Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Treatment of rodent cells with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate activates protein kinase C, leading to increased expression of several genes, including a gene originally designated TPA-S1 or phorbin (M. D. Johnson, G. M. Housey, P. T. Kirschmeier, and I. B. Weinstein, Mol. Cell Biol., 7: 2821-2829, 1987). Sequence analysis of this cloned gene indicated homology with human erythroid-potentiating activity and tissue inhibitor of metalloproteinase (TIMP-1). Elevated levels of phorbin mRNA have been observed in human colon tumors (J. G. Guillem, M. F. Levey, L. L. Hsieh, M. D. Johnson, P. LoGerfo, K. A. Forde, and I. B. Weinstein, Mol. Carcinogen., 3: 68-74, 1990) and this increase correlated with the extent of invasion. To further investigate this phenomenon at the protein level, monoclonal antibodies were developed against the recombinant form of TIMP-1. A competitive enzyme-linked immunosorbent assay was developed for quantitation of the TIMP-1 protein in tissue extracts. Elevated levels of TIMP-1 protein were found in 31 human colon tumors, compared to paired samples of adjacent normal mucosa. In a subset of samples, previously analyzed for phorbin mRNA levels (n = 25), there was a good correlation between the abundance of TIMP-1 protein and phorbin mRNA. Immunoaffinity column purification of tumor extracts followed by Western blot analysis was used to confirm the enzyme-linked immunosorbent assay data. These results provide evidence that phorbin and TIMP-1 represent the same gene. In addition, the immunoassays we have developed may be useful in further studies on the role of TIMP-1 in human colon cancer.
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PMID:Immunological quantitation of levels of tissue inhibitor of metalloproteinase-1 in human colon cancer. 193 83

1,25-Dihydroxyvitamin D3 (1,25-(OH)2D3) receptor concentration, cell proliferation, and the steady-state level of c-myc mRNA were examined in the C3H/10T1/2 mouse embryo fibroblasts, before and after exposing the cells to 1,25-(OH)2D3. The non-transformed, logarithmically growing C3H/10T1/2 Cl 8 cells contained a high concentration of 1,25-(OH)2D3 receptor (164 fmol/mg of protein). An up-regulation of the 1,25-(OH)2D3 receptor and a potent inhibition of cell growth were observed by exposing the cells to 10 nM 1,25-(OH)2D3. The concentration of 1,25-(OH)2D3 receptor in the two chemically transformed, tumorigenic cell lines. C3H/10T1/2 Cl 16 and C3H/10T1/2 TPA 482, was 218 and 63 fmol/mg of protein, respectively. In the two transformed cell lines, 10 nM 1,25-(OH)2D3 had only negligible effect on cell growth. In the Cl 16 cells, an up-regulation of the 1,25-(OH)2D3 receptor was demonstrated, but only a weak up-regulation was found in the TPA 482 cells by the 1,25-(OH)2D3 treatment. No major changes were found in c-myc mRNA levels by the 1,25-(OH)2D3 treatment. Despite inhibition of cell growth, the steady-state level of c-myc mRNA was slightly induced (35%, mean) in the Cl 8 cells compared to control cells. In the transformed cells, no consistent change of the c-myc level was found. In contrast to earlier reports, we did not find any correlation between the 1,25-(OH)2D3 receptor and c-myc level, nor did we find any decrease of c-myc mRNA by 1,25-(OH)2D3 treatment in the C3H/10T1/2 fibroblasts.
Mol Cell Endocrinol 1990 Dec 21
PMID:Effect of 1,25-(OH)2-vitamin D3 on growth, homologous receptor and c-myc regulation in C3H/10T1/2 cells. 196 47

Mitogen-activated protein (MAP) kinase is a serine/threonine-specific protein kinase which is activated in response to various mitogenic agonists (e.g., epidermal growth factor, insulin, and the tumor promoter tetradecanoyl phorbol acetate [TPA]) and requires both threonine and tyrosine phosphorylation for activity. This enzyme has recently been shown to be identical or closely related to pp42, a protein which becomes tyrosine phosphorylated in response to mitogenic stimulation. Neither the kinases which regulate MAP kinase/pp42 nor the in vivo substrates for this enzyme are known. Because MAP MAP kinase is activated and phosphorylated in response both to agents which stimulate tyrosine kinase receptors and to agents which stimulate protein kinase C, a serine/threonine kinase, we have examined the regulation and phosphorylation of this enzyme in 3T3-TNR9 cells, a variant cell line partially defective in protein kinase C-mediated signalling. In this communication, we show that in the 3T3-TNR9 variant cell line, TPA does not cause the characteristically rapid phosphorylation of pp42 or the activation and phosphorylation of MAP kinase. This defective response is not due to the absence of the MAP kinase/pp42 protein itself because both tyrosine phosphorylation of MAP kinase/pp42 and its enzymatic activation could be induced by platelet-derived growth factor in the 3T3-TNR9 cells. Thus, the defect in these variant cells apparently resides in some aspect of the regulation of MAP kinase phosphorylation. Since the 3T3-TNR9 cells are also defective with respect to the TPA-induced increase in ribosomal protein S6 kinase, these in vivo results reinforce the earlier in vitro finding that MAP kinase can regulate S6 kinase activity. These findings suggest a key role for MAP kinase in a kinase cascade cascade involved in the control of cell proliferation.
Mol Cell Biol 1991 Feb
PMID:Defective regulation of mitogen-activated protein kinase activity in a 3T3 cell variant mitogenically nonresponsive to tetradecanoyl phorbol acetate. 199 Feb 61

The involvement of the calcium messenger system in the control of steroidogenesis in the rat and bovine adrenal cortex has been studied extensively. However the role of these second messengers in the control of human adrenocortical function is not established. This was therefore studied by incubating collagenase-dispersed human adrenocortical cells with the calcium ionophore A23187 and the protein kinase C activator phorbol 12-myristate 13-acetate (TPA). The effects of the calcium channel blocker verapamil on basal and stimulated steroidogenesis were also studied. Both TPA (1 pmol/l-10 mumol/l) and A23187 (1 nmol/l-10 mumol/l) caused a dose-dependent increase in cortisol, aldosterone and corticosterone production. Verapamil (10 mumol/l) inhibited the increase in aldosterone, corticosterone and cortisol produced in response to ACTH(1-24), potassium, and desacetyl-alpha MSH. Unlike previous results in the rat, these effects were not specific for aldosterone secretion. The results suggest that, as in other species, calcium mobilization and protein kinase C activation have a role in the control of steroidogenesis in the human adrenal cortex. However, in contrast to the rat, these mechanisms appear to be involved in the control of steroidogenesis in both the zona glomerulosa and inner zone cells.
J Mol Endocrinol 1991 Feb
PMID:Control of steroidogenesis by the calcium messenger system in human adrenocortical cells. 201 56

In Xenopus oocytes, insulin or IGF-I activated glucose transport and maturation, but not amino acid transport, as measured by the uptake of alanine. Glucose transporter identical or closely related to the mammalian erythroid/brain transporter (Glut-1/EGT) were found in oocyte membranes. The EC50 for stimulation of glucose uptake and of maturation were similar (1-5 x 10(-8) M for insulin and 2-8 x 10(-10) M for IGF-I), confirming that these effects were mediated through IGF-I receptors. Other agents, such as phorbol 12-myristate 13-acetate (TPA) (0.5 microM) and vanadate (2 mM) evoked only part of the insulin effect on glucose uptake (50% and 65%, respectively), without being additive to insulin. In contrast, progesterone at 1 microM, a potent inducer of maturation, inhibited at least partially the insulin-induced glucose uptake. Uptake of alanine and glucose was decreased after prolonged incubations (3-6 h) with agents that trigger maturation, and was dramatically reduced in oocytes that have undergone maturation (unfertilized eggs). Maturation is thus accompanied by a reduction in glucose and amino acid transports. These result further document the validity of Xenopus oocytes as a model to study insulin and IGF-I signalling.
Mol Cell Endocrinol 1991 Feb
PMID:Effects of insulin, insulin-like growth factor-I (IGF-I) and progesterone on glucose and amino acid uptake in Xenopus laevis oocytes. 205 Feb 72

Approximately one third of the human breast tumors are estradiol (E2)-dependent in the initial stages of the disease. E2 is thought to stimulate growth indirectly, through induced production of autocrine polypeptide growth factors. In this hypothesis constitutive production of such growth factors would lead to the loss of E2 dependence, as associated with progression of the disease. Recent data, however, suggest that breast cancer cells do not react to the growth factors that they produce. Here we provide evidence that the direct stimulation of the c-fos proto-oncogene may be an important step in the stimulation by E2 of the human breast cancer cell line MCF7. E2 by itself, however, is poorly mitogenic, and it does not induce genes from the jun family, whose gene products are necessary for heterodimerization with the c-fos-encoded protein (Fos), leading to an important step in growth factor signalling pathways, stimulation of TPA-responsive element (TRE)-dependent transcriptional activity. In combination with insulin-like growth factors, that were found to be efficient inducers of c-jun in breast cancer cells, E2 synergistically stimulates TRE activity and proliferation. These effects of E2 on growth factor signalling pathways indicate that E2 may directly induce the proliferation of MCF7 cells, independent from autocrine growth factors.
Mol Endocrinol 1990 Nov
PMID:Stimulation of TPA-responsive element activity by a cooperative action of insulin and estrogen in human breast cancer cells. 212 40

The modulatory role of protein kinase C (PK-C)- and Gi-protein-mediated signal transduction systems was studied in the cyclic variation of follicle-stimulating hormone (FSH)-stimulated cAMP production of rat seminiferous tubules. FSH (Metrodin, Serono, 30 mg/l) stimulated cAMP production 10-fold (p less than 0.01) in a 3 h incubation of 5 mm segments of seminiferous tubules of stages II-VI of the epithelial cycle, but only 2-fold (p less than 0.01) in stages VII-VIII. The PK-C activator 12-O-tetradecanoylphorbol 13-acetate (TPA, 100 nmol/l) suppressed the FSH effect on cAMP output by 50-70% (p less than 0.01) in stages II-VI, but had no effect in stages VII-VIII. If the tubular segments were preincubated for 3 h in the presence of pertussis toxin (PT, 100 micrograms/l), the FSH-stimulated cAMP production of stages VII-VIII increased by 100-200% (p less than 0.01), and now they also became responsive to the TPA suppression. Conversely, no effect of PT was observed in stages II-VI. Cholera toxin (CT, 100 micrograms/l) and forskolin (Fk, 100 mumol/l) nearly similarly stimulated the cAMP production in both stages studied (about 10-fold, p less than 0.01), and TPA and PT potentiated the effects in a non-additive fashion. In conclusion, both Gi-protein and PK-C-mediated mechanisms modulate cAMP production of rat seminiferous tubules. A clear cyclic variation can only be demonstrated in FSH-stimulated cAMP production, but not if the Gs-protein or adenylate cyclase are directly stimulated.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Cell Endocrinol 1990 May 07
PMID:Protein kinase C and Gi-protein mediated modulation of cAMP production in different stages of the rat seminiferous epithelium. 216 36

Addition of human GH (hGH) to primary mouse osteoblasts resulted in rapid and transient induction of the c-fos and c-myc proto-oncogenes and preceded hGH-induced mitogenesis. Human GH-induced c-fos expression was maximal after 30 min, resulting in a 10- to 15-fold increase over unstimulated cells, and returned to prestimulation levels within 60 min of the addition of hGH. Induction of the c-fos gene by hGH was dose dependent and also occurred in the absence of protein synthesis, resulting in superinduction of the c-fos gene. The induction of the c-fos gene by hGH was mediated by a somatotrophic (GH) rather than a lactogenic (prolactin) receptor on primary mouse osteoblasts, as indicated by a 10- to 100-fold greater potency of hGH compared with ovine prolactin in stimulating the expression of the c-fos gene. Primary mouse osteoblasts also induced the c-fos gene in response to epidermal growth factor, insulin-like growth factor-I and several agents, including phorbol 12-myristate 13-acetate (TPA), forskolin and A23187, that are known to activate signal transduction pathways involved in the action of growth factors. Addition of hGH to primary mouse osteoblasts did not result in increased phosphoinositide breakdown, while selective deactivation of the diacylglycerol-protein kinase C and inositol 1,4,5-trisphosphate-Ca2+ pathways by long-term TPA pretreatment or depleting intracellular Ca2+ stores had no effect on hGH-induced c-fos expression. Human GH did not alter basal cyclic AMP levels in mouse osteoblasts. The immediate consequences of GH-receptor interaction as well as the mechanism of signal transduction leading to induction of the c-fos gene remain, therefore, unresolved.
J Mol Endocrinol 1990 Jun
PMID:Activation of mouse osteoblast growth hormone receptor: c-fos oncogene expression independent of phosphoinositide breakdown and cyclic AMP. 216 82

Expression of the c-fos proto-oncogene in rat neocortical astrocytes in culture was examined using Northern blotting and immunocytochemistry. Marked induction of c-fos mRNA in astrocytes was observed after treatment with epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), dibutyryl cyclic AMP (db-cAMP), and phorbol diester (TPA; 12-O-tetra-decanoylphorbol 13-acetate), which are known to induce the proliferation or differentiation of astrocytes. Increase of c-fos protein immunoreactivity (IR) was obtained after treatment with fetal calf serum, EGF, bFGF, db-cAMP and TPA. High concentrations of calcium ionophore A23187, which were lethal to cultured astrocytes, also increased c-fos protein-IR. Treatment with lower concentrations of calcium ionophore (which slightly increase Ca2+ uptake), high K+ and nerve growth factor had no detectable effect on c-fos expression. These results show that depolarization does not induce c-fos in astrocytes and suggest that c-fos may play a role in differentiation and proliferation of astrocytes.
Brain Res Mol Brain Res 1990 Jun
PMID:c-fos proto-oncogene expression in astrocytes associated with differentiation or proliferation but not depolarization. 216 2

Various oncogenes or epidermal growth factor (EGF) induce transcription of a 1.9-kilobase RNA (transin RNA) in rat fibroblasts. The induction by EGF can be blocked by cycloheximide. Thus the response of the transin gene to EGF appears to require de novo protein synthesis. Transin RNA induction is specific to EGF, as neither insulin, platelet-derived growth factor, fibroblast growth factor, nor transforming growth factor beta could elicit the same response. However, transforming growth factor beta could block the EGF induction of transin RNA. Whereas the calcium ionophore A23187 and the tumor promoter TPA, either alone or administered together, did not increase transin RNA levels, TPA could synergise with a serum factor to effect such an increase. Dibutyryl cyclic AMP also induced transin RNA. Treatment of cells with the microfilament-disrupting agent cytochalasin B, but not the microtubule-disrupting agent colcemid, resulted in an increase in transin RNA levels, suggesting a role for the cytoskeleton in control of transin gene expression. The transin RNA does not contain repeated sequences and appears to be encoded by a single-copy gene. The protein sequence encoded by the last four exons of the transin gene shows some homology to two regions of the heme-binding protein hemopexin.
Mol Cell Biol 1986 May
PMID:Isolation of the oncogene and epidermal growth factor-induced transin gene: complex control in rat fibroblasts. 243 Dec 84


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