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The NGFI-B Protein, an Inducible Member of the Thyroid/Steroid Receptor Family, Is Rapidly Modified Posttranslationally TIMOTHY J

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The NGFI-B Protein, an Inducible Member of the Thyroid/Steroid Receptor Family, Is Rapidly Modified Posttranslationally TIMOTHY J MOLECULAR AND CELLULAR BIOLOGY, Dec. 1990, p. 6454 6459 Vol. 10, No. 12 0270-7306/90/126454-06$02.00/0 Copyright © 1990, American Society for Microbiology The NGFI-B Protein, an Inducible Member of the Thyroid/Steroid Receptor Family, Is Rapidly Modified Posttranslationally TIMOTHY J. FAHRNER, STEVEN L. CARROLL, AND JEFFREY MILBRANDT* Departments ofPathology and Internal Medicine, Division of Laboratory Medicine, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110 Received 23 July 1990/Accepted 12 September 1990 The NGFI-B gene is rapidly activated by a variety of stimuli that induce cells to differentiate or proliferate. It encodes a protein with a predicted molecular mass of ==61 kDa and is a member of the thyroid/steroid hormone receptor gene family. To characterize this protein, monoclonal antibodies were raised against a bacterial TrpE-NGFI-B fusion protein that encompasses a large portion (Glu-410 to Leu-527) of the carboxy-terminal domain of NGFI-B. These antibodies detected a protein that was rapidly synthesized in response to nerve growth factor (NGF) and migrated as a broad band on sodium dodecyl sulfate- polyacrylamide gels with an apparent molecular mass that ranged from 63 to 88 kDa. Pulse-chase analysis demonstrated that NGFI-B was rapidly posttranslationally modified and was a short-lived protein. NGFI-B was found to be a phosphorylated protein, and the multiple NGFI-B species coalesced into a single, more rapidly migrating species when treated with alkaline phosphatase. PC12 cells grown in the absence of NGF contained low levels of NGFI-B that was underphosphorylated. Epidermal growth factor, phorbol ester, and the calcium ionophore A23187 stimulated the synthesis of NGFI-B that was composed largely of underphosphorylated, rapidly migrating species. In contrast, basic fibroblast growth factor, which promotes differentiation of PC12 cells, induced the synthesis of NGFI-B species similar to those synthesized in response to NGF treatment. The underphosphorylated NGFI-B found in uninduced PC12 cells was found only in the nucleus, whereas NGFI-B in NGF-stimulated PC12 cells was present in approximately equal quantities in the cytoplasm and nucleus. Consistent with the cellular distribution observed in nonstimulated PC12 cells, the highly phosphorylated species were predominantly cytoplasmic whereas the more rapidly migrating forms were nuclear. The cellular response to growth factors includes the acti- chromocytoma cells (21); its mouse homolog (nur77) was vation of a set of genes termed early-response genes (15). identified similarly in serum-stimulated fibroblasts (11). In These genes are characterized by several features: their PC12 cells, the 2.4-kb NGFI-B mRNA is normally present at transcription is activated within minutes of growth factor very low levels, but upon administration of NGF, the gene is administration, their induction is not dependent on de novo transcriptionally activated (37). The amount of NGFI-B protein synthesis, and their corresponding mRNAs and the mRNA increases dramatically within 30 min, but this in- proteins they encode are short-lived. Most early-response crease is very transient, with levels returning to base line genes have been isolated by differential hybridization tech- within 4 h. The NGFI-B gene is expressed at relatively high niques, and the functions of these genes are therefore largely levels in the adult rat brain, adrenal gland, and muscle (M. unknown. However, some (e.g., c-fos and c-jun) are known Watson and J. Milbrandt, Development, in press). As has to regulate transcription, and others are inferred to have been observed for a number of early-response genes, the similar functions because they share sequence homology level of NGFI-B mRNA rapidly and dramatically increases with other transcriptional regulators. These include the in the brain following Metrazol-induced seizures (37). genes encoding the zinc finger proteins NGFI-A (20) (also By virtue of its sequence similarity to other ligand-depen- called and Egrl [35], ztf7268 [5], Krox 24 [16]), Krox 20 dent transcriptional regulators, NGFI-B probably plays an (4)/Egr2 (13), and NGFI-B (21)Inur77 (11). Like many early- important role in regulating the cellular response to growth response genes, the NGFI-B gene is activated in a variety of factors. At present, little is known about the protein encoded cell types by multiple, diverse stimuli, including growth by the NGFI-B cDNA. In this we describe seizure calcium and study, the factors, induction, ionophores, phorbol production of antibodies to the NGFI-B protein and the esters. Thus, NGFI-B may function as a nuclear messenger subsequent characterization of NGFI-B biosynthesis, post- of the signal transduction process and represent, along with translational modification, and cellular location. NGFI-B the products of other early-response genes, the primary was detected as a heterogeneous collection of protein spe- effectors of the cellular response to environmental changes. cies ranging in apparent molecular mass from 63 to 88 kDa. The nucleotide sequence of the NGFI-B cDNA predicts a Pulse-chase analysis revealed that NGFI-B is a short-lived protein of 61 kDa that is closely related to members of the protein that undergoes rapid and extensive modification via thyroid/steroid receptor gene family. Each of these receptor phosphorylation in NGF-stimulated and, to a lesser degree, proteins functions as a ligand-dependent, transcriptional basic fibroblast that is growth factor (bFGF)-stimulated PC12 cells. regulator activated by binding to its respective hor- Other agents, including epidermal growth factor (EGF), mone ligand. The NGFI-B gene was identified by virtue of its phorbol ester, and the calcium ionophore A23187 induce nerve factor in rat induction by growth (NGF) PC12 pheo- NGFI-B synthesis but do not promote its phosphorylation. Cellular localization studies demonstrated that NGFI-B is found in approximately equal amounts in the cytoplasm and * Corresponding author. nucleus of NGF-stimulated PC12 cells. 6454 VOL. 10, 1990 POSTTRANSLATIONAL MODEL OF NGFI-B 6455 MATERIALS AND METHODS intestinal alkaline phosphatase in phosphatase buffer (12.5 mM Tris [pH 7.91, 6 mM MgCl2, 5% glycerol, 0.05% Nonidet Materials. NGF was the gift of Eugene Johnson (Depart- P-40, 50 mM KCI) for 30 min at 30°C, followed by a second ment of Pharmacology, Washington University School of incubation with 20 U of bacterial alkaline phosphatase for 30 Medicine). The pATH plasmids were the gift of A. Tza- min at 68°C in the same buffer. When indicated, phosphatase goloff, Columbia University. [35S]methionine (Translabel) inhibitors (100 mM NaF, 10 mM Na4P207, and 1 mM and 32Pi were obtained from ICN Biomedicals (Irvine, NaVO4) were added. Calif.). Leupeptin, 0-12-tetradecanoylphorbol-13-acetate Cell fractionation. Nuclear and cytoplasmic fractionation (TPA), A23187, and Pansorbin were obtained from Calbio- was done essentially as described by Challberg and Kelly chem (San Diego, Calif.). Calf intestinal alkaline phos- (3). Cell lysis was confirmed by examination under a phase- phatase was purchased from Boehringer-Mannheim (India- contrast microscope. After cell lysis, the nuclei were pel- napolis, Ind.). Bacterial alkaline phosphatase and restriction leted by centrifugation at 2,000 x g for 5 min. The cytosolic enzymes were obtained from New England BioLabs (Bev- fraction was decanted and brought to 0.1% sodium dodecyl erly, Mass.). All reagents, unless otherwise indicated, were sulfate (SDS). The nuclear pellet was homogenized in RIPA purchased from Sigma (St. Louis, Mo.). buffer equal in volume to the cytosolic fraction. Cell culture. PC12 cells were grown in Dulbecco modified Eagle medium supplemented with 10% fetal calf serum and RESULTS 5% horse serum (19). The DG44 CHO cell line was grown in F12 medium supplemented with 10% fetal calf serum (36). Production and characterization of anti-NGFI-B antibodies. Production of bacterial fusion proteins. A fusion protein To characterize the NGFI-B protein, we produced two containing the bacterial TrpE protein and a portion of MAbs (1A8 and 2E1) to a bacterial fusion protein (B1440) NGFI-B was produced by using the pATH expression vector containing a portion of NGFI-B that encodes part of the (10). This construct (pB1440) was made by ligating a 353- putative ligand-binding domain of this receptor. These anti- nucleotide Sacl fragment (nucleotides 1440 to 1793 of the NGFI-B MAbs were shown to immunoprecipitate NGFI-B NGFI-B cDNA) into pATH 11. Escherichia coli DHSa cells produced in a reticulocyte lysate system primed with bearing this plasmid produced a protein of the predicted NGFI-B RNA and by CHO cells transfected with an molecular mass when induced by tryptophan depletion and NGFI-B expression vector (data not shown). The specificity addition of 25 ,ug of indole acrylic acid per ml. The B1440 of these MAbs was confirmed by blocking experiments with fusion protein, which contains NGFI-B residues from Glu- the B1440 fusion protein (see Materials and Methods). 410 to Leu-527, was purified by preparing an insoluble NGFI-B is rapidly synthesized and modified in PC12 cells fraction from the bacterial lysate (39). after NGF administration. In the initial characterization of Production of MAbs. Female BALb/cJ mice (Jackson the MAbs, we noticed that NGFI-B produced in vitro Laboratory) were immunized with 30 ,ug of B1440 fusion migrated more rapidly on SDS-polyacrylamide gels than did protein. The mice were injected subcutaneously once each that synthesized by the transfected CHO cells. This obser- week for 3 weeks and then injected intraperitoneally every vation suggested that NGFI-B was posttranslationally mod- month for 4 months. Three days prior to fusion, 20 ,ug of ified and led us to examine the initial induction of NGFI-B in B1440 fusion protein was injected intravenously. The ani- PC12 cells treated with NGF. To examine the synthesis of mals were sacrificed, spleen cells were harvested, and hy- NGFI-B protein after NGF stimulation, PC12 cells were bridomas were generated by using the nonsecreting my- incubated in the presence of [35S]methionine and treated eloma cell line P3X63AG8.6.5.3 (34).
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