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The effect of mengovirus infection on the extent of phosphorylation of histone H1 was studied in Ehrlich ascites tumor cells. After prelabeling of the nuclear protein with [32P] orthophosphate, the excorporation of radioactivity was followed as a function of time postinfection. Employing high-resolution polyacrylamide gradient slab gel electrophoresis and autoradiography, it was found that, compared to a relatively slow turnover of phosphate groups in histone H1 in mock-infected cells, in mengovirus-infected cells the excorporation of radiolabel from histone H1 was significantly enhanced. In the latter case, the decrease of histone-bound radioactivity was paralleled by a reduction of the band multiplicity in the histone H1 region of the electrophoresis profile. It was also shown that the microheterogeneity in the histone H1 complements isolated at various times postinfection was reduced to the same basal 3-band level by incubation of the nuclear protein fractions in the presence of alkaline phosphatase. After this treatment, the band multiplicity equaled that found in histone H1 from stationary cells.
Mol Biol Rep 1978 Oct 16
PMID:Dephosphorylation of histone H1 after mengovirus infection of Ehrlich ascites tumor cells. 21 3

The retinoblastoma tumor suppressor gene product (pRb) is a nuclear protein subject to cell cycle-regulated hyperphosphorylation. I constructed a recombinant vaccinia virus vector that expresses both the underphosphorylated and hyperphosphorylated forms of pRb and purified the recombinant protein by using immunoaffinity chromatography directed toward a synthetic carboxy-terminal epitope. To investigate the hypothesis that hyperphosphorylation of pRb is a means of controlling its growth-regulating activity, I tested purified pRb for the ability to be reincorporated into pRb-deficient nuclei in vitro. The underphosphorylated form of pRb efficiently reassociated with nuclei, but the hyperphosphorylated form remained soluble in this assay. Nuclear binding of pRb was enhanced by phosphatase treatment and reduced by phosphorylation of pRb effected by using a preparation of the cell cycle-regulatory kinase p34cdc2. Mutant-encoded proteins with altered E1A-binding domains failed to bind to nuclei. Pretreatment of target nuclei with nucleases and high-salt extraction did not alter the specificity of binding for underphosphorylated pRb. These observations demonstrate that hyperphosphorylation of pRb can regulate its interaction with nuclei, supporting the hypothesis that hyperphosphorylation controls the growth-regulatory activities of pRb. Further, at least one target of pRb binding appears to be an integral component of the nuclear envelope.
Mol Cell Biol 1992 Feb
PMID:Nuclear binding of purified retinoblastoma gene product is determined by cell cycle-regulated phosphorylation. 131 Jan 46

We have previously reported on the presence of a CArG motif at -100 in the Rous sarcoma virus long terminal repeat which binds an avian nuclear protein termed enhancer factor III (EFIII) (A. Boulden and L. Sealy, Virology 174:204-216, 1990). By all analyses, EFIII protein appears to be the avian homolog of the serum response factor (SRF). In this study, we identify a second CArG motif (EFIIIB) in the Rous sarcoma virus long terminal repeat enhancer at -162 and show only slightly lower binding affinity of the EFIII/SRF protein for this element in comparison with c-fos serum response element (SRE) and EFIII DNAs. Although all three elements bind the SRF with similar affinities, serum induction mediated by the c-fos SRE greatly exceeds that effected by the EFIII or EFIIIB sequence. We postulated that this difference in serum inducibility might result from binding of factors other than the SRF which occurs on the c-fos SRE but not on EFIII and EFIIIB sequences. Upon closer inspection of nuclear proteins which bind the c-fos SRE in chicken embryo fibroblast and NIH 3T3 nuclear extracts, we discovered another binding factor, SRE-binding protein (SRE BP), which fails to recognize EFIII DNA with high affinity. Competition analyses, methylation interference, and site-directed mutagenesis have determined that the SRE BP binding element overlaps and lies immediately 3' to the CArG box of the c-fos SRE. Mutation of the c-fos SRE so that it no longer binds SRE BP reduces serum inducibility to 33% of the wild-type level. Conversely, mutation of the EFIII sequence so that it binds SRE BP with high affinity results in a 400% increase in serum induction, with maximal stimulation equaling that of the c-fos SRE. We conclude that binding of both SRE BP and SRF is required for maximal serum induction. The SRE BP binding site coincides with the recently reported binding site for rNF-IL6 on the c-fos SRE. Nonetheless, we show that SRE BP is distinct from rNF-IL6, and identification of this novel factor is being pursued.
Mol Cell Biol 1992 Oct
PMID:Maximal serum stimulation of the c-fos serum response element requires both the serum response factor and a novel binding factor, SRE-binding protein. 132 62

Sucrase-isomaltase (SI) is an enterocyte-specific gene which exhibits a complex pattern of expression during intestinal development and in the adult intestinal mucosa. In the studies described in this report, we demonstrate that enterocyte-specific transcription of the SI gene is regulated by an evolutionarily conserved promoter that extends approximately 180 bp upstream of the transcription start site. DNase I footprint analysis allowed the identification of three nuclear protein-binding sites within the SI promoter (SIF1, SIF2, and SIF3 [SI footprint]), each of which acted as a positive regulatory element for transcription in intestinal cell lines. SIF1 was shown to bind nuclear protein complexes present in primary mouse small intestinal cell and in an intestinal cell line (Caco-2). However, SIF1-binding proteins were absent in a variety of other epithelial and nonepithelial cells. In vitro mutagenesis experiments demonstrated that the SIF1 site is required for high-level promoter activity in intestinal cells. The SIF3 element formed prominent binding complexes with intestinal and liver nuclear extracts, whereas nuclear proteins from other epithelial and nonepithelial cells formed weaker complexes of different mobilities. The SIF2 element bound nuclear proteins in a pattern similar to that of SIF3, and cross-competition studies suggested that SIF2 and SIF3 may bind the same nuclear proteins. Taken together, these data have allowed the identification of novel DNA-binding proteins that play an important role in regulating intestine-specific transcription of the SI gene.
Mol Cell Biol 1992 Aug
PMID:Novel DNA-binding proteins regulate intestine-specific transcription of the sucrase-isomaltase gene. 137 30

The nature of a DNA element located in the -100 to -85 region of the rat PRL gene has been characterized. Previous studies demonstrated that this region may contribute to basal and hormonally regulated expression of the PRL gene. As this region contains a sequence with similarity to a consensus cAMP-responsive element (CRE), a possible role for the cAMP response element binding protein (CREB) has been explored. A point mutation which made the PRL CRE-like sequence less like a consensus CRE had little effect on basal or cAMP-stimulated expression of a PRL-luciferase reporter gene. DNase footprint studies demonstrated that the proximal region of the PRL gene does not contain a high affinity CREB binding site. Mobility shift experiments demonstrated that the major GH3 nuclear protein which interacts with the -100 to -85 region of the PRL gene in vitro is not CREB. Transfection of a dominant inhibitor of CREB action had little or no effect on expression of an indicator gene containing the PRL proximal region. Thus, the PRL proximal region does not contain a high affinity CREB binding site, and it is unlikely that CREB plays a major role in expression of the PRL gene. The functional capabilities of the -100 to -85 region of the PRL gene were then tested in a transfection assay. Synthetic multimers of this region were found to be sufficient to permit a transcriptional response to cAMP or TRH in GH3 cells and cAMP in Rat-1 cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Endocrinol 1992 Jun
PMID:Characterization of a non-tissue-specific, 3',5'-cyclic adenosine monophosphate-responsive element in the proximal region of the rat prolactin gene. 138 49

We have isolated mutants of the yeast Saccharomyces cerevisiae that are defective in localization of nuclear proteins. Chimeric proteins containing the nuclear localization sequence from SV40 large T-antigen fused to the N-terminus of the mitochondrial F1 beta-ATPase are localized to the nucleus. Npl (nuclear protein localization) mutants were isolated by their ability to grow on glycerol as a consequence of no longer exclusively targeting SV40-F1 beta-ATPase to the nucleus. All mutants with defects in localization of nucleolar proteins and histones are temperature sensitive for growth at 36 degrees C. Seven alleles of NPL3 and single alleles of several additional genes were isolated. NPL3 mutants were studied in detail. NPL3 encodes a nuclear protein with an RNA recognition motif and similarities to a family of proteins involved in RNA metabolism. Our genetic analysis indicates that NPL3 is essential for normal cell growth; cells lacking NPL3 are temperature sensitive for growth but do not exhibit a defect in localization of nuclear proteins. Taken together, these results indicate that the mutant forms of Npl3 protein isolated by this procedure are interfering with nuclear protein uptake in a general manner.
Mol Biol Cell 1992 Aug
PMID:A mutant nuclear protein with similarity to RNA binding proteins interferes with nuclear import in yeast. 139 78

A certain nucleotide sequence in the promoter region of Vicia faba rRNA genes that specifically binds to a nuclear protein fraction has been identified by using a gel retardation assay and DNase I footprinting technique. The binding site of this protein fraction is located about 60 bp upstream from the initiation site of the pre-rRNA transcript. This location does not correspond with previously reported results on maize rRNA genes. However, both of the binding sites share a bi-partite consensus sequence, TAT-G(N)xCAGG. Methylation interference experiments show that two G residues in TATG and the complementary strand of CAGG are important for specific DNA-protein interaction. Furthermore, competition analyses using point-mutated synthetic DNAs show that two G residues in CAGG are essential for this interaction. Similar sequences are found in promoter regions of other plant and animal rRNA genes. We suggest that these sequences may be a cis-control element commonly involved in rRNA transcription.
Plant Mol Biol 1992 Dec
PMID:Characterization of nucleotide sequences that interact with a nuclear protein fraction in rRNA gene of Vicia faba. 146 30

We have previously shown that a trans-acting protein produced in some tissue culture cells positively control the transcriptional activity directed by the mouse p12 promoter. This nuclear protein exerts its positive activity by interacting with a regulatory sequence designated p12.A and located between the TATA and CCAAT box elements on the p12 gene promoter. Using DNase I and dimethyl sulfate methylation interference footprinting techniques coupled with gel retardation assays, we found evidence that the protein which binds to the p12.A element is the well-known transcription factor Sp1. Mutational analysis in transient transfection assays confirmed the positive activity exerted by this protein in every cell line tested. In agreement with this observation, we detected a p12.A-Sp1 binding activity in nuclear extracts prepared from all cell lines used. However, a similar binding activity could not be detected in a number of nuclear extracts prepared from normal mouse tissues. In this report, we provide the evidence that the lack of Sp1-binding activity results from the degradation of Sp1 in the kidney, liver, and pancreas of the mouse.
Mol Cell Biol 1992 Sep
PMID:Transcription of the mouse secretory protease inhibitor p12 gene is activated by the developmentally regulated positive transcription factor Sp1. 150 85

The proopiomelanocortin (POMC) gene is highly expressed in adult mouse pituitary anterior lobe corticotrophs and intermediate lobe melanotrophs. To identify the DNA elements important for this tissue-specific expression, we analyzed a series of POMC reporter genes in transgenic mice. A DNA fragment containing rat POMC 5'-flanking sequences from -323 to -34 recapitulated both basal pituitary cell-specific and hormonally stimulated expression in adult mice when fused to a heterologous thymidine kinase promoter. Developmental onset of the reporter gene expression lagged by 1 day but otherwise closely paralleled the normal ontogeny of murine POMC gene expression, including corticotroph activation at embryonic day 14.5 (E14.5) followed by melanotroph activation at E15.5 to E16.5. AtT20 corticotroph nuclear protein extracts interacted with three specific regions of the functional POMC promoter in DNase I protection assays. The positions of these protected sites were -107 to -160 (site 1), -182 to -218 (site 2), and -249 to -281 (site 3). Individual deletions of these footprinted sites did not alter transgene expression; however, the simultaneous deletion of sites 2 and 3 prevented transgene expression in both corticotrophs and melanotrophs. Electrophoretic mobility shift and Southwestern (DNA-protein) assays demonstrated that multiple AtT20 nuclear proteins bound to these footprinted sites. We conclude that the sequences between -323 and -34 of the rat POMC gene promoter are both necessary and sufficient for correct spatial, temporal, and hormonally regulated expression in the pituitary gland. Our data suggest that the three footprinted sites within the promoter are functionally interchangeable and act in combination with promoter elements between -114 and -34. The inability of any reporter gene construction to dissociate basal and hormonally stimulated expression suggests that these DNA elements are involved in both of these two characteristics of POMC gene expression in vivo.
Mol Cell Biol 1992 Sep
PMID:Identification of DNA elements cooperatively activating proopiomelanocortin gene expression in the pituitary glands of transgenic mice. 150 98

T-cell translocation gene 1 (Ttg-1), also called rhombotin, is deregulated upon translocation into the alpha/delta T-cell receptor loci in acute lymphoblastic leukemias bearing the t(11;14)(p15;q11). Ttg-1 encodes a nuclear protein, expressed predominantly in neuronal cells, which belongs to a novel family of transcription factors possessing LIM domains. We utilized the lck proximal promoter to overexpress this candidate oncogene in immature thymocytes of transgenic mice. lckPr Ttg-1 mice develop immature, aggressive T-cell leukemia/lymphomas. Tumor incidence is proportional to the level of Ttg-1 expression. Most tumors contain CD4+8+ cells as well as CD4-8+ cells, which have an immature rather than a mature peripheral phenotype. Ttg-1-induced tumorigenesis preferentially affects a minority population of thymocytes representing an immature CD4-8+ intermediate stage between double-negative CD4-8- cells and double-positive CD4+8+ cells. This model indicates that the aberrant expression of putative transcription factors plays a primary role in the genesis of T-cell acute lymphoblastic leukemias.
Mol Cell Biol 1992 Sep
PMID:Thymic overexpression of Ttg-1 in transgenic mice results in T-cell acute lymphoblastic leukemia/lymphoma. 150 13


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