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 E26 and avian erythroblastosis virus (AEV) avian retroviruses induce acute leukemia in chickens. E26 can block both erythroid and myeloid differentiation at an early multipotent stage. Moreover, E26 can block erythroid differentiation at the erythroid burst-forming unit/erythroid CFU (BFU-E/CFU-E) stage, which also corresponds to the differentiation stage blocked by AEV. AEV carries two oncogenes, v-erbA and v-erbB, whereas E26 encodes a single 135-kDa Gag-Myb-Ets fusion oncoprotein. v-ErbA is responsible for the erythroid differentiation arrest through negative interferences with both the retinoic acid receptor (RAR) and the thyroid hormone receptor (T3R/c-ErbA). We investigated whether Myb-Ets could block erythroid differentiation in a manner similar to v-ErbA. We show here that Myb-Ets inhibits both RAR and c-ErbA activities on specific hormone response elements in transient-expression assays. Moreover, Myb-Ets abrogates the inactivation of transcription factor AP-1 by RAR and T3R, another feature shared with v-ErbA. Myb-Ets also antagonizes the biological response of erythrocytic progenitor cells to retinoic acid and T3. Analysis of a series of mutants of Myb-Ets reveals that the domains of the oncoprotein involved in these inhibitory activities are the same as those involved in oncogenic transformation of hematopoietic cells. These data demonstrate that the Myb-Ets oncoprotein shares properties with the v-ErbA oncoprotein and that inhibition of ligand-dependent RAR and c-ErbA functions by Myb-Ets is responsible for blocking the differentiation of hematopoietic progenitors.
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PMID:Myb-Ets fusion oncoprotein inhibits thyroid hormone receptor/c-ErbA and retinoic acid receptor functions: a novel mechanism of action for leukemogenic transformation by E26 avian retrovirus. 888 63

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

Avian fibroblasts transformed simultaneously by the v-myc and v-mil(raf) oncogenes of acute leukemia and carcinoma virus MH2 contain elevated levels of c-Fos and c-Jun, major components of the transcription factor complex AP-1. To define specific transcriptional targets in these cells, subtractive hybridization techniques were employed leading to the identification of strongly upregulated genes including OPN (osteopontin), 126MRP, and rac2. OPN is a cytokine and cell attachment protein which has been implicated in human tumor progression and metastasis, the calcium binding 126MRP protein is related to the human S100 protein family involved in invasive cell growth, and the Rac2 protein belongs to the Rho family of small GTPases regulating actin reorganization and cell migration. Promoter analysis indicated that OPN activation is mediated by a non-consensus AP-1 binding site located close to the transcription start site. Electrophoretic mobility shift assays, chromatin immunoprecipitation and transcriptional reporter gene analyses showed that c-Fos and c-Jun bind specifically to this site and that c-Fos efficiently transactivates the OPN promoter. High-level expression of OPN, 126MRP, or Rac2 proteins from a retroviral vector led to partial cell transformation, documented by morphological changes and anchorage-independent growth. The specific activation in v-myc/v-mil(raf)-transformed cells of target genes with intrinsic oncogenic potential may provide an explanation for the longstanding observation that concomitant expression of these oncogenes leads to strongly enhanced oncogenicity in vivo and in vitro compared to cell transformation by v-myc or v-mil(raf) alone.
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PMID:Cooperative cell transformation by Myc/Mil(Raf) involves induction of AP-1 and activation of genes implicated in cell motility and metastasis. 1649 Nov 16