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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin rapidly lowers serum insulin-like growth factor-binding protein-1 (IGFBP-1) levels in vivo. In studies reported here, HEP G2 cells were used as a model system to investigate how insulin achieves this effect. When HEP G2 cells were incubated with 100 nM insulin for 6, 14, or 24 h, IGFBP-1 protein levels in conditioned medium fell to approximately 50% of control values. This apparently was due to a fall in the rate of IGFBP-1 protein synthesis, since HEP G2 cells incorporated 46% less [35S]methionine into IGFBP-1 during a 4-h incubation with 100 nM insulin. IGFBP-1 mRNA levels were similarly affected by 100 nM insulin, falling to 45% of control values after 2 h, and to 9% of control values after 4 h of incubation with this hormone. The fall in IGFBP-1 mRNA level is consistent with data from nuclear transcription assays. HEP G2 nuclei isolated from cells that were incubated with 100 nM insulin for 2 h synthesized only approximately 1/3 the number of IGFBP-1 transcripts as did control nuclei. Further evidence that insulin decreases IGFBP-1 gene transcription comes from transient transfections using chimeric IGFBP-1 promoter-chloramphenicol acetyltransferase reporter gene constructs. IGFBP-1 promoter activity fell to approximately 50% of control values when HEP G2 cells transfected with a construct containing the first 1205 base pairs of the IGFBP-1 promoter were incubated with 100 nM insulin for 6, 14, or 24 h. Insulin lowered both IGFBP-1 protein levels and promoter activity in a dose-dependent manner. A half-maximal effect was found at approximately 1 nM insulin and a maximal effect was found at approximately 10 nM insulin in each instance. Transfections with constructs containing smaller IGFBP-1 promoter fragments showed that the region spanning from 103 to 529 base pairs 5' to the IGFBP-1 mRNA cap site was necessary to demonstrate the inhibitory effect of insulin. These studies indicate that insulin lowers IGFBP-1 protein levels, at least in part, by rapidly decreasing the rate of IGFBP-1 gene transcription, and suggest that this insulin-mediated fall in transcription is conferred through a specific region of the IGFBP-1 promoter.
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PMID:Insulin inhibits transcription of the human gene for insulin-like growth factor-binding protein-1. 171 56

Human esophageal and gastric carcinomas express multi-autocrine growth factors and hormones including epidermal growth factor (EGF), transforming growth factor (TGF)-alpha and beta, platelet-derived growth factor (PDGF), insulin-like growth factor (IGF) and sex hormones. Overexpression of EGF, TGF-alpha and EGF receptor (EGFR) by tumor cells is closely correlated with the tumor invasion and patient prognosis. This is substantiated by the facts that EGF and TGF-alpha act as autocrine growth factors and then induce the expression of mRNAs for multi-growth factors and their receptors (EGF, TGF-alpha, EGFR, ERBB2, PDGF). Moreover, they stimulate the expression of metalloproteinase genes suggesting that EGF and TGF-alpha successively evoke cascade phenomena which are most convenient for tumor progression, invasion and metastasis. On the other hand, multiple oncogene alterations take place in the process of tumor progression. HST-1 and INT-2 genes which is a member of fibroblast growth factor gene family, are amplified in approximately 50% of primary tumors and all the metastatic tumors of esophageal carcinomas. The amplification of ERBB2 gene in metastatic gastric carcinomas is detected more frequently than in primary carcinomas. Overexpression of multi-growth factor-receptor systems might lead to genetical alterations. Scirrhous gastric carcinoma has vast fibrous stroma with rapid and extensive growth and exhibits high malignancy. Its fibrous stroma may account for synchronous overexpression of EGF, TGF-alpha, PDGF, IGF and TGF-beta by tumor cells. Most of well differentiated adenocarcinomas show overexpression of p 185ERBB2 and coexpression of p 185ERBB2, and EGFR evidently correlates with high malignancy. In conclusion, the accumulation and interaction of several growth factors produced by tumor cells are necessary for the progression of human esophageal and gastric carcinomas. They may be attributed to genetic changes including activation of oncogenes, inactivation and deletion of anti-oncogenes and transcriptional regulatory sequences.
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PMID:Growth factors in progression of human esophageal and gastric carcinomas. 209 74

We have studied mRNA levels for a variety of growth factors in biopsy specimens from malignant, benign and normal breast tissue. We found TGFb mRNA in all breast cancers and neoplastic breast tissues but the level of the TGFb mRNA were found to be higher in breast cancer (P = 0.01). TGFa mRNA was detected in a similar proportion of cancers as in neoplastic breast tissues but the TGFa receptor EGFR mRNA was detected in only 55% of breast cancers but in all non-neoplastic breast tissue tested. The presence of EGFR mRNA was inverted related to oestrogen receptor status and coexpression of TGFa and EGFR was observed in 28% of carcinomas, and significantly more commonly in ER negative tumours (P = 0.01). PDGF a and b chain transcripts coexisted in all normal and malignant breast tissue. Insulin-like growth factor II mRNA was present in all 15 samples of non-malignant breast tissue but in only 11 of 21 (52%) of carcinomas.
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PMID:Growth factor expression in breast tissue. 228 95

The primary structure of an insulin-like growth factor (IGF) binding protein produced by human HEP G2 hepatoma cells has been deduced from the cDNA sequence. The 234 amino acid protein has a predicted molecular mass of 25,274 and contains a single, distinctive cysteine-rich region. The N-terminal sequence of this protein is quite similar to the limited sequence data available for a rat IGF binding protein produced by BRL-3A cells and suggests a common ancestral origin. In contrast, the HEP G2 IGF binding protein sequence bears no similarity to the N-terminal 15 amino acids of a 53 kilodalton binding protein purified from human plasma. Comparison of full-length protein sequences for the IGF-I and IGF-II receptors with that of the HEP G2 IGF binding protein also fails to demonstrate any significant similarities among these three proteins, and suggests that each contains a unique binding domain for the IGF peptides.
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PMID:Insulin-like growth factor (IGF) binding protein complementary deoxyribonucleic acid from human HEP G2 hepatoma cells: predicted protein sequence suggests an IGF binding domain different from those of the IGF-I and IGF-II receptors. 245 22

N-terminal as well as internal amino acid sequence data were obtained from the GH dependent, insulin-like growth factor (IGF) binding protein, BP-53, purified from human plasma. Based on these sequence data, full-length cDNA clones of BP-53 have been isolated, and the complete deduced sequence of BP-53 determined. This sequence contains a 27 amino acid putative signal sequence followed by a mature protein of 264 amino acids containing 18 cysteine residues clustered near the N- and C-terminus. The deduced protein sequence of BP-53 has 33% amino acid identity including conservation of all 18 cysteine residues with the recently cloned BP-28, a smaller human IGF-binding protein identified in amniotic fluid and also secreted by the cell line HEP G2. Expression of the cloned BP-53 cDNA in mammalian tissue culture cells results in secretion of the protein into the culture medium. This expressed protein is identical to plasma-derived BP-53 in its immunoreactivity, high affinity binding of IGF-I and IGF-II, and mobility on sodium dodecyl sulfate gel electrophoresis.
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PMID:Cloning and expression of the growth hormone-dependent insulin-like growth factor-binding protein. 246 30

The insulin-like growth factor binding proteins (IGF-BPs) are structurally and immunologically distinct from the IGF type 1 or type 2 receptors and are characterized by two major forms: a large, GH-dependent BP found in human plasma (Mr = 150 k) and a small GH-independent BP (Mr = 28-42 k) present in human plasma, amniotic fluid, and HEP G2 cells. Using affinity cross-linking techniques, we have identified several binding proteins secreted by human breast cancer cell lines (Hs578T, MDA-231, T-47D, and MCF-7). Under nonreducing conditions these proteins migrated at an apparent Mr = 35, 28, 27, and 24 k, while reducing conditions revealed bands of apparent Mr = 35, 32, 27, and 24 k. Competitive binding studies in T-47D-conditioned media demonstrated that these BPs bound more IGF-II than IGF-I, and that IGF-II potently inhibited binding of either IGF-I or -II. Immunological studies using a polyclonal antibody against the HEP G2 small BP revealed no immunoreactive BP in conditioned media from MCF-7 and T-47D and only slight immunoreactivity in conditioned media from Hs578T and MDA 231. Analysis by Northern blot, using a probe from the cDNA sequence of the HEP G2 BP, demonstrated that Hs578T and MDA-231 cell lines contained small amounts of the 1.65 kilobase mRNA characteristic of the HEP G2 BP, while MCF-7 and T-47D tested negative.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Characterization of insulin-like growth factor binding proteins from human breast cancer cells. 247 92

In hepatocytes, insulin-like growth factor-binding protein-1 (IGFBP-1) levels are increased by glucocorticoids and by agents that raise intracellular cAMP levels such as glucagon, theophylline, forskolin, and cAMP analogues. In contrast, insulin lowers IGFBP-1 levels, an effect dominant over the glucocorticoid and cAMP effects. Previous studies showed that dibutyryl cAMP (Bt2cAMP) and theophylline increase IGFBP-1 promoter activity in HEP G2 human hepatoma cells and that insulin abolishes this increase. In studies reported here, HEP G2 cells were used to further evaluate the role of cAMP in stimulating IGFBP-1 expression. Initial studies found that either 0.5 or 5.0 mM Bt2cAMP alone, or the combination of 0.5 mM Bt2cAMP and 2 mM theophylline, increased IGFBP-1 protein levels, mRNA levels, and promoter activity, but that the addition of theophylline to Bt2cAMP was required to give a approximately 5-fold increase in promoter activity. Deletion mutations of the IGFBP-1 promoter were used to show that much of the effect of Bt2cAMP and theophylline was conferred by the region between 269 and 246 base pairs (bp) 5' of the IGFBP-1 mRNA cap site. DNase I protection assays showed that HEP G2 nuclear extract footprinted the region from 273 to 249 bp 5' of the cap site; this region, designated P2, has a central CGTCA motif common to cAMP-responsive elements (CREs). Mutating the CGTCA motif in the 1205-bp IGFBP-1 promoter construct to TAGCA led to a 51% decrease in the ability of Bt2cAMP and theophylline to stimulate IGFBP-1 promoter activity above control levels. In addition, cotransfection of the catalytic subunit of cAMP-dependent protein kinase A (PKA) with the native 1205-bp IGFBP-1 promoter construct stimulated IGFBP-1 promoter activity 3.9-fold, but the TAGCA mutation decreased by 73% the ability of PKA to stimulate IGFBP-1 promoter activity above control levels. Mutating the CGTCA motif to TAGCA also blocked the ability of both crude HEP G2 nuclear extract and recombinant CRE-binding protein to bind to the P2 element. These data suggest that the P2 element is a CRE that confers at least part of the stimulatory effect of cAMP on the human IGFBP-1 promoter.
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PMID:Identification of a promoter element which participates in cAMP-stimulated expression of human insulin-like growth factor-binding protein-1. 768 58

Human tumors express high levels of growth factors and their receptors, and many types of malignant cells appear to exhibit autocrine- or paracrine-stimulated growth. Therefore, antireceptor directed therapies have the potential of being useful anti-cancer agents. A series of murine monoclonal antibodies (MAbs) directed against human growth factor receptors and their corresponding growth factors have been produced. MAbs against the receptors for epidermal growth factor, Her2/Neu, transferrin, insulin-like growth factor, interleukin, (IL)-2 and IL-1 are currently being evaluated. MAbs directed against epidermal growth factor, transforming growth factor-alpha, bombesin, IL-2, and IL-6 also are under study. These MAbs have shown promising preclinical activity, and some of them are being tested in clinical trials. So far, anti-tumor responses have been observed with anti-IL-2 receptor, anti-bombesin and anti-IL-6 MAbs. Further research is focusing in the production of "chimeric" and "humanized" MAbs, in order to obviate the problem of host immune reactions.
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PMID:Receptor blockade with monoclonal antibodies as anti-cancer therapy. 784 12

To gain insight into the signal transduction pathways utilized by the Wnt-1-responsive mammary epithelial cell line C57MG, we screened for non-src family member tyrosine kinases expressed in these cells using a polymerase chain reaction-based technique. We identified five cDNA clones encoding receptor tyrosine kinases for which the ligand is known (fibroblast growth factor receptor, platelet-derived growth factor receptor, epithelial growth factor receptor, insulin receptor, and insulin-like growth factor receptor), two putative receptor tyrosine kinases for which the ligand remains to be identified (the products of ryk and the mouse klg homolog), and a novel tyrosine kinase. We cloned cDNAs encoding both the murine and human homologs of this kinase, the sequences of which were subsequently published under the names sky (Ohashi, K., Mizuno, K., Kuma, K., Miyata, T., and Nakamura, T. (1994) Oncogene 9, 699-705) and rse (Mark, M. R., Scadden, D. T., Wang, Z., Gu, Q., Goddard, A., and Godowski, P. J. (1994) J. Biol. Chem. 269, 10720-10728). Mouse sky RNA levels are abundant in mammary tumors derived from transgenic mice that express wnt-1, fgf-3, or both oncogenes in their mammary glands. However, little or no expression of sky is detected in mammary glands from virgin animals or in preneoplastic mammary glands from wnt-1 transgenic mice. Moreover, we find that the human homolog of sky is expressed at elevated levels when normal human mammary epithelial cells are rendered tumorigenic by the introduction of two viral oncogenes. Transient transfection of the human SKY cDNA into the quail fibrosarcoma cell line QT6 reveals that SKY is an active tyrosine kinase that augments the level of cellular phosphotyrosine. Introduction of murine Sky into RatB1a fibroblasts by retrovirus-mediated gene transfer results in morphological transformation, growth in soft agar, and the formation of tumors in nude mice. These data raise the possibility that the Sky tyrosine kinase is involved in the development and/or progression of mammary tumors.
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PMID:Mouse mammary tumors express elevated levels of RNA encoding the murine homology of SKY, a putative receptor tyrosine kinase. 789 35

Glucocorticoids stimulate, while insulin inhibits, the hepatic transcription of insulin-like growth factor-binding protein-1 (IGFBP-1). In the present studies, human HEP G2 hepatoma cells were transiently transfected with human (h)IGFBP-1 promoter constructs. Activity of a construct containing the first 1205 base pairs (bp) of the hIGFBP-1 promoter was stimulated 6-9.5-fold by dexamethasone, and this increase was inhibited approximately 76% by insulin. Deletion and site-directed mutations of the hIGFBP-1 promoter (a) identified two glucocorticoid response elements, located within the first 200 bp of the promoter, which are essential for dexamethasone-stimulated promoter activity and which specifically bind human glucocorticoid receptor; (b) showed that a recently characterized insulin-responsive element, located approximately 110 bp 5' to the transcription start site (Suwanichkul, A., Morris, S.L., and Powell, D. R. (1993) J. Biol. Chem. 268, 17063-17068), confers the entire inhibitory effect of insulin not only on basal but also on glucocorticoid-stimulated promoter activity; and (c) showed that this insulin-responsive element is essential for maximal glucocorticoid-stimulated activity. These studies suggest that the interaction of proteins that bind to a cluster of cis elements located in the first 200 bp of the hIGFBP-1 promoter are of major importance in modulating the opposing effects of glucocorticoids and insulin on hepatic hIGFBP-1 expression.
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PMID:Glucocorticoids and insulin regulate expression of the human gene for insulin-like growth factor-binding protein-1 through proximal promoter elements. 798 14


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