Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Comprehensive expression profiling of tumors using DNA microarrays has been used recently for molecular classification and biomarker discovery, as well as a tool to identify and investigate genes involved in tumorigenesis. Application of this approach to a cohort of benign and malignant adrenocortical tissues would be potentially informative in all of these aspects. In this study, we generated transcriptional profiles of 11 adrenocortical carcinomas (ACCs), 4 adrenocortical adenomas (ACAs), 3 normal adrenal cortices (NCs), and 1 macronodular hyperplasia (MNH) using Affymetrix HG_U95Av2 oligonucleotide arrays representing approximately 10,500 unique genes. The expression data set was used for unsupervised hierarchical cluster analysis as well as principal component analysis to visually represent the expression data. An analysis of variance on the three classes (NC, ACA plus MNH, and ACC) revealed 91 genes that displayed at least threefold differential expression between the ACC cohort and both the NC and ACA cohorts at a significance level of P < 0.01. Included in these 91 genes were those known to be up-regulated in adrenocortical tumors, such as insulin-like growth factor (IGF2), as well as novel differentially expressed genes such as osteopontin (SPP) and serine threonine kinase 15 (STK15). Increased expression of IGF2 was identified in 10 of 11 ACCs (90.9%) and was verified by quantitative reverse transcriptase-polymerase chain reaction. Select proliferation-related genes (TOP2A and Ki-67) were validated at the protein level using immunohistochemistry and adrenocortical tissue microarrays. Our results demonstrated significant and consistent gene expression changes in ACCs compared to benign adrenocortical lesions. Moreover, we identified several genes that represent potential diagnostic markers and may play a role in the pathogenesis of ACC.
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PMID:Distinct transcriptional profiles of adrenocortical tumors uncovered by DNA microarray analysis. 1254 10

The human insulin receptor (IR) exists in two isoforms (IR-A and IR-B). IR-A is a short isoform, generated by the skipping of exon 11, a small exon encoding for 12 amino acid residues at the carboxyl terminus of the IR alpha-subunit. Recently, we found that IR-A is the predominant isoform in fetal tissues and malignant cells and binds with a high affinity not only insulin but also insulin-like growth factor-II (IGF-II). To investigate whether the activation of IR-A by the two ligands differentially activate post-receptor molecular mechanisms, we studied gene expression in response to IR-A activation by either insulin or IGF-II, using microarray technology. To avoid the interfering effect of the IGF-IR, IGF-II binding to the IR-A was studied in IGF-IR-deficient murine fibroblasts (R- cells) transfected with the human IR-A cDNA (R-/IR-A cells). Gene expression was studied at 0.5, 3, and 8 h. We found that 214 transcripts were similarly regulated by insulin and IGF-II, whereas 45 genes were differentially transcribed. Eighteen of these differentially regulated genes were responsive to only one of the two ligands (12 to insulin and 6 to IGF-II). Twenty-seven transcripts were regulated by both insulin and IGF-II, but a significant difference between the two ligands was present at least in one time point. Interestingly, IGF-II was a more potent and/or persistent regulator than insulin for these genes. Results were validated by measuring the expression of 12 genes by quantitative real-time reverse transcriptase-PCR. In conclusion, we show that insulin and IGF-II, acting via the same receptor, may differentially affect gene expression in cells. These studies provide a molecular basis for understanding some of the biological differences between the two ligands and may help to clarify the biological role of IR-A in embryonic/fetal growth and the selective biological advantage that malignant cells producing IGF-II may acquire via IR-A overexpression.
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PMID:Differential gene expression induced by insulin and insulin-like growth factor-II through the insulin receptor isoform A. 1288 24

Polyploidy is characterized by a greater than diploid content of DNA in a cell. Previous measurements of ploidy level in different organs of humans and rodents, including the aorta, indicated an increase in old versus young. We hypothesized that aortic vascular smooth muscle polyploidy is a biomarker for aging and that the augmented DNA dosage affects selective gene-specific transcript expression. Our results demonstrate that tetraploidy increases exponentially over the life span of the animal, serving as an indicator of age. Approximately 60% of the vascular smooth muscle cells in the thoracic aorta of 36-month-old Brown Norway rats are tetraploid compared with 8% in their 3-month-old counterparts. Microarray analysis and reverse transcriptase-PCR was performed with mRNA isolated from sorted diploid (2N) and tetraploid (4N) vascular smooth muscle cells from old rats to identify differentially expressed transcripts. For the majority of detectable transcripts, an increase in DNA content led to a proportional increase in mRNA. A select group of transcripts, however, were reduced in tetraploid compared with diploid cells. These mRNAs correspond to guanine deaminase, to the matrix proteins rat glypican 3 (OCI-5) and decorin, as well as to the inflammation-associated transcripts, insulin-like growth factor-binding protein 6, macrophage inflammatory protein 2 precursor, macrophage galactose N-acetylgalactoseamine-specific lectin, and complement component C4. Our study is the first to describe aortic ploidy level as a biomarker for aging and to indicate that changes associated with increased DNA content per cell may selectively suppress the expression of specific genes.
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PMID:Vascular smooth muscle polyploidization as a biomarker for aging and its impact on differential gene expression. 1463 4

HaCaT keratinocytes are derived from adult human skin and although spontaneously immortalized, remain highly related to their normal counterparts. We observed that HaCaT cells can proliferate in serum-free medium (SFM), in contrast to normal human keratinocytes whose growth in vitro requires a feeder layer and/or the supplementation with hormones and growth factors. Since autocrine production of growth factors has been proposed as the pathway that cells may exploit to escape growth regulation, we have investigated whether this is occurring in HaCaT cultured in SFM. Either epidermal growth factor (EGF) or insulin-like growth factor-1 (IGF-I) was effective and dose-dependently stimulated HaCaT replication. The ability of these keratinocytes to express EGF and IGF-I and their receptors was investigated by northern blot and reverse transcriptase-polymerase chain reaction (RT-PCR). We report that HaCaT cells synthesize mRNAs for IGF-I, IGF-II, IGF-IR and EGF-R but not EGF mRNA. Immunoneutralization of IGF-I with specific monoclonal antibodies blocked spontaneous HaCaT proliferation in SFM, as did incubation with antibodies against IGF-IR. These data demonstrate that an autocrine/paracrine loop based on IGF-I may allow HaCaT keratinocytes to proliferate autonomously in culture in contrast to keratinocytes in primary culture. A similar mechanism may be involved in the development of hyperproliferative diseases of human skin and its functional disruption may represent the target for therapeutic approaches.
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PMID:IGF-I stimulates proliferation of spontaneously immortalized human keratinocytes (HACAT) by autocrine/paracrine mechanisms. 1512 9

Human fetal cord blood contains subsets of mononuclear cells with the potential to form both hematological and endothelial cells. Vascular progenitor cells, which can produce all three elements of mature blood vessels, including smooth muscle, have been identified in animals. We hypothesized that similar multipotential progenitor cells exist in humans and used the expression of alpha-smooth muscle actin (alpha-SMA) to identify such cells in fetal cord blood. Mononuclear cell preparations were isolated from human umbilical cord blood and CD34(+) and CD133(+) cells obtained by magnetic bead separation. Isolated cells were cultured on fibronectin-coated dishes with medium containing vascular endothelial growth factor, basic fibroblast growth factor, and insulin-like growth factor. mRNA was extracted, and the expression of alpha-SMA and a number of endothelial cell markers (VEGFR-2, vWF, eNOS, VE-Cadhein, PECAM-1 and Tie-2) was determined by reverse transcriptase-PCR techniques. Human umbilical vein endothelial cells (HUVECs) were used as positive controls. Freshly isolated CD34(+) and CD133(+) cells expressed all endothelial cell markers, but did not express alpha-SMA. HUVECs expressed alpha-SMA. Following 4 weeks of culture, CD34(+) isolates produced morphologically endothelial-like cells that expressed both endothelial cell markers and alpha-SMA. CD133(+) cells failed to produce morphological endothelial-like cells but expressed a range of endothelial markers. However, they did not express alpha-SMA. Following culture in an endothelial cell-promoting environment, CD34(+), but not CD133(+), isolates produced endothelial-like cells that expressed alpha-SMA. Human fetal cord blood contains a population of cells that may differentiate toward both an endothelial and a smooth muscle phenotype in culture.
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PMID:Smooth muscle alpha-actin expression in endothelial cells derived from CD34+ human cord blood cells. 1558 9

The insulin-like growth factor (IGF) system is an important regulator of growth and differentiation in a variety of tissues. In the present study, the expression of IGF family members in the taste buds of mice and rats was examined. By reverse transcriptase polymerase chain reaction (RT-PCR) analysis, mRNA of IGF-I and -II, IGF-I receptor (IGF-IR), insulin receptor (insulin R), and IGF-binding protein (IGFBP)-2, -3, -4, -5, and -6 was detected in the taste bud-containing epithelium of the circumvallate papillae of mice. As suggested by the study using degenerate PCR (McLaughlin [2000] J. Neurosci. 20:5679-5688), IGF-IR was expressed in most of the taste bud cells of adult mice, as found by immunohistochemistry, and in those of postnatal day (P) 6 mice by in situ hybridization. Insulin R, which has strong homology to IGF-IR, was also detected in most of the taste bud cells of mice by immunohistochemistry and in situ hybridization. IGF-I immunoreactivity was detected in a few taste bud cells and in the epithelium surrounding taste buds. Northern blot analysis revealed that the amount of IGF-I mRNA in taste bud-containing epithelium was very low compared with that in liver. IGF-II immunoreactivity was weakly detected in mouse taste buds and the surrounding epithelium. In the rat tissue, a subset of the taste bud cells was positive for IGF-II. Among the six IGFBPs, IGFBP-2, -5, and -6 were detected in the mouse taste buds: IGFBP-2 and -5 immunoreactivity was seen in the majority of the taste bud cells, whereas IGFBP-6 immunoreactivity was found in the nerve fibers innervating the taste buds. In situ hybridization study also revealed that IGFBP-2 and -5 mRNA was synthesized in the taste buds of P6 mice and that the expression of these mRNAs overlapped in von Ebner's glands. These data reveal that IGF-I and -II might be produced in taste bud cells and (or) surrounding lingual epithelium and act through IGF-IR and insulin R locally in a paracrine and autocrine manner. The activity of these IGFs may be modulated through their interaction with IGFBP-2, -5, and 6.
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PMID:Distinct expression pattern of insulin-like growth factor family in rodent taste buds. 1561 15

Sex steroids and growth factors interact at the intracellular level in a variety of tissues to control numerous physiological functions. Oestrogen is known to stimulate prolactin synthesis and secretion, but the effect of insulin-like growth factor (IGF)-I is less clear. We used GH3 cells, a somatolactotroph cell line, to study the interaction of 17beta-oestradiol (E(2)) and IGF-I on prolactin protein levels and the intracellular mechanisms involved. Cell cultures were treated with E(2) (10 nM) and/or IGF-I (10 ng/ml) for 8 h. The real-time reverse transcriptase-polymerase chain reaction, Western blot and enzyme-immunoassay were used to determine changes in prolactin mRNA and protein levels. At this time-point, there were no significant changes in cell number, prolactin mRNA expression, or the amount of secreted prolactin. However, E(2) increased intracellular prolactin concentrations. IGF-I alone had no effect, but blocked the stimulatory effect of E(2). MAPK (ERK1/2) activation, as determined by Western blot analysis, increased with both E(2) and IGF-I, but not with the combination of these factors. The MAPK inhibitor PD98059 blocked the ability of E(2) to increase intracellular prolactin concentrations. Similarly, the IGF-I receptor antagonist, JB1, blocked the effect of E(2) on prolactin synthesis and MAPK activation, as did the oestrogen receptor antagonist ICI182 780. These results suggest that, to stimulate prolactin synthesis, E(2) activates the MAPK cascade and that this requires the presence of both oestrogen and IGF-I receptors.
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PMID:Oestrogen requires the insulin-like growth factor-I receptor for stimulation of prolactin synthesis via mitogen-activated protein kinase. 1579 60

To verify the expression of type 1 insulin-like growth factor receptor (IGF-IR) and its impact on hematopoietic cells apoptosis in myelodysplastic syndromes (MDS) and acute myeloid leukemias (AML), marrow samples from 16 patients with MDS and 16 patients with AML were examined along with 16 healthy donors as controls. Immunocytochemical methods (alkaline phosphatase anti-alkaline phosphatase) and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (fluorescence) were used simultaneously on nucleated cell cytospins. The ratio of IGF-IR positive cells and apoptotic cells as well as the relationship between them were then analyzed separately. A quantitative real-time reverse transcriptase-polymerase chain reaction (PCR) was administrated for six MDS cases and two normal controls to validate IGF-IR expression detected by immunochemistry. In our assay, IGF-IR appeared to have higher to lower expression rate in turn from AML (86.8+/-13.8%) to MDS (56.8+/-14.3%) and then to normal controls (40.4+/-9.6%) (P<0.01 between each group). In MDS nucleated cells, IGF-IR showed stronger expression in refractory anemia with excess blasts (RAEB)/RAEB in transformation/chronic myelomonocytic leukemia subgroup when compared to RA/RA with ringed sideroblasts cases (64.1+/-3.2 vs 53.5+/-16.2%) (P>0.05). Nucleated cells from MDS marrow underwent more apoptosis (5.4+/-3.0%) than that in normal marrow (1.2+/-0.9%) (P<0.01) and AML marrow (0.3+/-0.4%) (also, P<0.01 between each compared group). For both AML and MDS cases, apoptotic signals presented mainly in individual IGF-IR negative cells (9.0+/-4.8%) and less so in IGF-IR positive cells (1.4+/-2.4%) (P<0.01). When analyzed by groups, cell number with IGF-IR expression showed a negative correlation to apoptotic cells amount (r=-0.852; P<0.01) but positive correlation to their blast count (r=0.677; P<0.01). Outcome from real-time quantitative PCR appeared to have a trend of enhanced IGF-IR expression in advanced MDS subtypes. In conclusion, overexpression of IGF-IR existed in hematopoietic cells in MDS and AML marrows, which appeared to be contributed to disease progress.
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PMID:Expression of type 1 insulin-like growth factor receptor in marrow nucleated cells in malignant hematological disorders: correlation with apoptosis. 1632 78

Cell proliferation and mRNA expression of insulin-like growth factor (IGF-I) and "mechanogrowth factor" (MGF) were studied in osteoblasts in response to overload. Static and cyclic-stretching were used to apply superphysiological strains to cells. Overload was found to increase cell growth. IGF-I and its splicing variant, MGF, were measured using reverse transcriptase-polymerase chain reaction method and were found to be regulated differentially by mechanical signals at the mRNA level. Cyclic-stretching had a more significant effect on cell proliferation and mRNA expression levels of IGF-I and MGF, while unstrained cells did not express MGF at the mRNA level. These results demonstrated that gene expression is regulated by mechanical stimulation. MGF expression in osteoblasts in response to strain may be related to an autocrine mechanism.
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PMID:The MGF expression of osteoblasts in response to mechanical overload. 1693 42

It is unclear whether cardiac hypertrophy and hypertrophy-related pathways will be induced by long-term intermittent hypoxia. Thirty-six Sprague-Dawley rats were randomly assigned into three groups: normoxia, and long-term intermittent hypoxia (12% O(2), 8 h per day) for 4 weeks (4WLTIH) or for 8 weeks (8WLTIH). Myocardial morphology, trophic factors and signalling pathways in the three groups were determined by heart weight index, histological analysis, Western blotting and reverse transcriptase-polymerase chain reaction from the excised left ventricle. The ratio of whole heart weight to body weight, the ratio of left ventricular weight to body weight, the gross vertical cross-section of the heart and myocardial morphological changes were increased in the 4WLTIH group and were further augmented in the 8WLTIH group. In the 4WLTIH group, tumour necrosis factor-alpha(TNFalpha), insulin-like growth factor (IGF)-II, phosphorylated p38 mitogen-activated protein kinase (P38), signal transducers and activators of transcription (STAT)-1 and STAT-3 were significantly increased in the cardiac tissues. However, in the 8WLTIH group, in addition to the above factors, interleukin-6, mitogen-activated protein kinase (MEK)5 and extracellular signal-regulated kinase (ERK)5 were significantly increased compared with the normoxia group. We conclude that cardiac hypertrophy associated with TNFalpha and IGF-II was induced by intermittent hypoxia. The longer duration of intermittent hypoxia further activated the eccentric hypertrophy-related pathway, as well as the interleukin 6-related MEK5-ERK5 and STAT-3 pathways, which could result in the development of cardiac dilatation and pathology.
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PMID:Eccentric cardiac hypertrophy was induced by long-term intermittent hypoxia in rats. 1718 50


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