Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The proto-oncogene c-jun encodes a component of the AP-1 transcription-activating complex and has been implicated in the regulation of diverse cellular processes, including cell proliferation, differentiation, transformation, and most recently, apoptosis. We have used a U937 monocytic leukemia cell line stably expressing a c-jun dominant-negative, transactivation-domain deletion mutant (TAM67) to assess the role of c-jun in apoptotic events induced by exposure to the antimetabolite 1-beta-D-arabinofuranosylcytosine (ara-C). Mutant cells produce a truncated M(r) 29,000 protein that interferes with the function of normal c-Jun (and c-Fos) proteins through a quenching mechanism. Parental U937, cells expressing TAM67, and cells carrying only the empty vector (pMM) were exposed to ara-C for 6 h, and apoptosis was monitored by cell morphology as well as qualitative and quantitative assays of DNA damage. No differences in apoptosis could be detected between the three cell lines at any of the ara-C concentrations evaluated. In addition, ara-C concentrations > or = 1.0 x 10(-6) M were equally inhibitory to the clonogenic growth of U937 and TAM67-expressing cells. In contrast, lower concentrations of ara-C (i.e., < 5.0 x 10(-7) M) were significantly less inhibitory to mutant U937 cell colony formation than to their parental counterparts. The reduced sensitivity of TAM67-expressing cells to low concentrations of ara-C could not be attributed to biochemical or cytokinetic factors, since the two cell lines were indistinguishable with respect to 1-beta-D-arabinofuranosylcytosine 5'-triphosphate (ara-CTP) formation, ara-CTP:dCTP ratios, and S-phase fraction. However, a significantly lower percentage of TAM67-expressing cells exposed to submicromolar concentrations of ara-C exhibited features associated with a differentiated monocytoid phenotype (i.e., increased plastic adherence and CD11b expression) compared to their parental counterparts. Lower concentrations of ara-C were also significantly less effective in decreasing the percentage of S-phase cells and in down-regulating c-myc mRNA levels in the mutant line, events associated with induction of leukemic cell differentiation. Finally, ara-C-induced up-regulation of c-jun message and protein was markedly attenuated in TAM67-expressing cells, findings consistent with a c-jun dominant-negative model. Collectively, these findings suggest that dysregulation of c-jun in U937 cells antagonizes low-dose ara-C-mediated cellular maturation but does not prevent higher concentration of this agent from triggering apoptosis. They also raise the possibility that separate aspects of the antiproliferative actions of ara-C may be differentially regulated by c-jun.
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PMID:Effect of 1-beta-D-arabinofuranosylcytosine on apoptosis and differentiation in human monocytic leukemia cells (U937) expressing a c-Jun dominant-negative mutant protein (TAM67). 873 70

The antimetabolite cytosine arabinoside (ara-C) represents a prototype of the nucleoside analog class of antineoplastic agents and remains one of the most effective drugs used in the treatment of acute leukemia as well as other hematopoietic malignancies. The ability of ara-C to kill neoplastic cells is regulated at three distinct but interrelated levels. First, the activity of ara-C depends on conversion to its lethal triphosphate derivative, ara-CTP, a process that is influenced by multiple factors, including nucleoside transport, phosphorylation, deamination, and levels of competing metabolites, particularly dCTP. Second, the antiproliferative and lethal effects of ara-C are linked to the ability of ara-CTP to interfere with one or more DNA polymerases as well as the degree to which it is incorporated into elongating DNA strands, leading to DNA fragmentation and chain termination. Finally, the fate of the cell is ultimately determined by whether a threshold level of ara-C-mediated DNA damage is exceeded, thereby inducing apoptosis, or programmed cell death. The latter process is influenced by components of various signal transduction pathways (e.g., PKC) and expression of oncogenes (e.g., bcl-2, c-Jun), perturbations in which may significantly alter ara-C sensitivity. A better understanding of these factors could eventually lead to the development of novel therapeutic strategies capable of overcoming ara-C resistance and improving therapeutic efficacy.
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PMID:Ara-C: cellular and molecular pharmacology. 933 77

Synthetic alkyl-lysophospholipids represent a family of promising anticancer drugs that induce apoptosis in a variety of tumor cells. Here we have found a differential subcellular distribution of the alkyl-lysophospholipid edelfosine in leukemic and solid tumor cells that leads to distinct anticancer responses. Edelfosine induced rapid apoptosis in human leukemic cells, including acute T-cell leukemia Jurkat and Peer cells, but promoted a late apoptotic response, preceded by G(2)/M arrest, in human solid tumor cells such as cervix epitheloid carcinoma HeLa cells and lung carcinoma A549 cells. c-Jun amino-terminal kinase (JNK) and caspase-3 were accordingly activated at earlier times in edelfosine-treated Jurkat cells as compared with drug-treated HeLa cells. Both leukemic and solid tumor cells took up this alkyl-lysophospholipid and expressed the two putative edelfosine targets, namely cell surface Fas death receptor (also known as APO-1 or CD95) and endoplasmic reticulum CTP: phosphocholine cytidylyltransferase. However, edelfosine was mainly located to plasma membrane lipid rafts in Jurkat and Peer leukemic cells and to endoplasmic reticulum in solid tumor HeLa and A549 cells. Edelfosine induced translocation of Fas, Fas-associated death domain-containing protein, and JNK into membrane rafts in Jurkat cells, but not in HeLa cells. In contrast, edelfosine inhibited phosphatidylcholine biosynthesis in both HeLa and A549 cells, but not in Jurkat or Peer leukemic cells, before the triggering of apoptosis. These data indicate that edelfosine targets two different subcellular structures in a cell type-dependent manner, namely cell surface lipid rafts in leukemic cells and endoplasmic reticulum in solid tumor cells.
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PMID:Differential targets and subcellular localization of antitumor alkyl-lysophospholipid in leukemic versus solid tumor cells. 1654 Apr 73