Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Protein kinase assays that use recombinant pp90rsk as a substrate were developed in an attempt to identify growth-regulated enzymes responsible for the phosphorylation and activation of pp90rsk S6 phosphotransferase activity. With this assay we have ientified a pp60v-src-, growth factor-, phorbol ester-, and vanadate-regulated serine/threonine protein kinase activity that is not related to two other cofactor-independent, growth-regulated protein kinases, pp70-S6 protein kinase and pp90rsk. The pp90rsk-protein kinase activity (referred to as rsk-kinase) is also not related to cofactor-dependent signal transducing protein kinases such as the cyclic AMP-dependent protein kinases, members of the protein kinase C family, or other Ca2(+)-dependent protein kinases. In vitro, partially purified rsk-kinase phosphorylates several of the sites (serine and threonine) that are phosphorylated in growth-stimulated cultured cells. A detailed examination of the mitogen-regulated activation kinetics of rsk-kinase and pp90rsk activities demonstrated that they are coordinately regulated. In addition, protein kinase C is not absolutely required for epidermal and fibroblast growth factor-stimulated activation of rsk-kinase, whereas, like pp90rsk, platelet-derived growth factor- and vanadate-stimulated rsk-kinase activity exhibits a greater dependence on protein kinase C-mediated signal transduction. The characterization and future purification of the rsk-kinase(s) will improve our understanding of the early signaling events regulating cell growth.
Mol Cell Biol 1991 Apr
PMID:Coordinate regulation of pp90rsk and a distinct protein-serine/threonine kinase activity that phosphorylates recombinant pp90rsk in vitro. 182 43

Halothane, an anesthetic with marked depressant effects on the circulation, was studied for its ability to inhibit inositol phosphate and Ca2+ signaling evoked by the vasoactive hormone arginine vasopressin (AVP) and Ca2+ responses elicited by platelet-derived growth factor and by thapsigargin in cultured A7r5 vascular smooth muscle cells. Changes in apparent [Ca2+]i were measured using the indicator indo-1 and flow cytometry, whereas inositol phosphate levels were determined using myo-[3H]inositol and column chromatography. Preincubation with clinically relevant concentrations of halothane resulted in dose-dependent depression of [Ca2+]i responses evoked on stimulation with AVP. Halothane (2.0%) inhibited the increases in [Ca2+]i by 34-45%. In cells incubated in Ca(2+)-free medium plus 0.5 mM ethylene glycol bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid, the halothane effect was more marked, with 1.5% halothane inhibiting the responses by approximately 53-61%. However, when Ca2+ influx was stimulated by addition of 5 mM Ca2+ in the continued presence of the agonist, the [Ca2+]i response was inhibited by only 15%, suggesting that release of Ca2+ rather than Ca2+ influx is more sensitive to inhibition by the anesthetic. The effects of halothane on Ca2+ homeostasis are not explained solely by anesthetic-induced depletion of Ca2+ from intracellular stores, because the anesthetic inhibited increases in [Ca2+]i elicited by thapsigargin in cells suspended in Ca(2+)-free medium by only 31%. Halothane inhibited inositol phosphate formation elicited by AVP, suggesting an additional means by which the anesthetic may alter agonist-induced Ca2+ responses. The current results also demonstrate that halothane actions are not specific solely to responses evoked by AVP, which acts via a guanine nucleotide-binding protein-linked signaling pathway, but include responses stimulated by platelet-derived growth factor, an agonist that elevates [Ca2+]i via receptor-latent tyrosine kinase activity. The current results demonstrate that, in vascular smooth muscle cells, halothane alters Ca2+ homeostasis, an action that may underlie the in vivo vasodilator effects of the anesthetic.
Mol Pharmacol 1991 Dec
PMID:Halothane inhibits agonist-induced inositol phosphate and Ca2+ signaling in A7r5 cultured vascular smooth muscle cells. 183 33

A phosphoinositide kinase specific for the D-3 position of the inositol ring, phosphatidylinositol (PI) 3-kinase, associates with activated receptors for platelet-derived growth factor, insulin, and colony-stimulating factor 1, with products of the oncogenes src, fms, yes, crk, and with polyomavirus middle T antigen. Efficient fibroblast transformation by proteins of the abl and src oncogene families requires activation of their protein-tyrosine kinase activity and membrane association via an amino-terminal myristoylation. We have demonstrated that the PI 3-kinase directly associates with autophosphorylated, activated protein-tyrosine kinase variants of the abl protein. In vivo, this association leads to accumulation of the highly phosphorylated products of PI 3-kinase, PI-3,4-bisphosphate and PI-3,4,5-trisphosphate, only in myristoylated, transforming abl protein variants. Myristoylation thus appears to be required to recruit PI 3-kinase activity to the plasma membrane for in vivo activation and correlates with the mitogenicity of the abl protein variants.
Mol Cell Biol 1991 Feb
PMID:Activation of phosphatidylinositol 3-kinase in cells expressing abl oncogene variants. 184 63

Alveolar macrophages (AM) recovered from the lower respiratory tract of individuals with interstitial lung disease (ILD) proliferate at a 2- to 15-fold increased rate (P.B. Bitterman et al. 1984. J. Clin. Invest. 74:460-469). Normal AM stimulated with immune complexes or asbestos release platelet-derived growth factor and insulin-like growth factor-I (IGF-I), and AM activated in vivo in ILD release these growth factors. We evaluated normal unstimulated and activated AM for the receptor for IGF-I to determine if macrophage IGF-I could be involved in the enhanced macrophage proliferation. Although normal AM did not have specific 125I-labeled recombinant IGF-I binding, AM activated by chrysotile asbestos or lipopolysaccharide in vitro or from individuals with ILD had detectable binding that could be inhibited by an anti-IGF-I receptor monoclonal antibody in a dose-dependent fashion. Autoradiography with 125I-labeled recombinant IGF-I revealed binding to the IGF-I receptor on the surface of activated AM, and the percentage of labeled cells was reduced with anti-IGF-I receptor monoclonal antibody or excess unlabeled recombinant IGF-I. Hybridization of total AM RNA to a 32P-labeled IGF-I receptor riboprobe using solution hybridization demonstrated IGF-I receptor mRNA transcripts in AM from an individual with asbestosis, consistent with active expression of the IGF-I receptor gene. In the context of the known role of IGF-I as a growth factor for many cells, these data are consistent with the concept that IGF-I and its receptor may play an important role in the proliferation of AM in the inflamed lower respiratory tract.
Am J Respir Cell Mol Biol 1991 May
PMID:Activated alveolar macrophages express the insulin-like growth factor-I receptor. 185 Jun 6

Quiescent benzo[alpha]pyrene-transformed BALB/c 3T3 fibroblasts (line BP-A31), continue to express 'competence' genes (such as c-myc) and do not require platelet-derived growth factor ('competence' factor) in order to resume the cell division cycle. Insulin-like growth factor I (IGF-I), as well as insulin (at high concentrations, where it interacts with IGF-I-receptors) are potent mitogens in these cells. In contrast with the original non-transformed A31 cell line, we show that insulin/IGF-I (even in the absence of de novo protein synthesis) induce actin transcription in BP-A31 cells. We have verified that 'CArG' boxes, major actin promoter elements, can act as insulin-inducible elements in BP-A31 cells. Insulin-induced actin transcription is also observed in quiescent A31 cells stably transfected with a myc expression vector, suggesting a correlation between constitutive myc expression and insulin-induced actin transcription.
Mol Cell Endocrinol 1991 Mar
PMID:Insulin/insulin-like growth factor I induce actin transcription in mouse fibroblasts expressing constitutively myc gene. 185 Nov 11

The autocrine, paracrine, or systemic growth factors responsible for fetal lung cell growth are not completely defined. The progression-type insulin-like growth factors and epidermal growth factor, or transforming growth factor-alpha acting through the epidermal growth factor receptor, appear to act on the developing lung epithelium. The competence factors that facilitate the actions of progression factors during lung growth are unknown. Fetal rat lung cells in vitro synthesize a platelet-derived growth factor (PDGF)-like polypeptide, which we have hypothesized may play a paracrine role in normal lung development. Slot blot and Northern blot analyses of fetal rat lung mRNA have been used to determine if there is a relationship between expression of message for PDGF-A or PDGF-B chains, or their cognate receptors, and periods of maximal growth during late fetal rat lung development. Whole lung mRNA was extracted on 18, 19, 20, 21, and 22 days of gestation (term = 22 days). The peak of DNA synthesis, as assessed by expression of message for DNA polymerase alpha, histone 3, and the proto-oncogenes c-fos and c-myc, which are stimulated by binding of growth factors including PDGF, occurred during the canalicular stage of lung development on days 19 and 20 of gestation. Expression of message for PDGF-A and PDGF-B chains was low during the pseudoglandular stage on day 18, peaked during the canalicular stage on days 19 and 20, then fell again during the saccular stage at days 21 and 22 of gestation.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1991 Oct
PMID:Platelet-derived growth factor and growth-related genes in rat lung. I. Developmental expression. 191 Aug 22

Normal lung structure is maintained by the presence of mesenchymal cells and their extracellular matrix products. The slow normal turnover of these cells is disrupted in fibrotic disorders, resulting in the in situ accumulation of mesenchymal cells and their extracellular matrix leading to a progressive alveolar wall thickening. Idiopathic pulmonary fibrosis (IPF) is a chronic fibrotic disorder of the lung characterized by a diffuse interstitial and intra-alveolar inflammation dominated by macrophages and polymorphonuclear neutrophils. Evaluation of alveolar macrophages (AM) obtained by bronchoalveolar lavage has previously shown that AM from normal individuals spontaneously release small amounts of platelet-derived growth factor (PDGF), a chemotactic and growth factor for mesenchymal cells, whereas AM from IPF patients spontaneously release increased amounts of biologically active PDGF, suggesting its involvement in mesenchymal cell accumulation. However, other cells such as endothelial cells and vascular smooth muscle cells can also release PDGF in vitro. In order to specify PDGF location in lung parenchyma, open lung biopsies from normal individuals and IPF patients were examined by immunohistochemistry using an anti-PDGF antibody and by in situ hybridization using PDGF A-chain and B-chain gene probes. In normal as well as in fibrotic lung, PDGF was only present in relation with interstitial macrophages but not with any other inflammatory cells or mesenchymal cells. Furthermore, the percentage of PDGF-positive macrophages in IPF was 3-fold increased in comparison to normal lung. In addition, the percentage of PDGF-positive macrophages was the same in fibrotic and nonfibrotic areas of IPF lungs.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1991 Dec
PMID:Presence of platelet-derived growth factor in normal and fibrotic lung is specifically associated with interstitial macrophages, while both interstitial macrophages and alveolar epithelial cells express the c-sis proto-oncogene. 195 75

The steady-state mRNA levels of the proliferating cell nuclear antigen (PCNA) gene are growth regulated. In a previous paper (L. Ottavio, C.-D. Chang, M. G. Rizzo, S. Travali, C. Casadevall, and R. Baserga, Mol. Cell. Biol. 10:303-309, 1990), we reported that introns (especially intron 4) participate in growth regulation of the PCNA gene. We have now investigated the role of the 5'-flanking sequence of the human PCNA gene stably transfected into BALB/c 3T3 cells. Promoters of different lengths (from -2856 to -45 upstream of the cap site) were tested. All promoters except the AatII promoter (-45), including a short HpaII promoter (-210), were sufficient for a response to serum, platelet-derived growth factor, and to a lesser extent epidermal growth factor. No construct responded to insulin or platelet-poor plasma. The AatII promoter had little detectable activity. Transcriptional activity was also determined in BALB/c 3T3 cells carrying various constructs of the human PCNA gene by two methods: run-on transcription and reverse transcription-polymerase chain reaction (the latter measuring the heterogeneous nuclear RNA [hnRNA] steady-state levels). There was very little difference in the rate of transcription of the PCNA gene between G0 cells and serum-stimulated cells, although the levels of hnRNA were much higher after stimulation. In G0 cells carrying a human PCNA gene without introns 4 and 5, both transcription rate and hnRNA levels were high. Together with data on the mRNA half-life, these results suggest a posttranscriptional component in the regulation of PCNA mRNA levels after serum stimulation but a transcriptional regulation by intron 4.
Mol Cell Biol 1990 Jul
PMID:Transcriptional and posttranscriptional regulation of the proliferating cell nuclear antigen gene. 197 40

The human uterus repeatedly exhibits cyclic biochemical and cytological changes during the reproductive period of life. These changes are the result of a well-characterized endocrine network involving the hypothalamus, pituitary, and ovary. The exact nature of the mechanism(s) by which the sex steroids act on the uterus remains to be elucidated. Possible local mediators of hormonal action on the uterus include polypeptide growth factors. Using the method of RNA transfer blot hybridization, we have analyzed tissue samples from the cycling human endometrium and tissue samples of human myometrium and myometrial benign tumor (leiomyoma) for the presence of platelet-derived growth factor (PDGF) and insulin-like growth factor (IGF) RNA. All the uterine tissues examined possessed RNA for PDGF-B chain and IGF-I and -II. Two transcripts were observed for PDGF-B chain, four were observed for IGF-I, and eight were observed for IGF-II. Overall, the relative abundance of PDGF-B chain RNA was consistent in all of the uterine tissues examined. In contrast, IGF RNA relative abundance varied. IGF-I RNA was highest in late proliferative stage endometrium, and IGF-II RNA was highest in early proliferative stage endometrium. Both IGF-I and IGF-II RNAs were greater in amount of leiomyoma than in myometrium. The increased IGF-I RNA in late proliferative-stage human endometrium correlates with the known elevation of estradiol secretion by the ovary and the increased concentration of uterine estradiol receptors during this stage of the menstrual cycle.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Reprod Dev 1990 Oct
PMID:Expression of the insulin-like and platelet-derived growth factor genes in human uterine tissues. 197 7

We have examined the expression of mRNAs for epidermal growth factor (EGF), transforming growth factor-alpha (TGF-alpha), EGF receptor (EGFR), PDGF-A chain (PDGFA), PDGF-B chain (PDGFB) and PDGF receptor (PDGFR) genes in seven human colorectal carcinoma cell lines and 18 human colorectal carcinomas. In surgically resected specimens of the 18 colorectal tumors, TGF-alpha, EGFR, PDGFA, PDGFB and PDGFR mRNAs were detected at various levels in 15 (83%), 9 (50%), 18 (100%), 8 (44%) and 12 (67%), respectively. They were also detected in normal tissues. Interestingly, EGF mRNA was detected in only five (28%) of the tumors, but not in normal mucosa. Expression of EGF was also confirmed immunohistochemically in tumor cells. Of the five tumors expressing EGF, four expressed EGFR mRNA and showed a tendency to invade veins and lymphatics. All the colorectal carcinoma cell lines expressed TGF-alpha mRNA, and five cell lines expressed EGFR mRNA simultaneously. Production of TGF-alpha protein by DLD-1 and CoLo320DM cells was confirmed by TGF-alpha specific monoclonal antibody binding assay. The spontaneous 3H-thymidine uptake by DLD-1 was suppressed by an anti-TGF-alpha monoclonal antibody. PDGFA and PDGFB mRNA were also expressed in four cell lines, but PDGFR and EGF mRNA was not detected. These results suggest that human colorectal carcinomas express multi-loops of growth factors and that TGF-alpha produced by tumor cells functions as an autocrine growth factor in human colonic carcinoma.
Virchows Arch B Cell Pathol Incl Mol Pathol 1990
PMID:Expression of several growth factors and their receptor genes in human colon carcinomas. 198 Jul 64


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