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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The nuclear oncogenes v-myc or v-myb specifically transform avian myeloid cells. In both cases, the transformed cells remain dependent on chicken myelomonocytic growth factor (cMGF). This factor dependence can be relieved by expression of kinase-type oncogenes such as v-mil or v-erbB, leading to expression of cMGF and autocrine growth stimulation. In erythroid cells the same kinase-type oncogenes cause transformation but do not induce cMGF expression. Here we investigated the molecular mechanisms of the observed lineage specific oncogene collaboration. We found that kinase-type oncogenes and TPA activate the cMGF promoter via AP-1 like transcription factors. The activation of the cMGF promoter is, however, strictly dependent on the binding of nuclear proteins to both halves of an inverted repeat adjacent to the AP-1 binding site. These proteins are related to C/EBP. They are expressed exclusively in myeloid cells and were therefore termed NF-M. Our results indicate that the lineage specific cooperation of kinase type oncogenes with v-myb or v-myc in leukemia formation is based on the concerted action of AP-1 and NF-M on the cMGF promoter.
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PMID:Autocrine growth induced by kinase type oncogenes in myeloid cells requires AP-1 and NF-M, a myeloid specific, C/EBP-like factor. 134 59

The present work has examined the effects of okadaic acid, an inhibitor of type 1 and 2A protein phosphatases, on the regulation of c-jun expression during monocytic differentiation of U-937 leukemia cells. The results demonstrate that okadaic acid treatment is associated with induction of a differentiated monocyte phenotype characterized by: (a) growth arrest; (b) increases in Mac-1 cell surface antigen expression; (c) down-regulation of c-myc transcripts; and (d) induction of tumor necrosis factor gene expression. This induction of monocytic differentiation was associated with transient increases in c-jun mRNA levels, which were maximal at 6 h. Similar effects were obtained for the c-fos gene. Run-on analysis demonstrated detectable levels of c-jun transcription in U-937 cells and that this rate is increased approximately 40-fold following okadaic acid exposure. c-jun mRNA levels were superinduced in cells treated with both okadaic acid and cycloheximide, whereas inhibition of protein synthesis had little, if any, effect on okadaic acid-induced c-jun transcription. The half-life of c-jun mRNA was similar (45-50 min) in both untreated and okadaic acid-induced cells. In contrast, treatment with both okadaic acid and cycloheximide was associated with stabilization (t 1/2 = 90 min) of c-jun transcripts. Taken together, these findings indicate that the induction of c-jun transcription by okadaic acid is controlled primarily by a transcriptional mechanism. Since previous studies have demonstrated that the c-jun gene is autoinduced by Jun/AP-1, we also studied transcription of c-jun promoter (positions -132/+170)-reporter gene constructs with and without a mutated AP-1 element.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of c-jun expression during induction of monocytic differentiation by okadaic acid. 141 3

A novel DNA-binding activity, hereafter referred to as MECA, is induced upon transformation of rat embryo fibroblasts by the collaborative action of the oncogenes myc and ras. MECA is targeted to the enhancer "core" element of the Moloney Murine Leukemia Virus LTR. Its binding site can direct transcription from a heterologous promoter and EJras, but not c-myc, potentiates the transcriptional activity. A two point mutation within the enhancer "core" abolishes both DNA-binding by MECA and transcriptional activity. MECA may mediate some of the transforming effects of ras, and thus belongs in the family of transformation-specific DNA-binding activities with members such as AP-1, PEA3 and NF-kB.
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PMID:An enhancer "core" DNA-binding and transcriptional activity is induced upon transformation of rat embryo fibroblasts. 158 May 45

Resistance to radiation leukemia virus-induced leukemia is mediated by gene(s) in the H-2D region of the MHC; a clear correlation exists between disease resistance and increased H-2Dd expression on the thymocyte surface. We have investigated the molecular basis for this stimulation of H-2Dd class I expression. Elevated H-2 mRNA and H-2 transcription are demonstrated in the infected thymocytes as compared to normal thymocytes indicating that the elevation of H-2 surface expression is the result of transcriptional activation. Gel mobility assays performed with nuclear extracts of normal and infected thymocytes and sequences 5' of the H-2Dd gene show that specific binding occurs with both extracts; the binding differs both quantitatively and qualitatively, however. DNase I protection analysis detects a protein binding site that is protected only by extracts from infected cells. The protected region contains a sequence similar to the AP-1 consensus sequence. Gel shift competition assays and UV photo-cross-linking to an oligonucleotide containing this sequence demonstrate that specific binding of an H-2 binding factor 1 occurs and that this factor is not the AP-1 binding complex. This novel binding factor, activated in vivo, might also be involved in the normal regulation of H-2 gene expression by recognizing the highly conserved binding sequence (TGACGCG) found in the 5' flanking region of many MHC class I genes. This is the first demonstration of the parallel stimulation of a DNA binding activity and increased transcription occurring in thymocytes after infection with a leukemogenic retrovirus.
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PMID:A novel DNA binding activity is elevated in thymocytes expressing high levels of H-2Dd after radiation leukemia virus infection. 163 76

Transcriptional activation endowed by AP-1 or CREB binding sites can be significantly reduced in transient transfection tests by expression from the corresponding cloned cDNAs of protein tyrosine phosphatases. Both the protein tyrosine phosphatase 1B and the T-cell protein tyrosine phosphatase, as well as a novel form of this latter protein generated by an alternative splicing even show this activity. The effect is specific, as none of the protein tyrosine phosphatases alters transcriptional activation by either the estrogen receptor, GAL4, or a GAL4-VP16 fusion protein. Furthermore, the activities of the SV40 early gene promoter and a Moloney murine leukemia virus long terminal repeat promoter are not reduced by these phosphatases. We conclude that a yet to be identified protein phosphorylated on tyrosine is necessary for a full transcriptional response via AP-1 or CREB binding sites.
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PMID:Activation of transcription via AP-1 or CREB regulatory sites is blocked by protein tyrosine phosphatases. 165 Apr 42

Early studies showed that resistance to RadLV-induced leukaemia is mediated by gene(s) in the H-2D region of the MHC. Furthermore, these experiments correlated disease resistance with changes in H-2 expression occurring very early after virus inoculation. In the present study, we have begun to study at the molecular level this stimulation of H-2Dd class I expression in thymocytes of resistant mouse strains following infection by RadLV. The resistant strain of B10.T(6R) mice is used in these studies. When these infected thymocytes are assayed by fluorescence-activated cell sorting analysis, we can detect increased levels of H-2Dd expression on the surface of the thymocytes as early as 12 days following intrathymic injection of RadLV. RNA was prepared and examined by Northern blot analysis; H-2 mRNA levels are shown to be elevated on the order of four-fold. Nuclei were prepared from normal and infected thymocytes and the run-off transcripts were analysed by slot-blot hybridization. The rate of H-2 mRNA transcription is shown to be two- to three-fold higher in RadLV-infected thymocytes at 14 days post-infection when compared to that of normal thymocytes. These data demonstrate that elevation of H-2 surface expression following RadLV infection is the result of transcriptional activation. Extracts have been prepared from both normal and infected B10.T(6R) thymocytes and have been used in gel mobility assays in order to detect the interaction of potential trans-acting regulatory factors with sequences 5' of the H-2Dd gene. Specific binding occurs in both extracts, but the assay shows that the extracts differ both quantitatively and qualitatively; the extracts from infected thymocytes bind to additional sequences and to a higher degree than that from normal thymocytes. DNase I protection analysis locates a number of protein-binding sites, some of which are protected by extracts of either origin and some of which are only protected by extracts from infected cells. Two of these sequences are similar to the previously recognized consensus recognition sequences for the binding of AP-1 and NF-chi B. Oligonucleotides have been synthesized for both the genomic sequences being protected from DNase I digestion as well the published consensus sequences. While the DNA-binding activity in infected thymocytes for both AP-1 and NF-chi B-binding sites is increased, the binding to the genomic "AP-1 like" binding site is activated to a considerably greater level.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:In vivo stimulation of H-2Dd expression following RadLV infection of thymocytes: increased transcription and DNA-binding activity to sequences 5' of the Dd gene. 175 16

Human T-cell leukemia virus type 1 (HTLV-1) is an etiological agent of adult T-cell leukemia (ATL). We showed here by mobility-shift assay that T-cell lines transformed with the virus contained high levels of AP-1 activities. Consistent with this result, these cell lines expressed increased levels of mRNAs encoding the AP-1 proteins, c-Fos, Fra-1, c-Jun, JunB, and JunD. Previously, transcription of the c-fos gene has been reported to be transactivated by the viral transcription factor, Tax1. By using the human T-cell line (JPX-9), in which expression of the Tax1 is inducible, we showed that expression of mRNAs for Fra-1, c-Jun, and JunD was also transactivated by Tax1. Moreover, Tax1 activated expression of two other transcription factors having zinc finger motifs, Egr-1 and Egr-2, in the same cells. The Tax1-inducible transcription factors identified here are encoded by the members of immediate early genes under the control of growth signals. Thus, Tax1 was suggested to replace growth signals, at least in part, by this mechanism.
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PMID:HTLV-1 Tax induces expression of various immediate early serum responsive genes. 190 55

Short-term stimulation (up to 16 hours) of interleukin-3 (IL-3)-dependent mouse bone marrow-derived mast cells, Abelson transformed mouse liver-derived mast cells, or rat basophilic leukemia cells by either IgE-Ag or calcium ionophore A23187 resulted in inhibition of their proliferation as measured by 3H-thymidine incorporation and MTT (tetrazolium) assays, and in accumulation of the mRNAs of c-fos, c-jun, junB and slightly of junD proto-oncogenes. The involvement of protein kinase C (PKC) in these responses was investigated by using several approaches of enzyme activity regulation. Direct activation of the PKC was achieved by short-term exposure of the cells to the PKC-specific activator phorbol 12-myristate-13-acetate (PMA). Inhibition of PKC activity was obtained by either prolonged treatment of the cells with PMA or by exposure of the cells to the PKC inhibitors H-7 and staurosporine. The results showed the following: (1) Short-term exposure of mast cells to PMA was sufficient to induce inhibition of proliferation. (2) An increase in PKC activity was associated with a decrease in the proliferation of IgE-dinitrophenol (DNP) or calcium ionophore A23187-stimulated cells. (3) A direct correlation was found between the increase in PKC activity and the increase in the level of the mRNAs of the jun proto-oncogenes in cells activated by both stimuli mentioned. (4) While an increase in PKC activity was associated with the upregulation of the level of c-fos mRNA during calcium ionophore A23187 stimulation, it showed the opposite effect on the expression of the mRNA of this proto-oncogene when the cells were triggered by IgE-DNP. Therefore, we concluded that PKC plays various roles in the expression of the mRNA of c-fos in activated mast cells depending on the stimulus involved. In addition, the expression of the mRNA of c-jun and junB proto-onogenes is not coordinately regulated with that of c-fos during immunologic stimulation. This discordancy, which is associated with the increase in PKC activity in mast cells, may play a role in the regulation of the transcription of AP-1-responsive genes, and therefore could be associated with the regulation of proliferation of these cells.
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PMID:Protein kinase C regulates proliferation of mast cells and the expression of the mRNAs of fos and jun proto-oncogenes during activation by IgE-Ag or calcium ionophore A23187. 193 49

Previous studies have shown that treatment of human myeloid leukemia cells with 12-O-tetradecanoylphorbol-13-acetate (TPA) is associated with induction of monocytic differentiation and expression of the c-jun and c-fos early response genes. The present work demonstrates that the glucocorticoid dexamethasone inhibits TPA-induced increases in c-jun and c-fos mRNA levels in U-937 leukemia cells. These findings were associated with a block in appearance of the monocytic phenotype, including inhibition of TPA-induced increases in lamin A, lamin C, and vimentin transcripts. Other studies have demonstrated that TPA-induced monocytic differentiation and expression of the c-jun and c-fos genes in myeloid leukemia cells are regulated by protein kinase C (PKC). The finding that dexamethasone has no effect on TPA-induced activation of PKC suggests that this glucocorticoid inhibits signals downstream or parallel to this enzyme. Nuclear run-on assays demonstrate that: (1) induction of c-jun and c-fos expression by TPA is regulated by transcriptional mechanisms, (2) TPA-induced expression of c-jun and c-fos does not require protein synthesis, and (3) TPA-induced expression of both genes is inhibited at the transcriptional level by dexamethasone. To further define the effects of dexamethasone at the molecular level, we prepared a series of deleted c-jun promoter fragments linked to the chloramphenicol acetyltransferase (CAT) gene. Increases in CAT activity during transient expression of these constructs in TPA-treated U-937 cells could be assigned to the region (-97 to -20) of the promoter that contains the AP-1 binding site. This induction of CAT activity was sensitive to dexamethasone. These findings suggest that dexamethasone down-regulates TPA-induced transcription of the c-jun gene during monocytic differentiation by inhibiting activation of the AP-1 site.
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PMID:Inhibition of phorbol ester-induced monocytic differentiation by dexamethasone is associated with down-regulation of c-fos and c-jun (AP-1). 193 41

Induction of differentiation to macrophages in two different clones of myeloid leukemic cells by the hematopoietic regulatory proteins interleukin-6 (IL-6), or by granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-3 (IL-3), is shown to be associated with sustained accumulation of c-jun, jun-B, and c-fos mRNA that code for proteins that form complexes that are transcription factors (AP-1). In one but not in the other of these leukemic clones, differentiation is also associated with sustained accumulation of mRNA for the putative transcription factor zif/268. The results indicate that differentiation of myeloid cells by normal hematopoietic regulatory proteins is associated with induction of sustained elevated levels of mRNA for transcription factors that can regulate and maintain gene expression in the differentiation program, and that zif/268 gene expression is not essential for differentiation to macrophages.
Leukemia 1990 Dec
PMID:Induction of genes for transcription factors by normal hematopoietic regulatory proteins in the differentiation of myeloid leukemic cells. 224 2


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