGF-I and IGF-II, present in high concentrations in the developing brain, might activate the ER expressed in several embryonic brain nuclei.
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PMID:Insulin-like growth factors activate estrogen receptor to control the growth and differentiation of the human neuroblastoma cell line SK-ER3. 798 52

Insulin-like growth factors (IGF-I and IGF-II) are mitogenic polypeptides expressed in both developing and adult tissues. To examine the effects of IGFs on neuronal growth, we used SH-SY5Y neuroblastoma cells as an in vitro model of nervous system development. In the current study, we found that either IGF-I (0.1 to 10 nM), insulin (0.1 to 5 micrograms/ml) or calf serum (0.1 to 3%) increased SH-SY5Y proliferation over a 3 day period in a dose dependent manner. In each case, treatment with anti-IGF-I receptor antibodies blocked cell proliferation. IGF-II mRNA levels correlated with SH-SY5Y cell density; subconfluent cells expressed high levels of IGF-II mRNA while low levels of IGF-II mRNA were present in confluent cells. Similarly, serum deprivation increased IGF-I receptor mRNA by 4-fold. Collectively, these results support the concept that an IGF/IGF-I receptor system at least partially mediates SH-SY5Y cell proliferation and suggests the importance of IGFs in regulating neuronal growth.
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PMID:Effects of serum and insulin-like growth factors on human neuroblastoma cell growth. 826 10

In the human neuroblastoma cell line SH-SY5Y, insulin-like growth factors I (IGF-I) and II (IGF-II) are established mitogens, and IGF-I appears to promote SH-SY5Y neuronal differentiation. Studies show that c-myc gene product is a transcription factor associated with cell proliferation, and that c-myc messenger RNA levels decrease in differentiating SH-SY5Y neurons. Using Northern analysis we show that 24 h exposure of SH-SY5Y cells to IGF-I (3-10 nM) causes a 3- to 5-fold decrease in c-myc expression. The decrease in c-myc expression due to IGF-I is mediated via the type I IGF receptor and coincides with an IGF-I-mediated induction of the neuronal differentiation markers growth cone associated protein 43 and tissue type plasminogen activator. Under these conditions, IGF-I (10 nM) did not markedly affect the levels of Max messenger RNA expression. Thus, the differentiation promoting activity of IGF-I in SH-SY5Y cells in part due to IGF-I-dependent regulation of the expression of genes involved in neuronal differentiation.
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PMID:Insulin-like growth factor I regulates c-myc and GAP-43 messenger ribonucleic acid expression in SH-SY5Y human neuroblastoma cells. 847 53

Growth in neuroblastoma cells is regulated by insulin-like growth factors (IGFs) whose action is modulated by IGF binding proteins (IGFBPs). In this study, SK-N-SH neuroblastoma cells were shown to produce IGF-II, IGFBP-2, IGFBP-4 and small quantities of IGFBP-6. We have studied the effects of a natural morphogen, retinoic acid (RA), on growth and IGFBP expression in these cells. In all experiments, cells were cultured in serum-free medium and treated with 1 mumol/l RA for 12 h. Cell number increased by almost 50% during the first 24 h after the beginning of treatment. This stimulation was inhibited by 80% or more in the presence of the anti-type 1 IGF receptor antibody alpha-IR3 and anti-IGF-II antibody. The IGF-II concentrations in the culture media, measured after acidic gel filtration, increased about 1.5-fold and Northern blotting showed a concomitant increase in IGF-II mRNA levels. The mitogenic effect of RA therefore reflects its stimulation of IGF-II production. The availability of IGF-II to the cells may also be enhanced because of the proteolysis of IGFBP-2 to which it is bound. After this initial phase, proliferation ceased despite continued IGF-II production between 24 and 72 h. Both IGFBP-2 and IGFBP-4 production decreased, whereas that of IGFBP-6 increased. These changes appeared both in the protein quantities and in their mRNAs. Insulin-like growth factor binding protein 6 has a strong affinity for IGF-II, 5-10 times that of IGFBP-2 and at least 10 times that of the type I IGF receptor, and the arrested proliferation may result, at least in part, from sequestration by IGFBP-6 of the IGF-II secreted.
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PMID:Modulation by retinoic acid of insulin-like growth factor (IGF) and IGF binding protein expression in human SK-N-SH neuroblastoma cells. 864 Mar

We have previously described a case of tumor-associated hypoglycemia secondary to the production of high molecular weight insulin-line growth factor (IGF)-II in a child with congenital neuroblastoma. The child's hypoglycemia resolved with GH therapy and has continued to be well controlled for 1 yr. This represents one of the first cases of nonislet cell tumor hypoglycemia (NICTH) treated successfully with long-term exogenous GH. We now present an in-depth analysis of the IGF axis in this patient, before and after GH treatment. Although IGF-II levels at presentation were in the normal range, they were inappropriate for the patient's low GH state. Furthermore, the percentage of "big" IGF-II was elevated, as was the level of the IGF-IIE peptide, which is normally cleaved in the processing of the mature peptide. On the initial evaluation, GH levels failed to rise in response to hypoglycemia, IGF-I levels were low, IGF binding protein-3 (IGFBP-3) levels were suppressed, and IGFBP-2 levels were elevated. We have shown that baseline IGFBP-3 levels were low by RIA and immunoblotting and have demonstrated that this decrease was not associated with IGFBP protease activity. We have also demonstrated the baseline suppression of the acid labile subunit (ALS) of the 150K ternary complex by a novel immunoblot assay. The ratio of IGFs to IGFBP-3 was dramatically elevated, presumably leading to hypoglycemia. Furthermore, the percentage of serum IGF-I and IGF-II present as part of a binary (50K) complex with IGFBPs was also increased. GH therapy resulted in a normalization of the levels of blood sugars, IGFBP-3, ALS, IGFBP-2, and IGF-I, as well as the IGF/IGFBP-3 ratio. In summary, we have presented evidence that the hypoglycemia in this patient resulted from tumor production of high molecular weight IGF-II, which suppressed GH secretion, leading to the described derangements in the IGF binding proteins. We speculate that as a result of the decreased IGFBP-3 and ALS levels, the IGF population was shifted from the stable 150K complex to lower molecular weight complexes with IGF binding proteins, increasing IGF availability to tissues due to rapid turnover of these low molecular weight complexes. We demonstrated the reversal of the abnormalities in the IGFBP levels with GH treatment, corresponding to the clinical response of euglycemia.
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PMID:The effect of growth hormone treatment on the insulin-like growth factor axis in a child with nonislet cell tumor hypoglycemia. 877 89

Physiologically, the action of insulin-like growth factors (IGFs) is controlled at different levels, from its transcription start by tissue-specific and development-specific transcriptional factors to its degradation by peptidases such as insulin-degrading enzyme (IDE). Since IGF-II is the major autocrine/paracrine growth factor for neuroblastoma cells, we studied the expression and the role of IDE in this system. Here, we show that (a) IDE is expressed in several human neuroectodermal tumor cell lines, including neuroblastoma cell lines; (b) in a neuroblastoma cell line, IDE expression is up-regulated by retinoic acid, a well-known inducer of neuronal differentiation and/or programmed cell death; (c) IDE is probably not the only IGF-degrading enzyme present in these cells, since the activity of a novel thermolysin-like metalloendopeptidase, clearly distinct from IDE, is also detected. The TME activity is inhibited by IGF-I, Des-IGF-I, and IGF-II, and it is down-regulated by retinoic acid. Since retinoic acid plays a relevant role in controlling the growth of these cells and affects the expression of IDE, we have also: (a) identified the retinoic acid receptors (RARs) and retinoid X receptors (RXRs) expressed in these cell lines and (b) by means of synthetic retinoid analogues identified the RAR/RXR isoforms whose activation may be sufficient to induce the expression of the IDE gene. These results provide evidence that complex posttranslational molecular mechanisms participate in the autocrine/paracrine growth control of the IGF-II loop in neuroblastomas involving proteolytic systems.
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PMID:Regulation by retinoic acid of insulin-degrading enzyme and of a related endoprotease in human neuroblastoma cell lines. 878 Aug 92


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