Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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

[1,2-Bis(4-methoxy/4-hydroxyphenyl)ethylenediamine]dichloroplatinum-(II) complexes with Cl-, CH3-, or OCH3-substituents in the ortho-positions of the aromatic rings (meso-1-PtCl2, D,L-1-PtCl2, meso-2-PtCl2, D,L-2-PtCl2, meso-3-PtCl2, meso-4-PtCl2, meso-5-PtCl2) were tested on the MDA-MB 231 breast cancer cell line, the lymphocytic leukemia P388, and the estrogen receptor-positive and -negative MXT mammary carcinoma of the mouse (MXT,ER(+)-MC, MXT,ER(-)-MC). The comparison of the effects of methoxy-substituted complexes (meso-1-PtCl2, D,L-1-PtCl2, meso-3-PtCl2) with those of the respective hydroxy-substituted ones (meso-2-PtCl2, D,L-2-PtCl2, meso-4-PtCl2) shows that a reduction of estrogenic effects as well as a total loss of the mammary tumor-inhibiting activity takes place on methylation of the 4-OH group. The exchange of the 2,6-standing chlorine atoms by methyl groups in meso-2-PtCl2 led to the non-estrogenic, but on the MXT,ER(+)-MC highly effective derivative meso-4-PtCl2 which proved to be also cytotoxic on ER(-)-tumors such as MXT,ER(-)-MC, and the P388 leukemia.
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PMID:Reduction of the estrogenic side effects of the mammary tumor-inhibiting drug [1,2-bis(2,6-dichloro-4-hydroxyphenyl)- ethylenediamine]dichloroplatinum(II) by variation of ring substituents. 761 41

The lactoferrin gene is highly expressed in many different tissues, and its expression is controlled by different regulators. In this report, we have defined a retinoic acid response element (RARE) in the 5'-flanking region of the lactoferrin gene promoter. The lactoferrin-RARE is composed of two AGGTCA-like motifs arranged as a direct repeat with 1-bp spacing (DR-1). A gel retardation assay demonstrated that it bound strongly with retinoid X receptor (RXR) homodimers and RXR-retinoic acid receptor (RAR) heterodimers as well as chicken ovalbumin upstream promoter transcription factor (COUP-TF) orphan receptor. In CV-1 cells, the lactoferrin-RARE linked with a heterologous thymidine kinase promoter was strongly activated by RXR homodimers in response to 9-cis-retinoic acid (9-cis-RA) but not to all-trans-RA. When the COUP-TF orphan receptor was cotransfected, the 9-cis-RA-induced RXR homodimer activity was strongly repressed. A unique feature of the lactoferrin-RARE is that it has an AGGTCA-like motif in common with an estrogen-responsive element (ERE). The composite RARE/ERE contributes to the functional interaction between retinoid receptors and the estrogen receptor (ER) and their ligands. In CV-1 cells, cotransfection of the retinoid and estrogen receptors led to mutual inhibition of the other's activity, while an RA-dependent inhibition of ER activity was observed in breast cancer cells. Furthermore, the lactoferrin-RARE/ERE showed differential transactivation activity in different cell types. RAs could activate the lactoferrin-RARE/ERE in human leukemia HL-60 cells and U937 cells but not in human breast cancer cells. By gel retardation analyses, we demonstrated that strong binding of the endogenous COUP-TF in breast cancer cells to the composite element contributed to diminished RA response in these cells. Thus, the lactoferrin-RARE/ERE functions as a signaling switch module that mediates multihormonal responsiveness in the regulation of lactoferrin gene expression.
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PMID:A retinoic acid response element that overlaps an estrogen response element mediates multihormonal sensitivity in transcriptional activation of the lactoferrin gene. 762 14

Widely used in breast cancer therapy, tamoxifen exhibits in vitro and in vivo pleiotropic activities that are generally attributed to its binding to the estrogen receptor. However, several reports have shown that the antiestrogen binding site (ABS) is also an intracellular target of the drug. This dual affinity determines at least two modes of action for the triphenylethylenic antiestrogens; one would be estrogen reversible and the other irreversible. Here, tamoxifen is shown to inhibit the production of Moloney murine leukemia virus virions by fibroblastic A9 cells, in which estrogen receptor is not detectable either by binding or by radioimmunoassay. Moreover, a specific ligand of the ABS induces effects equivalent to those of tamoxifen, suggesting that tamoxifen inhibits Moloney murine leukemia virus replication through an estrogen-independent pathway involving the ABS.
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PMID:Antiestrogens inhibit the replication of the retroviral Moloney murine leukemia virus in vitro. 768 44

The tax protein of Human T-cell leukemia virus type 1 (HTLV-1) is important for the transforming properties of this virus in vitro and is considered to be responsible for the early stages of leukemogenesis in infected hosts. To address the early consequences of HTLV-1 tax function, we have constructed fusion proteins containing tax sequence either aminoterminal (taxER) or carboxy-terminal (ERtax) of the hormone binding domain of the human estrogen receptor (ER). Addition of estrogen or the antagonist hydroxytamoxifen to Jurkat T-cells expressing these constructs led to the trans-activation or responsive promoters and upregulation of cell surface markers CD28, CD69 and CD5 but not CD25 (IL2R-alpha subunit) or B7 (ligand for CD28). Additional stimulation of the T-cell receptor CD3 complex, led to the upregulation of CD25. B7 was upregulated by concomittent activation of ERtax and CD3 or CD28 pathways. These events were in part reversible upon withdrawal of hormone and inactivation of ERtax. Severe inhibition of proliferation, and apoptosis was observed with cells which had been subjected to short term (3 days) activation of the tax fusion proteins and the CD3 complex. Induction of ERtax activity for longer than 3 days promoted cell death independently of CD3 stimulation. Co-stimulation through the CD28 cell surface molecule did not suppress induction of apoptosis.
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PMID:Immediate effects of reversible HTLV-1 tax function: T-cell activation and apoptosis. 783 27

The estrogen receptor (ER) appears to be down-regulated by its own ligand in some estrogen (E2)-responsive tissues as well as in cell lines such as MCF-7 and GH3. Surprisingly, we observed ER down-regulation in a newly constructed E2-responsive cell line (Rat1 + ER), in which expression of the coding region of the ER cDNA was driven by the Moloney murine leukemia virus long terminal repeat. We present evidence that the coding region of the ER cDNA, but not the Moloney murine leukemia virus long terminal repeat, possesses a sequence(s) necessary for ER down-regulation. The observed down-regulation occurs at ligand-binding and protein, as well as mRNA, levels. Marked decreases in both protein and mRNA levels were observed as early as 3 h after E2 treatment. Furthermore, maximal down-regulation occurred by 18-24 h with ligand-binding, and mRNA levels reached approximately 20% that of controls. ER down-regulation in Rat1 + ER cells is only partially inhibited by the presence of cycloheximide and therefore suggests a direct participation of the ER in this process. E2 does not appear to influence the stability of the ER transcript, which implies that negative regulation is occurring at the transcriptional level. Finally, since we can demonstrate ER binding to a portion of the cDNA sequence, we propose a mechanism whereby ER binding to its putative negative element leads to transcriptional repression of the upstream promoter.
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PMID:Involvement of the coding sequence for the estrogen receptor gene in autologous ligand-dependent down-regulation. 841 12

Breast tumors that have become resistant to endocrine therapy have been found to contain estrogen receptor (ER) variants due to aberrant splicing mechanisms of the ER gene. Exon skipping can give rise to dominant-positive receptors that are transcriptionally active in the absence of estrogen, or dominant-negative receptors that are themselves transcriptionally inactive but prevent the action of the normal receptor. ER splice variants similar to those in breast cancer have also been reported in human meningiomas. Androgen receptor (AR) variants have been detected in some prostate cancers that exhibit resistance to androgen therapy. In leukemia and lymphoma, mutations in the glucocorticoid receptor (GR) cause resistance to cell lysis by dexamethasone. Thus, there is increasing evidence that mutations in the genes of steroid receptors can cause loss of hormone dependency in different cancer types.
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PMID:Hormone resistance in cancer: the role of abnormal steroid receptors. 851 10

Leukemia-inhibitory factor (LIF) is an inflammatory cytokine with pleiotropic activities. LIF was originally described as a differentiation factor of a murine leukemia cell line and was subsequently found to possess a broad spectrum of biological functions. Although LIF has been extensively studied in the hematopoietic system, little is known about its effects in solid tumors. We investigated the role of LIF in breast, kidney and prostate cancers. Using a clonogenic assay, we found that LIF significantly stimulated proliferation of 2 estrogen receptor-positive breast cancer cell lines (MCF-7 and T47-D) in a dose-dependent fashion at concentrations ranging from 10 to 200 ng/ml. This effect was observed both in the presence of FCS and under serum- and estrogen-free culture conditions, suggesting that the effect of LIF is direct and does not depend on estrogen or any other cytokine. Neither line produced LIF protein, as assessed by ELISA. In contrast, the estrogen receptor-negative breast cancer line MDA MB-231 produced LIF but did not respond to either LIF or its neutralizing antibodies. Similarly, increasing concentrations of LIF did not affect the growth of primary kidney (A-498), metastatic kidney (ACHN) and prostate (DU 145) cancer cell lines. These lines produce LIF, however, and antibodies to LIF significantly suppressed their proliferation, suggesting that they were maximally stimulated by the endogenously produced cytokine. Taken together, our data suggest that LIF acts as either a paracrine or an autocrine growth factor for breast, kidney and prostate cancers.
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PMID:Leukemia-inhibitory factor stimulates breast, kidney and prostate cancer cell proliferation by paracrine and autocrine pathways. 863 67

Estrogen appears to be a negative regulator of normal hematopoiesis. Chromosome 6q, which contains the estrogen receptor (ER) gene, is frequently altered in human hematopoietic neoplasms. The ER gene, which has growth and metastasis suppressor activity in many different cell types, is inactivated by promoter methylation in some ER-negative breast tumors and 100% of colorectal tumors. We now report that the promoter region of the ER gene is aberrantly methylated in 86% of human hematopoietic tumors, including 8 of 9 pediatric acute lymphocytic leukemia, 17 of 18 adult acute lymphocytic leukemia, 21 of 23 adult acute myelogenous leukemia, 3 of 6 chronic phase chronic myelogenous leukemia, 9 of 9 blast crisis chronic myelogenous leukemia and 5 of 8 lymphomas. This methylation event was also present in all nine leukemia cell lines examined, where it was associated with very low or absent ER expression. In addition, rat and mouse leukemia cell line also exhibited this change, indicating that ER CpG island methylation in leukemias is conserved among species. Our results suggest that ER CpG island methylation could be an important step in the genesis of human hematopoietic neoplasms and might be a useful molecular marker for monitoring the clinical status of these diseases.
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PMID:The estrogen receptor CpG island is methylated in most hematopoietic neoplasms. 864 Jul 88

Human T-cell leukemia virus type I (HTLV-I) is an etiological agent of adult T-cell leukemia. The Tax protein of HTLV-I may play a central role in cellular transformation. By serum deprivation, Tax-transformed Rat-1 cells undergo apoptotic cell death. These cells exhibit DNA fragmentation and chromatin condensation. Constitutive expression of bcl-2, blocked Tax-mediated apoptosis. Activation of fusion protein containing Tax and estrogen receptor, also led to the trans-activation and caused inhibition of proliferation and apoptosis. However Tax inhibited anti-Apo-1-induced apoptosis. Apoptosis appear to be the most important process of HTLV-I associated myelopathy (HAM). In spinal cords from autopsied patients with HAM/TSP, apoptosis of helper-inducer T lymphocytes was observed. HTLV-I carrier WKAH rats developed myeloneuropathy and apoptotic death of oligodendrocytes. The apoptosis was consistent with HTLV-I pX expression.
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PMID:[The human T-cell leukemia virus type I (HTLV-I) tax protein induces apoptosis]. 874 78

Cloning is reported of a cDNA homologue to the breast carcinoma-associated D52 cDNA, termed D53, and of a mouse D52 cDNA (HGMW-approved symbols TPD52L1 and TPD52). Human D53 and mouse D52 proteins are predicted to be 52 and 86% identical to human D52, respectively. Analysis of the three protein sequences identified a coiled-coil domain and N- and C-terminally located PEST domains in each. The conservation of homology between the D52 and the D53 sequences, combined with a lack of homology between these and known proteins, defines a new mammalian gene/protein family, the D52 family. The human D52 locus has been previously mapped to chromosome 8q21, and using in situ mapping in the present study, a human D53 locus was mapped to chromosome 6q22-q23. We observed coexpression of the human D52 and D53 genes in some breast tumors and derivative cell lines and found that maintenance of D52 and D53 transcript levels in estrogen receptor-positive MCF7 breast carcinoma cells depends upon estradiol. However, D52 and D53 genes were specifically expressed in HL-60 and K-562 leukemia cells, respectively, with 12-O-tetra-decanoylphorbol-13-acetate treatment decreasing D52 and D53 transcript levels in these cell lines. The presence of a coiled-coil domain, combined with observed co- or independent expression of the D52 and D53 genes, suggests that D52 and D53 proteins may be capable of hetero- and/or homodimer formation.
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PMID:Definition of the tumor protein D52 (TPD52) gene family through cloning of D52 homologues in human (hD53) and mouse (mD52). 881 87


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