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Query: UNIPROT:P06889 (Mol)
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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 congruent to 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.
Mol Cell Biol 1990 Dec
PMID:The NGFI-B protein, an inducible member of the thyroid/steroid receptor family, is rapidly modified posttranslationally. 224 65

A TSH receptor (TSH-R) cDNA has been isolated from a human thyroid lambda GT11 library. Unexpectedly, several cDNAs encoding the human LH/CG receptor (LH/CG-R), previously thought to be expressed solely in gonadal cells, were also isolated from the thyroid library. The receptors are structurally related, consisting of a signal sequence, a large extracellular amino terminal domain, seven membrane spanning domains, and a short carboxyl-terminal portion. The TSH-R is encoded by a single 4.2 kilobase mRNA specific to the thyroid. Introns were not present in any hTSH-R cDNAs examined, however, sequencing of several LH/CG-R cDNAs and RNase protection experiments demonstrated that the majority of hLH/CG-R mRNA in the thyroid is incompletely spliced. Consequently, tissue-specific splicing may be an important step in the regulation of the glycoprotein hormone receptor family.
Mol Endocrinol 1990 Aug
PMID:Isolation of TSH and LH/CG receptor cDNAs from human thyroid: regulation by tissue specific splicing. 229 30

The silent mating-type genes (HML and HMR) of Saccharomyces cerevisiae are kept under negative transcriptional control by the trans-acting products of the four MAR/SIR loci. MAR/SIR gene mutations result in the simultaneous derepression of HML and HMR gene expression. The sum1-1 mutation was previously identified as an extragenic suppressor of mutations in MAR1 (SIR2) and MAR2 (SIR3). As assayed genetically, sum1-1 is capable of restoring repression of silent mating-type information in cells containing mar1 or mar2 null mutations. We show here that the mating-type phenotype associated with sum1-1 results from a dramatic reduction in the steady-state level of HML and HMR gene transcripts. At the same time, the sum1-1 mutation has no significant effect on the level of each of the four MAR/SIR mRNAs.
Mol Cell Biol 1990 Jan
PMID:The sum1-1 mutation affects silent mating-type gene transcription in Saccharomyces cerevisiae. 240 45

ABFI (ARS-binding protein I) is a yeast protein that binds specific DNA sequences associated with several autonomously replicating sequences (ARSs). ABFI also binds sequences located in promoter regions of some yeast genes, including DED1, an essential gene of unknown function that is transcribed constitutively at a high level. ABFI was purified by specific binding to the DED1 upstream activating sequence (UAS) and was found to recognize related sequences at several other promoters, at an ARS (ARS1), and at a transcriptional silencer (HMR E). All ABFI-binding sites, regardless of origin, provided weak UAS function in vivo when examined in test plasmids. UAS function was abolished by point mutations that reduced ABFI binding in vitro. Analysis of the DED1 promoter showed that two ABFI-binding sites combine synergistically with an adjacent T-rich sequence to form a strong constitutive activator. The DED1 T-rich element acted synergistically with all other ABFI-binding sites and with binding sites for other multifunctional yeast activators. An examination of the properties of sequences surrounding ARS1 left open the possibility that ABFI enhances the initiation of DNA replication at ARS1 by transcriptional activation.
Mol Cell Biol 1990 Mar
PMID:A yeast ARS-binding protein activates transcription synergistically in combination with other weak activating factors. 240 70

The action of 10-deazaaminopterin, its 10-alkyl derivatives, and their polyglutamates against thymidylate synthase (TMPS) from human acute myeloblastic leukemia was examined. Comparison of aminopterin with methotrexate showed that the methylation of the N10-position (methotrexate) increased the inhibitory effect of aminopterin on TMPS. In contrast, alkylation of the 10-position of 10-deazaaminopterin decreased inhibition of TMPS, and the 50% inhibitory concentration values were progressively higher, in the order 10,10-dimethyl-, 10-methyl-, and 10-ethyl-derivatives. The addition of gamma-glutamyl moieties to both 10-deazaaminopterin, and one of its alkylated analogs, 10-ethyl-10-deazaaminopterin, enhanced inhibition. The maximum inhibition was achieved with the addition of three glutamyl moieties to 10-deazaaminopterin and two glutamyl moieties to 10-ethyl-10-deazaaminopterin, respectively. Thus, 10-deazaaminopterin-tetraglutamate was 138-fold and 10-ethyl-10-deazaaminopterin-triglutamate was greater than 51-fold more active than their respective parental compound. The compounds 10-deazaaminopterin and its polyglutamates, 10-methyl- and 10,10-dimethyl-analogs, inhibited TMPS in a noncompetitive fashion with respect to 5,10-methylene-tetrahydropteroylglutamate. Ki values for the monoglutamates were 220 microM, 310 microM, and 225 microM, respectively. In contrast, 10-ethyl-10-deazaaminopterin and its polyglutamates inhibited TMPS in a competitive fashion with a Ki value of 410 microM for the monoglutamate. With 5,10-methylene-tetrahydropteroylpentaglutamate as a substrate, 10-deazaaminopterin and its polyglutamates behaved as mixed type inhibitors, and 10-ethyl-10-deazaaminopterin, monoglutamate and diglutamate, behaved as noncompetitive inhibitors, whereas its pentaglutamate behaved as a mixed-type inhibitor. These results suggest that the addition of gamma-glutamyl moieties to the substrate also caused the change in the mode of inhibitory action of these compounds. These findings also show that both replacement of the N10-position of the 4-aminopteroyl structure with a methylene group and its alkylation caused interesting and unexpected changes in the structure-activity relationships and the mode of action for these 4-aminopteroyl antifolates as inhibitors of TMPS, which may be therapeutically relevant.
Mol Pharmacol 1986 Aug
PMID:Inhibitory action of 10-deazaaminopterins and their polyglutamates on human thymidylate synthase. 242 68

Ubiquitin is a multifunctional 76-amino-acid protein which plays critical roles in many aspects of cellular metabolism. In Caenorhabditis elegans, the major source of ubiquitin RNA is the polyubiquitin locus, UbiA. UbiA is transcribed as a polycistronic mRNA which contains 11 tandem repeats of ubiquitin sequence and possesses a 2-amino-acid carboxy-terminal extension on the final repeat. The UbiA locus possesses several unusual features not seen in the ubiquitin genes of other organisms studied to date. Mature UbiA mRNA acquires a 22-nucleotide leader sequence via a trans-splicing reaction involving a 100-nucleotide splice leader RNA derived from a different chromosome. UbiA is also unique among known polyubiquitin genes in containing four cis-spliced introns within its coding sequence. Thus, UbiA is one of a small class of genes found in higher eucaryotes whose heterogeneous nuclear RNA undergoes both cis and trans splicing. The putative promoter region of UbiA contains a number of potential regulatory elements: (i) a cytosine-rich block, (ii) two sequences resembling the heat shock regulatory element, and (iii) a palindromic sequence with homology to the DNA-binding site of the mammalian steroid hormone receptor. The expression of the UbiA gene has been studied under various heat shock conditions and has been monitored during larval moulting and throughout the major stages of development. These studies indicate that the expression of the UbiA gene is not inducible by acute or chronic heat shock and does not appear to be under nutritional or developmental regulation in C. elegans.
Mol Cell Biol 1989 Jan
PMID:UbiA, the major polyubiquitin locus in Caenorhabditis elegans, has unusual structural features and is constitutively expressed. 253 20

A cDNA encoding a novel member of the thyroid/steroid hormone receptor superfamily, called Rev-ErbA alpha, has been isolated from a rat GH3 cell library. Rev-ErbA alpha is an approximately 56-kilodalton protein most similar in structure to the thyroid hormone receptor (c-erbA) and the retinoic acid receptor, but it does not bind either thyroid hormone or retinoic acid. The mRNA encoding Rev-ErbA alpha is present in many tissues and is particularly abundant in skeletal muscle and brown fat. A genomic DNA fragment containing the entire Rev-ErbA alpha cDNA sequence was isolated and characterized. Remarkably, this DNA fragment also contained a portion of the c-erbA alpha gene. r-erbA alpha-1 and r-erbA alpha-2 are alternative splice products of the c-erbA alpha gene and are members of the receptor superfamily. The genes encoding Rev-ErbA alpha and r-erbA alpha-2 overlap, with their coding strands oriented opposite one another. A 269-base-pair segment of the bidirectionally transcribed region is exonic in both the Rev-ErbA alpha and r-erbA alpha-2 genes, resulting in complementary mRNAs. Thus, through alternative splicing and opposite-strand transcription, a single genomic locus codes for three different members of the thyroid/steroid hormone receptor superfamily. Potential implications of this unusual genomic arrangement are discussed.
Mol Cell Biol 1989 Mar
PMID:A novel member of the thyroid/steroid hormone receptor family is encoded by the opposite strand of the rat c-erbA alpha transcriptional unit. 254 65

Plasmodium falciparum was shown to synthesize pteroylpolyglutamate de novo from guanosine 5'-triphosphate (GTP), p-aminobenzoate (PABA), and L-glutamate (L-Glu). The parasite also had the capacity to synthesize pteroylpolyglutamate from both intact and degradation moieties (p-aminobenzoylglutamate and pterin-aldehyde) of exogenous folate added into the growth medium. The major product was identified as 5-methyl-tetrahydroteroylpentaglutamate following exposure to pteroylpolyglutamate hydrolase and oxidative degradation of the C9-N10 bond in the molecule and identification of products by reversed-phase high performance liquid chromatography. Inhibition of pteroylpentaglutamate synthesis from the radiolabelled metabolic precursors (GTP, PABA, L-Glu) and folate by the antifolate antimalarials, pyrimethamine and sulfadoxine at therapeutic concentrations, may suggest the existence of a unique biosynthetic pathway in the malaria parasite.
Mol Biochem Parasitol 1989 Jan 01
PMID:De novo and salvage biosynthesis of pteroylpentaglutamates in the human malaria parasite, Plasmodium falciparum. 264 36

The replication of putative replication origins (ARS elements) was examined for 200 kilobases of chromosome III of Saccharomyces cerevisiae. By using synchronous cultures and transfers from dense to light isotope medium, the temporal pattern of mitotic DNA replication of eight fragments that contain ARSs was determined. ARS elements near the telomeres replicated late in S phase, while internal ARS elements replicated in the first half of S phase. The results suggest that some ARS elements in the chromosome may be inactive as replication origins. The actively expressed mating type locus, MAT, replicated early in S phase, while the silent cassettes, HML and HMR, replicated late. Unexpectedly, chromosome III sequences were found to replicate late in G1 at the arrest induced by the temperature-sensitive cdc7 allele.
Mol Cell Biol 1989 Oct
PMID:Time of replication of ARS elements along yeast chromosome III. 268 53

The alpha 2 protein, the product of the MAT alpha 2 cistron, represses various genes specific to the a mating type (alpha 2 repression), and when combined with the MATa1 gene product, it represses MAT alpha 1 and various haploid-specific genes (a1-alpha 2 repression). One target of a1-alpha 2 repression is RME1, which is a negative regulator of a/alpha-specific genes. We have isolated 13 recessive mutants whose a1-alpha 2 repression is defective but which retain alpha 2 repression in a genetic background of ho MATa HML alpha HMRa sir3 or ho MAT alpha HMRa HMRa sir3. These mutations can be divided into three different classes. One class contains a missense mutation, designated hml alpha 2-102, in the alpha 2 cistron of HML, and another class contains two mat alpha 2-202, in the MAT alpha locus. These three mutants each have an amino acid substitution of tyrosine or acid substitution of tyrosine or phenylalanine for cysteine at the 33rd codon from the translation initiation codon in the alpha 2 cistron of HML alpha or MAT alpha. The remaining 10 mutants make up the third class and form a single complementation group, having mutations designated aar1 (a1-alpha 2 repression), at a gene other than MAT, HML, HMR, RME1, or the four SIR genes. Although a diploid cell homozygous for the aarl and sir3 mutations and for the MATa, HML alpha, and HMRa alleles showed alpha mating type, it could sporulate and gave rise to asci containing four alpha mating-type spores. These facts indicate that the domain for alpha2 repression is separable from that for a1-alpha2 protein interaction or complex formation in the alpha2 protein and that an additional regulation gene, AAR1, is associated with the a1-alpha2 repression of the alpha1 cistron and haploid-specific genes.
Mol Cell Biol 1989 Oct
PMID:Mating-type control in Saccharomyces cerevisiae: isolation and characterization of mutants defective in repression by a1-alpha 2. 268 55


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