Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04141 (granulocyte-macrophage colony-stimulating factor)
 6,790 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To characterize the interactions between human T-cell leukemia virus (HTLV) infection and cellular gene expression, we examined the expression of the lymphokine interleukin 3 (IL-3) in the presence and absence of HTLV infection. IL-3, like granulocyte-macrophage colony-stimulating factor (GM-CSF), is produced by activated but not resting T cells, but although GM-CSF is constitutively expressed in HTLV-infected T cells IL-3 mRNA cannot be detected in either unstimulated or mitogen-stimulated HTLV-infected cells by polymerase chain reaction (PCR) analysis. In contrast, transient co-transfection studies with an IL-3 promoter-CAT reporter gene and an HTLV-II Tax expression construct demonstrate that Tax can transactivate the IL-3 promoter in HTLV-uninfected T cells. To determine whether differences in IL-3 promoter-binding proteins present in HTLV-infected and uninfected T cells account for this discrepancy, DNAase I footprinting of the IL-3 promoter was performed. Although crude nuclear extracts from both cell types protected the IL-3 sequences located between base pairs -168 and -125, the sequences between -125 and -103, which contain the lymphokine consensus sequences CK-1 and CK-2, were protected by extracts from HTLV-infected but not HTLV-uninfected T cells. Deletion of the region containing the CK-1 and CK-2 sequences from an IL-3 promoter CAT construct resulted in a sixfold rise in promoter activity in HTLV-infected but not uninfected T-cell lines, indicating that this region participates in the repression of IL-3 gene expression in HTLV-infected T cells.
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PMID:Differential effect of HTLV infection and HTLV Tax on interleukin 3 expression. 851 Sep 34

Human T-cell leukemia virus type-I (HTLV-I), the etiologic agent of adult T-cell leukemia (ATL) transforms human T cells both in vivo and in vitro. However, the long latency period between infection and development of ATL, as well as the small fraction of the infected population that actually develops this disease, suggest that factors in addition to the virus are involved in its pathogenesis. Mutation of tumor suppressor gene p53 has been found in both HTLV-I-transformed T-cell lines and ATL cases at relatively low frequency. However, increasing evidence supports p53 functional impairment in HTLV-I-transformed T cells. Tax, the major transactivator of HTLV-I, is critical for the initial events involved in transformation. We have considered the possibility that p53 may regulate transcription of viral and cellular genes important for viral replication and transformation. Inactivation of p53 function might then permit constitutive expression of these viral and cellular genes. We have investigated the effects of wild-type and mutant p53 on Tax-mediated activation of the HTLV-I long terminal repeat (LTR) and the promoters of several cellular genes including the interleukin (IL)-1alpha, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF ), and IL-2 receptor alpha chain gene. Jurkat, HuT78, and U937 cells were cotransfected with plasmids containing a chloramphenicol acetyltransferase (CAT ) reporter gene under viral or cellular promoter control and the Tax expression vector, in addition to vectors for a wild-type or mutant p53. Wild-type p53 is a potent repressor of viral and cellular activation by Tax. Mutations within p53 severely inhibit this downregulation. We also show that wild-type p53 suppresses transcription from the HTLV-I LTR in Jurkat-Tax, a T-cell line stably expressing Tax, and MT-2, a HTLV-I-transformed T-cell line. Wild-type, but not mutant, p53 interfered with the binding of TATA-binding protein (TBP) to the TATA motif of the HTLV-I LTR. These results suggest that p53 inactivation may lead to upregulation of viral and cellular genes and may also be important for establishment of productive viral infection and development of ATL.
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PMID:Repression of transcription from the human T-cell leukemia virus type I long terminal repeat and cellular gene promoters by wild-type p53. 938 10

Granulocyte-macrophage colony-stimulating factor (GM-CSF) activates several kinases and transcription factors through interaction with a heterodimeric receptor complex. We previously demonstrated that phosphorylation of the cyclic adenosine monophosphate (cAMP) response element-binding protein, CREB, occurs through a protein kinase A-independent pathway and is required for GM-CSF-induced transcriptional activation of the immediate early gene, early growth response-1 (egr-1). Recent reports indicate that receptor tyrosine kinases can induce CREB phosphorylation through activation of pp90RSK. We performed immune complex kinase assays in the human myeloid leukemic cell line, TF-1, which revealed that GM-CSF induced pp90RSK activation and phosphorylation of CREB within 5 minutes of stimulation. Transfection with the kinase-defective pp90RSK expression plasmid demonstrated a statistically significant decrease in transcriptional activation of a -116 CAT/egr-1 promoter construct in response to GM-CSF. Furthermore, activation of pp90RSK, CREB and egr-1 in GM-CSF-treated cells was inhibited by the presence of the inhibitor, PD98059. In this study, we report that GM-CSF induces CREB phosphorylation and egr-1 transcription by activating pp90RSK through an MEK-dependent signaling pathway. (Blood. 2000;95:2552-2558)
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PMID:Granulocyte-macrophage colony-stimulating factor stimulation results in phosphorylation of cAMP response element-binding protein through activation of pp90RSK. 1075 34

Immunotoxins are molecules that contain a protein toxin and a ligand that is either an antibody or a growth factor. The ligand binds to a target cell antigen, and the target cell internalizes the immunotoxin, allowing the toxin to migrate to the cytoplasm where it can kill the cell. In the case of recombinant immunotoxins, the ligand and toxin are encoded in DNA that is then expressed in bacteria, and the purified immunotoxin contains the ligand and toxin fused together. Among the most active recombinant immunotoxins clinically tested are those that are targeted to hematologic malignancies. One agent, containing human interleukin-2 and truncated diphtheria toxin (denileukin diftitox), has been approved for use in cutaneous T-cell lymphoma, and has shown activity in other hematologic malignancies, including leukemias and lymphomas. Diphtheria toxin has also been targeted by other ligands, including granulocyte-macrophage colony-stimulating factor and interleukin-3, to target myelogenous leukemia cells. Single-chain antibodies containing variable heavy and light antibody domains have been fused to truncated Pseudomonas exotoxin to target lymphomas and lymphocytic leukemias. Recombinant immunotoxins anti-Tac(Fv)-PE38 (LMB-2), targeting CD25, and RFB4(dsFv)-PE38 (BL22, CAT-3888), targeting CD22, have each been tested in patients. Major responses have been observed after failure of standard chemotherapy. The most successful application of recombinant immunotoxins today is in hairy cell leukemia, where BL22 has induced complete remissions in most patients who were previously treated with optimal chemotherapy.
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PMID:Recombinant immunotoxins containing truncated bacterial toxins for the treatment of hematologic malignancies. 1934 87

EBV has been reported to impair monocyte in vitro differentiation into dendritic cells (DCs) and reduce cell survival. In this study, we added another layer of knowledge to this topic and showed that these effects correlated with macroautophagy/autophagy, ROS and mitochondrial biogenesis reduction. Of note, autophagy and ROS, although strongly interconnected, have been separately reported to be induced by CSF2/GM-CSF (colony stimulating factor 2) and required for CSF2-IL4-driven monocyte in vitro differentiation into DCs. We show that EBV infects monocytes and initiates a feedback loop in which, by inhibiting autophagy, reduces ROS and through ROS reduction negatively influences autophagy. Mechanistically, autophagy reduction correlated with the downregulation of RAB7 and ATG5 expression and STAT3 activation, leading to the accumulation of SQSTM1/p62. The latter activated the SQSTM1-KEAP1- NFE2L2 axis and upregulated the anti-oxidant response, reducing ROS and further inhibiting autophagy. ROS decrease correlated also with the reduction of mitochondria, the main source of intracellular ROS, achieved by the downregulation of NRF1 and TFAM, mitochondrial biogenesis transcription factors. Interestingly, mitochondria supply membranes and ATP required for autophagy execution, thus their reduction may further reduce autophagy in EBV-infected monocytes. In conclusion, this study shows for the first time that the interconnected reduction of autophagy, intracellular ROS and mitochondria mediated by EBV switches monocyte differentiation into apoptosis, giving new insights into the mechanisms through which this virus reduces immune surveillance. Abbreviations: ACTB: actin beta; ATG5: autophagy related 5; BAF: bafilomycin A1; BECN1: beclin 1; CAT: catalase; CSF2: colony stimulating factor 2; CT: control; CYCS (cytochrome C: somatic); DCs: dendritic cells; EBV: Epstein-Barr virus; GSR: glutathione-disulfide reductase; KEAP1: kelch like ECH associated protein 1; IL4: interleukin 4; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MET: metformin; NAC: N-acetylcysteine; NFE2L2/NRF2 nuclear factor: erythroid 2 like 2; NRF1 (nuclear respiratory factor 1); clPARP1: cleaved poly(ADP-ribose) polymerase; Rapa: Rapamycin; ROS: reactive oxygen species; SQSTM1/p62: sequestosome 1; TFAM: (transcription factor A: mitochondrial); TUBA1A: tubulin alpha 1a.
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PMID:EBV reduces autophagy, intracellular ROS and mitochondria to impair monocyte survival and differentiation. 3032 53